Angel or Devil ? - CDK8 as the new drug target.

Cyclin-dependent kinase 8 (CDK8) plays an momentous role in transcription regulation by forming kinase module or transcription factor phosphorylation. A large number of evidences have identified CDK8 as an important factor in cancer occurrence and development. In addition, CDK8 also participates in the regulation of cancer cell stress response to radiotherapy and chemotherapy, assists tumor cell invasion, metastasis, and drug resistance. Therefore, CDK8 is regarded as a promising target for cancer therapy. Most studies in recent years supported the role of CDK8 as a carcinogen, however, under certain conditions, CDK8 exists as a tumor suppressor. The functional diversity of CDK8 and its exceptional role in different types of cancer have aroused great interest from scientists but even more controversy during the discovery of CDK8 inhibitors. In addition, CDK8 appears to be an effective target for inflammation diseases and immune system disorders. Therefore, we summarized the research results of CDK8, involving physiological/pathogenic mechanisms and the development status of compounds targeting CDK8, provide a reference for the feasibility evaluation of CDK8 as a therapeutic target, and guidance for researchers who are involved in this field for the first time.

Anti-platelet effects of anti-glaucomatous eye drops: an in vitro study on human platelets.

PURPOSE: Altered platelet aggregability has been implicated in the pathogenesis of glaucoma. This study aims to investigate the anti-platelet potential of intraocular pressure lowering drops, with the possibility of establishing it as an additional mechanism of anti-glaucomatous action. MATERIALS AND METHODS: The anti-aggregating effects of a series of anti-glaucomatous eye drops were determined on human platelets in the platelet aggregation model, using four known aggregating factors (platelet activating factor [PAF], adenosine diphosphate [ADP], thrombin receptor-activating peptide [TRAP], and arachidonic acid [AA]). RESULTS: Almost all of the tested samples inhibited platelet aggregation induced by PAF, ADP, TRAP, and AA, except for Alphagan, which did not demonstrate inhibition of ADP- and TRAP-induced aggregation at a wide range of concentrations. Trusopt, Betoptic, and Azarga eye drops were the most potent inhibitors of all four aggregating factors, while Alphagan was the least potent (P<0.05). CONCLUSION: This study shows that anti-glaucomatous eye drops possess anti-platelet effects, and this was shown for the first time by experimenting on human platelets.

Effect of vitamin D receptor activator therapy on vitamin D receptor and osteocalcin expression in circulating endothelial progenitor cells of hemodialysis patients.

BACKGROUND: The effects of vitamin D receptor (VDR) and osteocalcin (OC) expression as well as VDR agonist (VDRA) therapy on circulating endothelial progenitor cells (EPCs) has not been elucidated yet. METHODS: We therefore analyzed EPCs in 30 healthy controls and 82 patients undergoing dialysis (no VDRA therapy: 28; oral calcitriol: 30, and intravenous paricalcitol, PCTA: 24). The percentage of EPCs (CD34+/CD133-/KDR+/CD45-) expressing VDR or OC, and VDR and OC expression defined by mean fluorescence intensity (MFI) were analyzed using flow cytometry. The in vitro effect of VDRAs was evaluated in EPCs isolated from each patient group. RESULTS: The percentage of VDR+ EPCs correlated positively with VDRA therapy and 25(OH)D, and negatively with diabetes, C-reactive protein, hemoglobin and osteopontin. VDR-MFI correlated positively with VDRA therapy, parathyroid hormone (PTH) and 25(OH)D, and negatively with diabetes and osteopontin. The percentage of OC+ EPCs correlated positively with the calcium score, PTH and phosphate, and negatively with 25(OH)D. OC-MFI correlated positively with calcium score, PTH, phosphate and hemoglobin, and negatively with albumin, 25(OH)D and osteopontin. Cell cultures from patients without VDRA therapy had the highest levels of calcium deposition and OC expression, which both significantly decreased following in vitro VDRA administration: in particular extracellular calcium deposition was only reduced by adding PCTA. CONCLUSIONS: Our data suggest that 25(OH)D serum levels and VDRA therapy influence VDR and OC expression on circulating EPCs. Since OC expression may contribute to vascular calcification, we hypothesize a putative protective role of VDRA therapy.

Temporal effects of thyroid hormone (TH) and decabrominated diphenyl ether (BDE209) on Purkinje cell dendrite arborization.

Thyroid hormones (TH) 3,3',4-tri-iodothyronine (T3) and 3,3',4,4'-tetra-iodothyronine (T4) plays crucial role in cerebellar development. Deficiency of TH consistently results in aberrant growth and development of the cerebellum including reduced growth and branching of the Purkinje cells. In rodents, the critical period of thyroid hormone action on cerebellum development is within the first two to three weeks, after which thyroid hormone replacement cannot fully reverse abnormal cerebellar development induced by thyroid hormone insult. Decabrominated diphenyl ether (BDE209) is an industrial reagent used as an additive flame retardant to reduce flammability of various commercial and household produce. BDE209 has bio-accumulative potential and is neurotoxic. Previously, we have shown that T4 (10-8 M) induced extensive dendrite arborization of Purkinje cells and low dose BDE209 (10-10 M) remarkably suppressed TH-induced Purkinje cell dendrite arborization. In the present study, we show that the critical period for TH-induced Purkinje cell growth and dendrite arborization in culture is much earlier than reported in animal models. Also, we show for the first time that low dose BDE209 suppressed TH-induced dendrite arborization in a time-dependent manner. Taken together, our study indicates that hypothyroidism and exposure to BDE209 during critical stage of cerebellar development can lead to impaired Purkinje cell growth and dendrite arborization and may consequently disrupt normal cerebellar functions.