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Osteoclast (OC) abnormalities lead to many osteolytic diseases, such as osteoporosis, inflammatory bone erosion, and tumor-induced osteolysis. Exploring effective strategies to remediate OCs dysregulation is essential. FTY720, also known as fingolimod, has been approved for the treatment of multiple sclerosis and has anti-inflammatory and immunosuppressive effects. Here, we found that FTY720 inhibited osteoclastogenesis and OC function by inhibiting nuclear factor kappa-B (NF- κ B) signaling. Interestingly, we also found that FTY720 inhibited osteoclastogenesis by upregulating histone deacetylase 4 (HDAC4) expression levels and downregulating activating transcription factor 4 (ATF4) expression levels. In vivo, FTY720 treatment prevented lipopolysaccharide- (LPS-) induced calvarial osteolysis and significantly reduced the number of tartrate-resistant acid phosphatase- (TRAP-) positive OCs. Taken together, these results demonstrate that FTY720 can inhibit osteoclastogenesis and ameliorate inflammation-induced bone loss. Which may provide evidence of a new therapeutic target for skeletal diseases caused by OC abnormalities., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this article., (Copyright © 2023 Chongwei Chen et al.)

In this study, the comparative effect of TeA, DCMU, bentazone, DBMIB and MV on prompt fluorescence and the MR 820 signal was simultaneously analyzed to provide an insight into how to elucidate their precise influence on Ageratina adenophora photosystems. The herbicides that interrupt electron transport beyond Q A , such as TeA, DCMU and bentazone, mainly increased the J-step level of fluorescence rise kinetics as a result of accumulation of Q A - , but showed differences in detail. The IP phase disappeared in the presence of DCMU and bentazone with a significant increase in F O value. TeA treatment retained the IP phase with lowering F M . As an inhibitor of plastoquinone re-oxidation, DBMIB increased the I-step (IP phase almost unnoticable) without changing F O and F M values. MV blocking PSI electron transfer through intercepting electrons from the FeS clusters suppressed the IP phase by decreasing the P level. Considering the W IP kinetics, TeA and DBMIB also affected PSI activity. After DCMU and MV treatment, the major change in the MR 820 kinetics was the loss of the slow phase due to the complete prevention of electron movement from PSII to re-reduce PC + and P 700 + . TeA, bentazone and DBMIB clearly suppressed the MR 820 slow phase and decreased the re-reduction rate of PC + and P 700 + (V red ), significantly. However, there were still parts of electrons being donated to PC + and P 700 + , showing a smaller slow phase and PC + and P 700 + re-reduction rate. Additionally, TeA and DBMIB also somewhat declined the fast phase and PC and P 700 oxidation rate (V ox )., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Purpose: To elucidate the role and molecular mechanism of Numb in prostate cancer and the functional contribution of Numb -/low prostate cancer cells in castration resistance. Experimental Design: The expression of Numb was assessed using multiple Oncomine datasets and prostate cancer tissues from both humans and mice. The biological effects of the overexpression and knockdown of Numb in human prostate cancer cell lines were investigated in vitro and in vivo In addition, we developed a reliable approach to distinguish between prostate cancer cell populations with a high or low endogenous expression of Numb protein using a Numb promoter-based lentiviral reporter system. The difference between Numb -/low and Numb high prostate cancer cells in the response to androgen-deprivation therapy (ADT) was then tested. The likely downstream factors of Numb were analyzed using luciferase reporter assays, immunoblotting, and quantitative real-time PCR. Results: We show here that Numb was downregulated and negatively correlated with prostate cancer advancement. Functionally, Numb played an inhibitory role in xenograft prostate tumor growth and castration-resistant prostate cancer development by suppressing Notch and Hedgehog signaling. Using a Numb promoter-based lentiviral reporter system, we were able to distinguish Numb -/low prostate cancer cells from Numb high cells. Numb -/low prostate cancer cells were smaller and quiescent, preferentially expressed Notch and Hedgehog downstream and stem-cell-associated genes, and associated with a greater resistance to ADT. The inhibition of the Notch and Hedgehog signaling pathways significantly increased apoptosis in Numb -/low cells in response to ADT. Conclusions: Numb -/low enriches a castration-resistant prostate cancer cell subpopulation that is associated with unregulated Notch and Hedgehog signaling. Clin Cancer Res; 23(21); 6744-56. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Cancer stem-like cells (CSC) drive cancer progression and recurrence. Self-renewal expansion of CSC is achieved through symmetric cell division, yet how external stimuli affect intracellular regulatory programs of CSC division modes and stemness remains obscure. Here, we report that the hTERT high prostate cancer cells exhibit CSC properties, including a stem cell-associated gene expression signature, long-term tumor-propagating capacity and epithelial-to-mesenchymal transition. In promoting the self-renewal symmetric division of hTERT high prostate cancer cells, WNT3a dramatically decreased the ratio of hTERT high prostate cancer cells undergoing asymmetric division. Increased WNT/β-catenin signal activation was also detected in hTERT high prostate cancer cells. hTERT-mediated CSC properties were at least partially dependent on β-catenin. These findings provide novel cellular and molecular mechanisms for the self-renewal of CSC orchestrated by tumor microenvironmental stimuli and intracellular signals. Cancer Res; 77(9); 2534-47. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Objective: Kinase Anchoring Proteins (AKAPs) have evolved to regulate the spatial and temporal organization of cellular signal transduction. As a typical member, AKAP5 which consisting of three orthologues: bovine AKAP75, rodent AKAP150 and human AKAP79, is the best known model in the anchoring and targeting properties. It is shown that AKAP5 can bind β2-adrenergic receptor, which is a member of GPCR superfamily, and orchestrate the interactions of various protein kinases, protein phosphatases and cytoskeletal element. AKAP5 is originally identified as a component of the postsynaptic density in neurons and plays a vital role in modulating neuronal activities. Subsequently, the AKAP5 complexes are also detected in other tissues and participated in various processes.

Androgen receptor (AR) plays a critical role during the development and progression of prostate cancer in which microRNA miR-375 is overexpressed and correlated with tumor progression. Although DNA methylation is a key mechanism for the repression of gene expression, the relationship between AR and the expression or the hypermethylation of miR-375 is unknown. In this study, we found that AR-positive prostate cancer (PCa) cells showed high expression levels and hypomethylation of the miR-375. In contrast, AR-negative PCa cells displayed low levels and hypermethylation of the miR-375. Addition of 5-Aza-2'-deoxycytidine, a specific inhibitor of DNA methylation, into the culture medium reversed the low expression levels of miR-375 in the AR negative PCa cells. In addition, the total activity levels of DNA methyltransferases (DNMTs) were high in AR-negative PCa cells, in which hypermethylation of miR-375 promoter and low expression levels of miR-375 were observed. Taken together, these findings indicate that the negative correlation between AR and total DNMT activity is one of mechanisms to influence the methylation status of miR-375 promoter, which in turn regulates the expression of miR-375.