Search

Abstract Targeting receptor‐interacting protein kinase 1 (RIPK1) has emerged as a promising therapeutic stratagem for neurodegenerative disorders, particularly Alzheimer's disease (AD). A positron emission tomography (PET) probe enabling brain RIPK1 imaging can provide a powerful tool to unveil the neuropathology associated with RIPK1. Herein, the development of a new PET radioligand, [11C]CNY‐10 is reported, which may enable brain RIPK1 imaging. [11C]CNY‐10 is radiosynthesized with a high radiochemical yield (41.8%) and molar activity (305 GBq/µmol). [11C]CNY‐10 is characterized by PET imaging in rodents and a non‐human primate, demonstrating good brain penetration, binding specificity, and a suitable clearance kinetic profile. It is performed autoradiography of [11C]CNY‐10 in human AD and healthy control postmortem brain tissues, which shows strong radiosignal in AD brains higher than healthy controls. Subsequently, it is conducted further characterization of RIPK1 in AD using [11C]CNY‐10‐based PET studies in combination with immunohistochemistry leveraging the 5xFAD mouse model. It is found that AD mice revealed RIPK1 brain signal significantly higher than WT control mice and that RIPK1 is closely related to amyloid plaques in the brain. The studies enable further translational studies of [11C]CNY‐10 for AD and potentially other RIPK1‐related human studies.

Abstract Histone deacetylase 6 (HDAC6) is one of the key histone deacetylases (HDACs) that regulates various cellular functions including clearance of misfolded protein and immunological responses. Considerable evidence suggests that HDAC6 is closely related to amyloid and tau pathology, the two primary hallmarks of Alzheimer's disease (AD). It is still unclear whether HDAC6 expression changes with amyloid deposition in AD during disease progression or HDAC6 may be regulating amyloid phagocytosis or neuroinflammation or other neuropathological changes in AD. In this work, the pathological accumulation of HDAC6 in AD brains over age as well as the relationship of its regulatory activity ‐ with amyloid pathogenesis and pathophysiological alterations is aimed to be enlightened using the newly developed HDAC6 inhibitor (HDAC6i) PB118 in microglia BV2 cell and 3D‐AD human neural culture model. Results suggest that the structure‐based rational design led to biologically compelling HDAC6i PB118 with multiple mechanisms that clear Aβ deposits by upregulating phagocytosis, improve tubulin/microtubule network by enhancing acetyl α‐tubulin levels, regulate different cytokines and chemokines responsible for inflammation, and significantly reduce phospho‐tau (p‐tau) levels associated with AD. These findings indicate that HDAC6 plays key roles in the pathophysiology of AD and potentially serves as a suitable pharmacological target through chemical biology‐based drug discovery in AD.

Abstract Background Ribosomal RNA (rRNA) consists of four non‐coding RNAs, the 28S, 5.8S, 18S, and 5S rRNA. Abnormal expression of rRNA has been found in multiple tumors, and the methylation of rDNA promoter may affect rRNA expression as an epigenetic regulatory mechanism. Oral squamous cell carcinoma (OSCC) is a kind of aggressive tumors which occurs in multiple sites in oral cavity. rRNA expression and the methylation of rDNA promoter in modulating rRNA expression in OSCC maintain unclear. This study aims to investigate the rRNA expression, the methylation status within rDNA promoter, and the underlying mechanism of methylation in regulating rRNA expression in OSCC. Methods Twelve primary OSCC and matched normal tissue samples were collected from patients with OSCC. Quantitative real‐time PCR was used to evaluate the rRNA level. HpaII/MspI digestion and bisulfite sequencing were used to investigate the methylation status of rDNA promoter. Results Ribosomal RNA levels were suppressed in OSCC as compared with matched normal tissues. HpaII/MspI digestion and bisulfite sequencing showed no significant differences for the methylation of rDNA promoter between the tumor and matched normal tissues. Conclusion The methylation in rDNA promoter could not explain for the suppressed rRNA expression in OSCC tissues.