Although emerging evidence suggests that the pathogenesis of Parkinson’s disease (PD) is closely related to the aggregation of alpha-synuclein (α-syn) in the midbrain, the clearance of α-syn remains an unmet clinical need. Here, we develop a simple and efficient strategy for fabricating the α-syn nanoscavenger for PD via a reprecipitation self-assembly procedure. The curcumin analogue-based nanoscavenger (NanoCA) is engineered to be capable of a controlled-release property to stimulate nuclear translocation of the major autophagy regulator, transcription factor EB (TFEB), triggering both autophagy and calcium-dependent exosome secretion for the clearance of α-syn. Pretreatment of NanoCA protects cell lines and primary neurons from MPP+-induced neurotoxicity. More importantly, a rapid arousal intranasal delivery system (RA-IDDS) was designed and applied for the brain-targeted delivery of NanoCA, which affords robust neuroprotection against behavioral deficits and promotes clearance of monomer, oligomer, and aggregates of α-syn in the midbrain of an MPTP mouse model of PD. Our findings provide a clinically translatable therapeutic strategy aimed at neuroprotection and disease modification in PD.

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Clusterin (CLU), a multifunctional glycoprotein, is ubiquitously produced in mammalian tissues. CLU has been shown to play significant roles in many of the biological behaviours of human tumors, such as cell proliferation, apoptosis, chemoresistance and angiogenesis. However, the relationship of CLU expression with angiogenesis in ovarian cancer has not been studied. A total of 275 epithelial ovarian tumors were obtained from archives of paraffin‑embedded tissues. Immunohistochemical (IHC) staining for CLU and vascular endothelial growth factor (VEGF) was performed on a tissue microarray (TMA) including 181 primary ovarian epithelial cancer, 40 borderline ovarian tumors and 54 ovarian cancer mesenteric metastasis samples. Of the 174 cases, overexpression of CLU and VEGF were detected in 107 (61.5%) and 109 (62.9%) cases of primary ovarian carcinoma, respectively. Of the 107 cases of primary ovarian carcinoma with overexpression of CLU, expression of VEGF was increased in 82 (75.2%) cases. However, in another 67 cases without CLU overexpression, overexpression of VEGF was observed in only 27 (24.8%) cases (P<0.05). Overexpression of CLU in epithelial ovarian cancer appears to be correlated with increased tumor angiogenesis, consistent with the established role of CLU as an oncogene in the biology of ovarian cancer. In the treatment of ovarian cancer, these two markers may be used in the selection of patients for targeted therapy.

Estrogen signaling influences the development and progression of ovarian tumors, but the underlying mechanisms are not well understood. In a previous study we demonstrated that impairment of estrogen receptor alpha (ERα)-mediated olfactomedin 4 (OLFM4) expression promotes the malignant progression of endometrioid adenocarcinoma, and we identified OLFM4 as a potential target of miR-486-5p. In this study we investigated the role of OLFM4 in ovarian serous adenocarcinoma. Ovarian serous adenocarcinoma tissues had reduced OLFM4 expression. Expression of OLFM4 was positively correlated with ERα expression, and estrogen (E2) treatment in ovarian cancer cells induced OLFM4 expression in an ERα-dependent manner. In contrast to ERα, miR-486-5p levels were inversely correlated with OLFM4 expression in ovarian serous adenocarcinoma. Ovarian cancer cells transfected with miR-486-5p mimics showed decreased OLFM4 mRNA expression, and ovarian cancer cells treated with E2 showed reduced cellular miR-486-5p levels. OLFM4 knockdown enhanced proliferation, migration, and invasion by ovarian cancer cells. Low expression of OLFM4 was also associated with high tumor FIGO stage and poor tumor differentiation. These results suggest OLFM4 is downregulated by miR-486-5p, which contributes to ovarian cancer tumorigenesis. Conversely, estrogen receptor signaling downregulates miR-486-5p and upregulates OLFM4 expression, slowing the development and progression of ovarian cancer.

BackgroundIn a previous analysis on the patients with ovarian cancers, we have found that clusterin is a biomarker associated with ovarian cancer in vivo and may be a prognostic factor associated with adverse outcome. Here, we explored the effect of lentivirus-mediated shRNA interference of clusterin, investigated whether clusterin was associated with adverse outcome of ovarian cancer cells in vitro.MethodsOVCAR-3 and TOV-21G cell lines were infected with the lentivirus for delivering clusterin shRNA, and the stably transfected cells were selected. The effect of clusterin silencing was detected by western blotting assay. The proliferation, clonability, migration, invasion and cell cycle of two cell lines were detected separately by MTT assay, clone formation assay, scratch assay, transwell assay and fluorescence-activated cell sorting.ResultsFollowing clusterin silencing with shRNA, the expression of clusterin in two cell lines were decreased. And the proliferation, clonability, migration, invasion of these two cell lines were down-regulated apparently. The cell cycle of two cell lines was disturbed, cells in G1 phase was increased, but cells in G2 and S phase was decreased.ConclusionsThe expression of clusterin is significantly correlated with the biological characteristics of ovarian cancer cells, it may be a potential molecular for ovarian cancer treatment.