ABSTRACT
CDK5 regulatory subunit associated protein 1-like 1 (CDKAL1) is a tRNA-modifying enzyme that catalyzes 2-methylthiolation (ms2) and has been implicated in the development of type 2 diabetes (T2D). CDKAL1-mediated ms2 is important for efficient protein translation and regulates insulin biosynthesis in pancreatic cells. Interestingly, an association between T2D and release of growth hormone (GH) has been reported in humans. However, it is unknown whether CDKAL1 is important for hormone production in the pituitary gland. The present study investigated the role of CDKAL1 in GH-producing pituitary adenomas (GHPAs). CDKAL1 activity was suppressed in GHPAs, as evidenced by a decrease in ms2, compared with non-functioning pituitary adenomas (NFPAs), which do not produce specific hormones. Downregulation of Cdkal1 using small interfering and short hairpin RNAs increased the biosynthesis and secretion of GH in rat GH3 cells. Depletion of Cdkal1 increased the cytosolic calcium level via downregulation of DnaJ heat shock protein family (Hsp40) member C10 (Dnajc10), which is an endoplasmic reticulum protein related to calcium homeostasis. This stimulated transcription of GH via upregulation of Pit-1. Moreover, CDKAL1 activity was highly sensitive to proteostatic stress and was upregulated by suppression of this stress. Taken together, these results suggest that dysregulation of CDKAL1 is involved in the pathogenesis of GHPAs, and that modulation of the proteostatic stress response might control CDKAL1 activity and facilitate treatment of GHPAs.
Subject(s)
Adenoma/genetics , Growth Hormone/biosynthesis , Pituitary Neoplasms/genetics , tRNA Methyltransferases/physiology , Adenoma/metabolism , Adenoma/pathology , Animals , Cells, Cultured , Endoplasmic Reticulum Stress/physiology , Gene Expression Regulation, Enzymologic/drug effects , Gene Expression Regulation, Neoplastic/drug effects , Growth Hormone/genetics , Growth Hormone-Secreting Pituitary Adenoma/genetics , Growth Hormone-Secreting Pituitary Adenoma/metabolism , Growth Hormone-Secreting Pituitary Adenoma/pathology , Human Growth Hormone/biosynthesis , Human Growth Hormone/genetics , Humans , Pituitary Neoplasms/metabolism , Pituitary Neoplasms/pathology , RNA, Small Interfering/pharmacology , Rats , Unfolded Protein Response/physiology , tRNA Methyltransferases/geneticsABSTRACT
BACKGROUND: Acute subdural hematoma (ASDH) is a common disease and craniotomy is the first choice for removing hematoma. However, patients for whom craniotomy or general anesthesia is contraindicated are increasing due to population aging. In our department, we perform burr hole surgery under local anesthesia with urokinase administration for such patients. We compared the patient background and outcomes between burr hole surgery and craniotomy to investigate the surgical safety criteria for burr hole surgery. METHODS: We reviewed 24 patients who underwent burr hole surgery and 33 patients who underwent craniotomy between January 2010 and April 2020 retrospectively. RESULTS: The median age of the burr hole surgery group was older (P = 0.01) and they had multiple pre-existing conditions. Compared with the craniotomy group, neurological deficits and CT findings were minor in the burr hole surgery group, whereas the maximum hematoma thickness was not significantly different. The hematoma was excreted after a total of 54,000 IU of urokinase was administered for a median of 3 days. The Glasgow Coma Scale score improved in all patients in the burr hole surgery group and there were no deaths. Age, especially over 65 y.o., (OR 1.16, 95% CI 1.04-1.30) and the absence of basal cistern disappearance (OR 0.04, 95% CI 0.004-0.39) were significant factors. CONCLUSION: Burr hole surgery was performed safely in all patients based on the age, especially older than 65 y.o., and the absence of basal cistern disappearance. ASDH in the elderly is increasing and less invasive burr hole surgery with urokinase is suitable for the super-aging society.