1.Screening for somatisation in an Asian children's hospital emergency setting.
Siok Hoon ANG ; Juliet S K TAN ; Jiahui LEE ; Vicknesan J MARIMUTTU ; Xin Yi LIM ; Lois L E TEO ; Shannon N EDWARD ; Mavis TEO ; Joyce S T LIM ; Sashikumar GANAPATHY ; Angelina ANG
Annals of the Academy of Medicine, Singapore 2022;51(8):507-509
2.18FMAGL-4-11 positron emission tomography molecular imaging of monoacylglycerol lipase changes in preclinical liver fibrosis models.
Tuo SHAO ; Zhen CHEN ; Jian RONG ; Vasily BELOV ; Jiahui CHEN ; Andre JEYARAJAN ; Xiaoyun DENG ; Hualong FU ; Qingzhen YU ; Steve H RWEMA ; Wenyu LIN ; Mikhail PAPISOV ; Lee JOSEPHSON ; Raymond T CHUNG ; Steven H LIANG
Acta Pharmaceutica Sinica B 2022;12(1):308-315
Monoacylglycerol lipase (MAGL) is a pivotal enzyme in the endocannabinoid system, which metabolizes 2-arachidonoylglycerol (2-AG) into the proinflammatory eicosanoid precursor arachidonic acid (AA). MAGL and other endogenous cannabinoid (EC) degrading enzymes are involved in the fibrogenic signaling pathways that induce hepatic stellate cell (HSC) activation and ECM accumulation during chronic liver disease. Our group recently developed an 18F-labeled MAGL inhibitor ([18F]MAGL-4-11) for PET imaging and demonstrated highly specific binding in vitro and in vivo. In this study, we determined [18F]MAGL-4-11 PET enabled imaging MAGL levels in the bile duct ligation (BDL) and carbon tetrachloride (CCl4) models of liver cirrhosis; we also assessed the hepatic gene expression of the enzymes involved with EC system including MAGL, NAPE-PLD, FAAH and DAGL that as a function of disease severity in these models; [18F]MAGL-4-11 autoradiography was performed to assess tracer binding in frozen liver sections both in animal and human. [18F]MAGL-4-11 demonstrated reduced PET signals in early stages of fibrosis and further significantly decreased with disease progression compared with control mice. We confirmed MAGL and FAAH expression decreases with fibrosis severity, while its levels in normal liver tissue are high; in contrast, the EC synthetic enzymes NAPE-PLD and DAGL are enhanced in these different fibrosis models. In vitro autoradiography further supported that [18F]MAGL-4-11 bound specifically to MAGL in both animal and human fibrotic liver tissues. Our PET ligand [18F]MAGL-4-11 shows excellent sensitivity and specificity for MAGL visualization in vivo and accurately reflects the histological stages of liver fibrosis in preclinical models and human liver tissues.
3.Development of a highly-specific
Zhen CHEN ; Wakana MORI ; Jian RONG ; Michael A SCHAFROTH ; Tuo SHAO ; Richard S VAN ; Daisuke OGASAWARA ; Tomoteru YAMASAKI ; Atsuto HIRAISHI ; Akiko HATORI ; Jiahui CHEN ; Yiding ZHANG ; Kuan HU ; Masayuki FUJINAGA ; Jiyun SUN ; Qingzhen YU ; Thomas L COLLIER ; Yihan SHAO ; Benjamin F CRAVATT ; Lee JOSEPHSON ; Ming-Rong ZHANG ; Steven H LIANG
Acta Pharmaceutica Sinica B 2021;11(6):1686-1695
As a serine hydrolase, monoacylglycerol lipase (MAGL) is principally responsible for the metabolism of 2-arachidonoylglycerol (2-AG) in the central nervous system (CNS), leading to the formation of arachidonic acid (AA). Dysfunction of MAGL has been associated with multiple CNS disorders and symptoms, including neuroinflammation, cognitive impairment, epileptogenesis, nociception and neurodegenerative diseases. Inhibition of MAGL provides a promising therapeutic direction for the treatment of these conditions, and a MAGL positron emission tomography (PET) probe would greatly facilitate preclinical and clinical development of MAGL inhibitors. Herein, we design and synthesize a small library of fluoropyridyl-containing MAGL inhibitor candidates. Pharmacological evaluation of these candidates by activity-based protein profiling identified