Silibinin Inhibits LPS-Induced Macrophage Activation by Blocking p38 MAPK in RAW 264.7 Cells

We demonstrate herein that silibinin, a polyphenolic flavonoid compound isolated from milk thistle (Silybum marianum), inhibits LPS-induced activation of macrophages and production of nitric oxide (NO) in RAW 264.7 cells. Western blot analysis showed silibinin inhibits iNOS gene expression. RT-PCR showed that silibinin inhibits iNOS, TNF-alpha, and IL1beta. We also showed that silibinin strongly inhibits p38 MAPK phosphorylation, whereas the ERK1/2 and JNK pathways are not inhibited. The p38 MAPK inhibitor abrogated the LPS-induced nitrite production, whereas the MEK-1 inhibitor did not affect the nitrite production. A molecular modeling study proposed a binding pose for silibinin targeting the ATP binding site of p38 MAPK (1OUK). Collectively, this series of experiments indicates that silibinin inhibits macrophage activation by blocking p38 MAPK signaling.

Radicicol Inhibits iNOS Expression in Cytokine-Stimulated Pancreatic Beta Cells

Here, we show that radicicol, a fungal antibiotic, resulted in marked inhibition of inducible nitric oxide synthase (iNOS) transcription by the pancreatic beta cell line MIN6N8a in response to cytokine mixture (CM: TNF-alpha, IFN-gamma, and IL-1beta). Treatment of MIN6N8a cells with radicicol inhibited CM-stimulated activation of NF-kappaB/Rel, which plays a critical role in iNOS transcription, in a dose-related manner. Nitrite production in the presence of PD98059, a specific inhibitor of the extracellular signal-regulated protein kinase-1 and 2 (ERK1/2) pathway, was dramatically diminished, suggesting that the ERK1/2 pathway is involved in CM-induced iNOS expression. In contrast, SB203580, a specific inhibitor of p38, had no effect on nitrite generation. Collectively, this series of experiments indicates that radicicol inhibits iNOS gene expression by blocking ERK1/2 signaling. Due to the critical role that NO release plays in mediating destruction of pancreatic beta cells, the inhibitory effects of radicicol on iNOS expression suggest that radicicol may represent a useful anti-diabetic activity.

Hyperhomocysteinemia and Cerebrovascular Diseases in Koreans

BACKGROUND: Hyperhomocysteinemia as a risk factor for cerebrovascular disease is well known. Our aim of this study was to demonstrate positive association between elevated homocysteine levels and cerebrovascular diseases in Koreans. METHODS: With a case-control design, 186 stroke (infarction 134, hemorrhage 52) patients, diagnosed by brain CT or MRI and 359 control patients were evaluated. We used multiple logistic regression analyses conditioned on the matching variables (sex, age, hypertension, DM, smoking, hyperlipidemia, hyperhomocysteinemia) and calculated odds ratio and 95% CIs. RESULTS: Multivariated adjusted odds ratios (OR) for cerebrovascular diseases associated with hypertension compared with normal blood pressure were 2.45 (95% CI, 1.16 to 5.15) in prehypertension and 3.33 (95% CI, 1.56 to 7.10) in stage 1 hypertension and 3.77 (95% CI, 1.32 to 10.74) in stage 2 hypertension. OR for cerebrovascular diseases associated with hyperhomocysteinemia compared with or =17 micromol/L. CONCLUSION: Not only hypertension but also hyperhomocysteinemia was a significant risk factor for cerebrovascular diseases in Koreans.

A Study of Anger, Alexithymia, and Depression in the Functional Dyspepsia

BACKGROUND: Functional dyspepsia (FD) is a commonly encountered disturbance of gut function and has been shown to be associated with psychological disturbance such as depression and anxiety. Of particular importance to clinicians are the relationship between anger, alexithymia, and depression. In this study, we investigated anger, alexithymia, and depression in patients with functional dyspepsia. METHODS: Thirty patients who visited Wonkwang University Hospital from January 2001 to June 2001, were diagnosed with functional dyspepsia by a gastroenterologist and compared with 37 healthy control group. Medical investigation of FD including gastrofiberscopy, esophageal manometry, and ambulatory 24-hours intraesophageal reflux test were negative. All subjects were evaluated for depression, anxiety, anger and anger expression, and alexithymia. The measures included Beck Depression Inventory (BDI), Spielberger State-Trait Anxiety Inventory (STAI), Spielberger State-Trait Anger Expression Scale (STAXI), and Toronto Alexithymia Scale (TAS). RESULTS: The FD patients reported significantly more symptoms of depression, more difficulty describing feeling to others in TAS, less anger-in and anger-out expression in STAXI than the control subjects. Depressive symptoms in FD were positively correlated with state anxiety, trait anxiety, alexithymia, state anger, trait anger, and anger-in expression. In multiple regression model, state anger and trait anxiety together accounted for 69.1% of the depression in FD. CONCLUSION: The FD patients reported more depressive symptoms, and the depressive symptoms were related to anxiety, anger and anger-in, and alexithymia. These finding lend support that FD is a syndrome in which biopsychosocial process and affect dysregulation may play a role in features of FD.