RESUMO
Infantile cholestatic hepatopathy (ICH) is a clinical syndrome characterized by the accumulation of cytotoxic bile acids in infancy, leading to serious liver cirrhosis or liver failure. The aetiology of ICH is complicated and some of them is unknown. Regardless of the aetiology, the finial pathology of ICH is hepatocyte apoptosis caused by severe and persistent cholestasis. It is already known that activation of calcium-sensing receptor (CaSR) could lead to the apoptosis of cardiomyocytes. However, the mechanism by CaSR-mediated cholestasis-related hepatocyte apoptosis is not fully understood. Li-Dan-He-Ji (LDHJ), a Traditional Chinese Medicine prescription, was developed to treat ICH. Another aim of this study was to investigate the possible mechanisms of LDHJ in cholestasis-related hepatocyte apoptosis. Using the primary hepatocytes, we first investigated the molecular mechanism of CaSR-mediated hepatocyte apoptosis in cholestasis. Then we prepared LDHJ granules and used ultra-high-performance liquid chromatography to identify the predominant drugs; confirmed the stability of the main substances; and for cell experiments screened forsythoside-A, emodin and chlorogenic acid as the three active substances of LDHJ granules. In the young rats with ANIT-induced intrahepatic cholestasis and the primary hepatocytes with TCDC-induced cholestasis-related hepatocyte apoptosis, the levels of liver injury and cholestasis-related biomarkers, calcium-sensing receptor (CaSR), hepatocyte apoptosis, Bax/Bcl-2 ratio, Cytochrome-C, caspase-3, phosphorylated-c-Jun NH2-terminal kinase (p-JNK)/JNK, and p-P38/P38 were all increased, while the levels of p-extracellular signal-regulated kinase (p-ERK)/ERK were decreased. However, LDHJ granules and its three active substances effectively reversed these changes. Furthermore, the three active substances reduced the increases in the intracellular calcium concentration ([Ca2+]i) and ROS levels and attenuated the dissipation of the mitochondria membrane potential in the TCDC-induced primary hepatocytes. The opposite results were obtained from the TCDC-induced primary hepatocytes treated with an agonist of CaSR (GdCl3) plus forsythoside-A, emodin or chlorogenic acid. Based on the results from in vivo and in vitro studies, LDHJ functions as an antagonist of CaSR to regulate hepatocyte apoptosis in cholestasis through the mitochondrial pathway and mitogen-activated protein kinase pathway.
RESUMO
Subacute combined degeneration of the spinal cord (SCD) is often found in vitamin B-12 deficiency and typically shows hyperintensity on T2-weighted images of the lateral and posterior columns. The purpose of the study was to evaluate the use of conventional magnetic resonance examination in diagnosing SCD. Thirty-six patients were clinically confirmed and retrospectively analyzed; conventional spine MRIs were available for all patients and eight of them had contrast enhancement MRIs. 19 out of 36 patients showed abnormal signal intensity on T2 weighted images with a sensitivity of 52.8%, among which 18 in the posterior aspect of the spinal cord and 1 in the anterior horn of the thoracic spinal cord The spinal cord abnormalities were seen at the cervical spine in 12 patients (33.3%) and at the thoracic spine in the other 7 patients (19.4%). Axial T2-weighted images showed symmetric linear T2-hyperintensity as an "inverted V" at the cervical spinal cord in 5 patients, which has been reported as a typical sign of SCD. For patients with thoracic spinal cord abnormalities, the bilateral paired nodular T2-hyperintensity looked like "binoculars" at the thoracic spinal cord. Only one out of the eight patients showed slight enhancement after injection with contrast agent. All the 36 patients reported clinical improvement after appropriate vitamin B-12 treatment. The two follow-up spine MRIs showed a decreased extent of the lesion. Therefore, conventional MRI is useful in the diagnosis and management of SCD caused by vitamin B-12 deficiency.