Anti-Allergic and Anti-inflammatory Effects of Bakuchiol on Ovalbumin-Induced Allergic Rhinitis in Mice.

Allergic rhinitis (AR) is a prevalent inflammatory disease primarily affecting the nasal mucosa and is caused by allergies. The common symptoms of AR include rhinorrhea, sneezing, itchy nose, congestion, teary eyes, and nasal rubbings. The present study assessed the beneficial properties of bakuchiol on OVA-induced AR in mice via the regulation of inflammatory responses. AR was induced by injecting (i.p.) OVA (50 µg) and aluminum hydroxide (1 mg) into mice at various time intervals. The bakuchiol treatment was done at dosages of 10 and 20 mg/kg with dexamethasone (2.5 mg/kg) as a positive control. The body weight and nasal symptoms were measured on the day of the last OVA challenge. For in vitro tests, mouse splenocytes were isolated, sensitized with 20 µL OVA, and then treated with 10 µM bakuchiol. The levels of pro-inflammatory cytokines, immunoglobulins, histamine, leukotriene C4 (LTC-4), and prostaglandin D2 (PGD2) were assayed using the corresponding assay kits. The assay kits were also used to analyze the status of oxidative stress markers. The Th1/Th2 cell proportion was assessed using flow cytometry. The bakuchiol (10 and 20 mg/kg) treatment reduced the nasal symptoms in AR mice. Bakuchiol decreased the levels of IL-4, IL-5, IL-13, Igs (IgE and IgG1), histamine, IL-10, IL-33, and TNF-α in AR mice. Bakuchiol also reduced PGDA and LTC-4 levels in the NLF of AR mice. The ROS and MDA levels were decreased, whereas boosted SOD activity was observed in the bakuchiol-treated AR mice. The eosinophil count was decreased in the nasal tissues of bakuchiol-treated AR mice. Bakuchiol also influenced the Th1 and Th2 cell proportions in AR mice. The present findings suggest that bakuchiol is effective against OVA-mediated allergic and inflammatory responses in AR mice through its strong anti-inflammatory properties.

BAG3 Suppresses Loading of Ago2 to IL6 mRNA in Pancreatic Ductal Adenocarcinoma.

Pancreatic stellate cells (PSCs) are a subset of pancreatic cancer-associated fibroblasts, which play a critical role in pancreatic fibrosis, a characteristic feature of pancreatic cancer. The interplay between PSCs and pancreatic cancer cells is vital for promotion of tumor progression and metastasis. BAG3 is correlated with poor prognostics in patients with pancreatic ductal adenocarcinoma (PDAC), however, the exact mechanisms remain largely unknown. In this study, we demonstrated that BAG3 downregulation decreased IL6 release by PDACs, and IL6 reduction was, at least partially, responsible for suppression of PSCs activation by PDACs with BAG3 downmodulation. Importantly, BAG3 expression positively correlated with fibrosis in pancreatic cancer tissue. With regard to the underlying mechanism, we demonstrated that BAG3 knockdown facilitated recruitment of Agonaute 2 (Ago2) to IL6 mRNA, resulting in destabilization of IL6 mRNA. In addition, the current study demonstrated that phosphorylation at Serine (Ser) 387 site was required for recruitment of Ago2-containing miRISC to IL6 mRNA and BAG3 knockdown facilitated Ago2 loading to IL6 mRNA via increasing its phosphorylation at Ser 387. This study shed new light on the tumor-promoting role of BAG3 in PDAC tumors, suggesting BAG3 might represent an interesting therapeutic opportunity to PDAC patients.

BAG3 directly stabilizes Hexokinase 2 mRNA and promotes aerobic glycolysis in pancreatic cancer cells.

Aerobic glycolysis, a phenomenon known historically as the Warburg effect, is one of the hallmarks of cancer cells. In this study, we characterized the role of BAG3 in aerobic glycolysis of pancreatic ductal adenocarcinoma (PDAC) and its molecular mechanisms. Our data show that aberrant expression of BAG3 significantly contributes to the reprogramming of glucose metabolism in PDAC cells. Mechanistically, BAG3 increased Hexokinase 2 (HK2) expression, the first key enzyme involved in glycolysis, at the posttranscriptional level. BAG3 interacted with HK2 mRNA, and the degree of BAG3 expression altered recruitment of the RNA-binding proteins Roquin and IMP3 to the HK2 mRNA. BAG3 knockdown destabilized HK2 mRNA via promotion of Roquin recruitment, whereas BAG3 overexpression stabilized HK2 mRNA via promotion of IMP3 recruitment. Collectively, our results show that BAG3 promotes reprogramming of glucose metabolism via interaction with HK2 mRNA in PDAC cells, suggesting that BAG3 may be a potential target in the aerobic glycolysis pathway for developing novel anticancer agents.

Involvement of Nrf2 in proteasome inhibition-mediated induction of ORP150 in thyroid cancer cells.

Oxygen-regulated protein 150 (ORP150) is an inducible ER chaperone by numerous cellular insults and sustains cellular viability. We have previously reported that ORP150 is differentially induced in a panel thyroid cancer cells and represents as an unwanted molecular consequence during exposure to proteasome inhibition. However, the molecular basis for induction of ORP150 by proteasome inhibitors in thyroid cancer cells remains unclear. In the current study, we found that -421/-307 and -243/+53 regions at the ORP150 gene were responsible for its transactivation by MG132 in thyroid cancer cells. Nrf2 directly transactivated the ORP150 gene by direct binding with the -421/-307 region. Nrf2 also indirectly activated OPR150 transcription via facilitating recruitment of ATF4 to the -243/+53 region. Collectively, this study highlights the molecular mechanism by which proteasome inhibition stimulates ORP150 expression via Nrf2 in thyroid cancer cells.