Prostaglandins regulate many physiological functions, including reproduction, by binding to specific plasma membrane receptors. In this study we evaluated the regulation of PGF2 alpha (FP) and PGE (EP3 subtype) receptors in ovine corpora lutea. In the first study, tissue distribution of FP and EP3 receptors was evaluated in 13 ovine tissues. FP receptor mRNA was present in 100-fold higher concentration in corpora lutea than in other tissues. Similarly, [3H]PGF2 alpha binding was much greater in luteal plasma membranes than in membranes from other tissues. In contrast, EP3 receptor mRNA was more uniformly distributed, with high concentrations in adrenal medulla, inner myometrium, kidney medulla and heart. The distribution of [3H]PGE1 binding was generally similar to EP3 mRNA, with the exception that ovarian stroma, endometrium and outer myometrium had high [3H]PGE1 binding but low concentrations of EP3 receptor mRNA. The second study evaluated the action of PGF2 alpha on luteal mRNA encoding FP and EP3 receptors. Ewes had PGF2 alpha or saline infused into the ovarian artery and corpora lutea were removed at 0, 1, 4, 12 and 24 h. FP receptor mRNA decreased by 50% at 12 and 24 h after infusion with PGF2 alpha, whereas EP3 mRNA was unchanged. Treatment of large luteal cells with PGF2 alpha, phorbol didecanoate (protein kinase C activator), or ionomycin (calcium ionophore) decreased FP receptor mRNA after 24 h (P < 0.05). Glyceraldehyde 3-phosphate dehydrogenase mRNA was not changed by any treatment. These results show that EP3 receptors are expressed in many tissues and expression is not regulated by PGF2 alpha. In contrast, FP receptors are primarily expressed in corpora lutea and expression is inhibited by PGF2 alpha.

Background: Hidradenitis suppurativa (HS) is a severe dermatological disease that significantly reduces life quality. However, the etiology of this disease remains largely unknown. Objectives: We sought to identify the factors associated with clinical presentation and the severity of HS. The features of HS between genders and smokers/nonsmokers were compared. Methods: A single-center retrospective study of 161 patients with HS was conducted and analyzed. Results: The male-to-female ratio in HS was approximately 2:1 in Taiwan. The severity of HS was significantly associated with smoking (odds ratio 2.20, P = 0.018). HS in men more frequently occurred in the gluteal region. Nonsmokers in HS tended to have earlier onset age and axillary lesions. Smokers were prone to have exclusive gluteal involvement and negative family history of HS. Conclusion: Our data revealed smoking correlated with the severity of HS. Smoking status and gender influence the clinical characteristics in HS.

Background Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer characterized by early dissemination and poor drug response. Loss-of-function of dual specificity phosphatase 2 (DUSP2), a critical regulator of MAPKs signaling, is highly associated with cancer malignancies. Therefore, it may provide new therapeutic strategy if the actions of DUSP2 can be restored. Methods The tumor suppressor role of DUSP2 was demonstrated via DUSP2 re-expression in the orthotopic mouse model of pancreatic cancer and knockout of Dusp2 in the pancreas by transgenic mouse model. Immunohistochemical staining and histology analysis was performed to evaluate tumor development and progression. Bioinformatic analysis was utilized to identify potential drug which mimics DUSP2 re-expression. Pancreatic cancer cell survival, migration ability, and the expression and function of extracellular vesicle (EV) associated vascular endothelial growth factor C (VEGF-C) was measured. The effect of the novel HDAC inhibitor on pancreatic cancer progression was evalulated by orthotopic mouse model. Results Forced expression of DUSP2 abrogated tumor formation and loss of Dusp2 facilitated Kras-driven PDAC formation. Increased HDAC1 expression was found in PDAC and inhibition of HDAC showed similar gene profile as Kras knockdown and DUSP2 re-expression. Treatment with B390 inhibited growth and migration abilities of PDAC cells, decreased EV-associated VEGF-C expression, and suppressed lymphatic endothelial cell proliferation. In vivo, B390 not only suppressed tumor growth by increasing tumor cell death, it also inhibited lymphangiogenesis and lymphovascular invasion. Conclusions Our data provide the proof-of-concept evidence to demonstrate the potential of using novel HDAC inhibitor in PDAC treatment which alleviates loss-of-DUSP2-mediated pathological processes.

BackgroundPancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers because of its late diagnosis and chemoresistance. Primary cilia, the cellular antennae, are observed in most human cells to maintain development and differentiation. Primary cilia are gradually lost during the progression of pancreatic cancer and are eventually absent in PDAC. However, recent study showed that primary cilia regrowth contributes to the development of diverse kinase inhibitor resistance in lung cancer. We elucidated the role of regrowth primary ciliogenesis in PDAC chemoresistance and uncovered the underlying molecular mechanism. ResultsWe showed that cisplatin-resistant PDAC regrew primary cilia. Additionally, genetic or pharmacological disruption of primary cilia sensitized PDAC to cisplatin treatment. Mechanistically, ataxia telangiectasia mutated (ATM) and ATM and RAD3-related (ATR), tumor suppressors that initiate DNA damage responses, promoted the excessive formation of centriolar satellites (EFoCS) and autophagy activation.Disruption of EFoCS and autophagy inhibited primary ciliogenesis, sensitizing PDAC cells to cisplatin treatment. ConclusionsCollectively, our ndings revealed an unexpected interplay among the DNA damage response, primary cilia, and chemoresistance in PDAC and deciphered the molecular mechanism by which ATM/ATRmediated EFoCS and autophagy cooperatively regulate primary ciliogenesis.

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