Inhibition of astrocytic DRD2 suppresses CNS inflammation in an animal model of multiple sclerosis.

Astrocyte activation is associated with progressive inflammatory demyelination in multiple sclerosis (MS). The molecular mechanisms underlying astrocyte activation remain incompletely understood. Recent studies have suggested that classical neurotransmitter receptors are implicated in the modulation of brain innate immunity. We investigated the role of dopamine signaling in the process of astrocyte activation. Here, we show the upregulation of dopamine D2 receptor (DRD2) in reactive astrocytes in MS brain and noncanonical role of astrocytic DRD2 in MS pathogenesis. Mice deficient in astrocytic Drd2 exhibit a remarkable suppression of reactive astrocytes and amelioration of experimental autoimmune encephalomyelitis (EAE). Mechanistically, DRD2 regulates the expression of 6-pyruvoyl-tetrahydropterin synthase, which modulates NF-κB activity through protein kinase C-δ. Pharmacological blockade of astrocytic DRD2 with a DRD2 antagonist dehydrocorybulbine remarkably inhibits the inflammatory response in mice lacking neuronal Drd2. Together, our findings reveal previously an uncharted role for DRD2 in astrocyte activation during EAE-associated CNS inflammation. Its therapeutic inhibition may provide a potent lever to alleviate autoimmune diseases.

[Expression of glucocorticoid receptor in prostate cancer and its clinical significance].

OBJECTIVE: To investigate the expression of glucocorticoid receptor (GR) in the PCa tissue and its correlation with the clinicopathological characteristics and prognosis of PCa. METHODS: Using immunohistochemical staining, we determined the expression of GR in the PCa tissue and analyzed its correlation with the clininicopathological features and prognosis of the malignancy. RESULTS: The positive expression of GR in the PCa tissue was 64%, of which the strongly positive rate was 34.7%. The GR expression was positively correlated with preoperative androgen-deprivation therapy (ADT) (χ2 = 22.307, P < 0.01), Gleason grades (χ2 = 16.534, P = 0.002) and clinical stages of the tumor (χ2 = 9.969, P = 0.041). Kaplan-Meier analysis showed that the GR expression was correlated not with the overall survival (P = 0.156), but with the PSA progression-free survival rate of the PCa patients (P = 0.042), with a shorter PSA progression-free survival time in those with a higher GR expression. Multivariate COX regression analysis revealed that the expression of GR was not an independent prognostic factor for PSA progression-free survival of the PCa patients. CONCLUSION: The expression of GR is related with preoperative ADT, and closely with the biological behavior of the malignancy and treatment resistance of the patients. GR is expected to be a new effective therapeutic target and a prognostic biomarker for PCa.

Suppression of astrocytic autophagy by αB-crystallin contributes to α-synuclein inclusion formation.

BACKGROUND: Parkinson's disease (PD) is characterized by a chronic loss of dopaminergic neurons and the presence of proteinaceous inclusions (Lewy bodies) within some remaining neurons in the substantia nigra. Recently, astroglial inclusion body has also been found in some neurodegenerative diseases including PD. However, the underlying molecular mechanisms of how astroglial protein aggregation forms remain largely unknown. Here, we investigated the contribution of αB-crystallin (CRYAB), a small heat shock protein, in α-synuclein inclusion formation in astrocytes. METHODS: Small interfering RNA (siRNA)-mediated CRYAB (siCRYAB) knockdown or CRYAB overexpression was performed to investigate the impact of CRYAB on the autophagy in human glioblastoma cell line U251 cells. Co-immunoprecipitation (co-IP) and immunoblotting were used to dissect the interaction among multiple proteins. The clearance of α-synuclein in vitro was evaluated by immunocytochemistry. CRYAB transgenic mice and transgenic mice overexpressing A30P mutant form of human α-synuclein were used to examine the influence of CRYAB to α-synuclein accumulation in vivo. RESULTS: We found that knockdown of CRYAB in U251 cells or primary cultured astrocytes resulted in a marked augmentation of autophagy activity. In contrast, exogenous CRYAB disrupted the assembly of the BAG3-HSPB8-HSC70 complex via binding with BAG3, thereby suppressing the autophagy activity. Furthermore, CRYAB-regulated autophagy has relevance to PD pathogenesis. Knockdown of CRYAB remarkably promoted cytoplasmic clearance of α-synuclein preformed fibrils (PFFs). Conversely, selective overexpression of CRYAB in astrocytes markedly suppressed autophagy leading to the accumulation of α-synuclein aggregates in the brain of transgenic mice expressing human α-synuclein A30P mutant. CONCLUSIONS: This study reveals a novel function for CRYAB as a natural inhibitor of astrocytic autophagy and shows that knockdown of CYRAB may provide a therapeutic target against proteinopathies such as synucleinopathies.

Extracellular αB-crystallin modulates the inflammatory responses.

Neuroinflammation is considered a challenging clinical problem. Chronic inflammatory responses play important roles in the onset and progression of various neurodegenerative diseases, including multiple sclerosis (MS). Previous studies have shown that astrocytes express small heat shock protein αB-crystallin (CRYAB) which is capable of inhibiting inflammatory responses in astrocytes per se. However, the underlying mechanisms of CRYAB-induced modulation of neuroinflammation are still not fully understood. In the present study, we investigated the role of extracellular CRYAB in the interaction between microglia and astrocytes in the context of MS-associated neuroinflammation. We found that the expression of CRYAB was profoundly increased in EAE mice. CRYAB was preferentially expressed in astrocytes and could be secreted via exosomes. Levels of exosomal CRYAB secreted from astrocytes were markedly increased under stress conditions. Furthermore, incubation of immortalized astrocytes or microglia cell lines with CRYAB remarkably suppressed astrocytes and microglia-mediated inflammatory responses in both autocrine and paracrine manners. Our results reveal a novel function for extracellular CRYAB in the regulation of neuroinflammation. Targeting extracellular CRYAB-modulated neuroinflammation is a potential therapeutic intervention for MS.

[Urothelial-type mucinous adenocarcinoma of the prostate: A case report and review of the literature].

OBJECTIVE: To investigate the clinical manifestations, pathological characteristics, and treatments of urothelial-type mucinous adenocarcinoma of the prostate (UMAP). METHODS: We reported a case of UMAP, reviewed relevant literature, and analyzed the clinicopaothological features, diagnosis, treatment, and prognosis of the disease. RESULTS: The patient was a 60-year-old male and underwent transurethral resection of the prostate for dysuria. Postoperative pathology indicated mucinous adenocarcinoma and sigmoidoscopy revealed no primary colon cancer. Immunohistochemical staining showed the negative expressions of PSA and P504s and positive expressions of CK7, CK34 ß E12, CK20, and CDX2. Thus UMAP was confirmed and treated by intensity-modulated radiotherapy. Then the patient was followed up for 30 months, which showed desirable therapeutic result, with neither local progression nor distant metastasis. CONCLUSION: UMAP has a bad prognosis and its diagnosis depends on pathological and immunohistocchemical examinations. It responds well to radical prostatectomy but is not sensitive to endocrine therapy. Radiotherapy can be considered for those who are not fit to receive radical prostatectomy.

[Expression and significance of macrophage migration inhibitory factor in bladder urothelial cell carcinoma].

OBJECTIVE: To evaluate the expression and clinical significance of macrophage migration inhibitory factor (MIF) in patients with bladder urothelial cell carcinoma. METHODS: Immunohistochemical staining for MIF was performed on tissue sections of 110 patients with bladder urothelial cell carcinoma and 10 normal controls, and the correlations between MIF and clinicopathological characteristics and prognosis were also analyzed. RESULTS: Normal bladder urothelium from control subjects showed negative or weak staining of MIF. Of the cancer specimens, 72/110 (65.5%) showed a moderate to strong staining of MIF. The expression of MIF protein was found predominantly in the tumor cell cytoplasm and inversely correlated with tumor stage. 27 cases also showed a positive intranuclear staining of MIF, which was inversely correlated with tumor grade, stage and tumor size. Kaplan-Meier analysis showed that the expression of MIF in the cell nuclei was associated with disease-free survival for the cancer patients, but multivariate analysis showed that MIF was not an independent prognostic factors. CONCLUSIONS: The expression of MIF in non-muscle invasive bladder cancer tissues was more frequently than that in muscle-invasive disease, the positive staining of MIF in cell nuclei might be a favorable biomarker for patients with bladder urothelial cell carcinoma.

[Diagnosis and therapy for penile cancer: a report of 46 cases with literature review].

BACKGROUND & OBJECTIVE: Penile cancer is an uncommon malignancy, which is mainly treated by surgery, radiation and chemotherapy. This study was to investigate reasonable curative methods for penile cancer. METHODS: Medical records of 46 patients with penile cancer in the Department of Urology, The First Affiliated Hospital of Sun Yat-sen University between Jan. 1996 to Jan. 2005 were analyzed retrospectively. Forty-four patients had squamous cell carcinoma, one had Paget disease, and one had verrucous carcinoma. RESULTS: Thirty-nine patients received partial penectomy, four received total penectomy and perineal urethrostomy, one Paget disease patient received lesion resection and skin grafting, two patients did not receive surgery. Nine out of 10 patients with positive lymph node received ilioinguinal lymphadenectomy, and five received pelvic lymphadenectomy. Forty-one cases were regularly followed up for one to 10 years. The 1-, 2-, 5- and 10- year survival rates were 95.1%, 95.1%, 82.9% and 31.7%, respectively. Prognosis of patients with pelvic lymph node metastasis was poor. Two patients who had pelvic lymph node metastasis died of lung metastasis within two years after surgery. CONCLUSIONS: Partial penectomy is an appropriate and effective management for penile cancer. Lymph node metastasis is an important prognostic factor for penile cancer. Patients with ilioinguinal lymph node metastasis should receive lymphadenectomy as early as possible to improve the therapeutic effect. The prognosis is poor for patients with pelvic lymph node metastases.

[Prevalence and related factors of prostatitis-like symptoms in young men].

OBJECTIVE: To investigate the prevalence and related factors of prostatitis-like symptoms among young men. METHODS: The study was a cross-sectional survey of 2500 young men aged 18-30 years in the city of Weifang, and all of them completed a questionnaire on prostatitis. The univariate and multivariate logistic regression procedures were used to investigate the risk factors among the young men with chronic prostatitis-like symptoms. RESULTS: The valid response rate was 85% (n = 2125). Of the 128 subjects (6.02%) identified as having chronic prostatitis-like symptoms, the mean age was 21.8 years, the average pain score was 6.98 +/- 0.29, and the average voiding score was 3.77 +/- 0.25. Of the sampled population, 39 men had prostatitis-like symptoms with an index pain score of 8 or more. Significant risk factors include frequent masturbation, prolonged sitting, long-time fixed posture, cold environment, stress at home and work. CONCLUSION: The study suggested that chronic prostatitis-like symptoms are common among young men, and the urethritis history, frequent masturbation, prolonged sitting, long-time urine holding, cold environment, and stress at home and work might be significant risk factors.