Several established liver diseases of various causes are highly associated with hepatic insulin resistance, which is characterized by the desensitization of target cells to insulin. Peripheral insulin resistance is observed in most patients who have cirrhosis. Conversely, insulin-resistant diabetic patients are at increased risk for developing liver disease. Current therapeutic interventions in insulin resistance are limited and therefore likely to be advanced by new tailor-made drugs. Oltipraz, a prototype dithiolthione, inhibits transforming growth factor 1 and has the ability to regenerate cirrhotic liver. We investigated the effects of oltipraz and synthetic dithiolthiones on hepatic insulin resistance and the molecular basis of action. Oltipraz and other dithiolethione compounds were tested on tumor necrosis factor ␣ (TNF-␣)-induced insulin resistance and glucose homeostasis in vitro and in vivo via immunoblotting, plasmid transfection, kinase analysis, and functional assays. Oltipraz treatment inhibited the ability of TNF-␣ to activate p70 ribosomal S6 kinase-1 (S6K1) downstream of mammalian target of rapamycin, thus preventing insulin receptor substrate-1 serine phosphorylation and protecting insulin signals. Moreover, oltipraz activated AMP-activated protein kinase (AMPK), whose inhibition by a dominant negative mutant abolished S6K1 inhibition and protected insulin signaling, indicating that AMPK activation leads to S6K1 inhibition. In hepatocyte-derived cell lines, oltipraz inhibited glucose production. Oltipraz prevented hepatic insulin resistance in C57BL/6 mice challenged with endotoxin (or TNF-␣), leptin-deficient mice, and mice fed a high-fat diet. Synthetic dithiolethiones comparably inhibited insulin resistance. Conclusion: Our findings led to the identification of dithiolethione compounds that prevent insulin resistance through a mechanism involving AMPK-mediated S6K1 inhibition and thereby sensitize hepatic insulin response. (HEPATOLOGY 2007;46:730-739.)
The AAA+ adenosine triphosphatase (ATPase) Thorase plays a critical role in controlling synaptic plasticity by regulating the expression of surface α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). Bidirectional sequencing of exons of , the gene encoding Thorase, in a cohort of patients with schizophrenia and healthy controls revealed rare Thorase variants. These variants caused defects in glutamatergic signaling by impairing AMPAR internalization and recycling in mouse primary cortical neurons. This contributed to increased surface expression of the AMPAR subunit GluA2 and enhanced synaptic transmission. Heterozygous Thorase-deficient mice engineered to express these Thorase variants showed altered synaptic transmission and several behavioral deficits compared to heterozygous Thorase-deficient mice expressing wild-type Thorase. These behavioral impairments were rescued by the competitive AMPAR antagonist Perampanel, a U.S. Food and Drug Administration-approved drug. These findings suggest that Perampanel may be useful for treating disorders involving compromised AMPAR-mediated glutamatergic neurotransmission.
BackgroundCaudal epidural injections have been commonly performed in patients with low back pain and radiculopathy. Although caudal injection has generally been accepted as a safe procedure, serious complications such as inadvertent intravascular injection and dural puncture can occur. The present prospective study was designed to investigate the influence of the depth of the inserted needle on the success rate of caudal epidural blocks.MethodsA total of 49 adults scheduled to receive caudal epidural injections were randomly divided into 2 groups: Group 1 to receive the caudal injection through a conventional method, i.e., caudal injection after advancement of the needle 1 cm into the sacral canal (n = 25), and Group 2 to receive the injection through a new method, i.e., injection right after penetrating the sacrococcygeal ligament (n = 24). Ultrasound was used to identify the sacral hiatus and to achieve accurate needle placement according to the allocated groups. Contrast dyed fluoroscopy was obtained to evaluate the epidural spread of injected materials and to monitor the possible complications.ResultsThe success rates of the caudal injections were 68.0% in Group 1 and 95.8% in Group 2 (P = 0.023). The incidences of intravascular injections were 24.0% in Group 1 and 0% in Group 2 (P = 0.022). No intrathecal injection was found in either of the two groups.ConclusionsThe new caudal epidural injection technique tested in this study is a reliable alternative, with a higher success rate and lower risk of accidental intravascular injection than the conventional technique.
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