Identification of novel benzimidazole derivatives as highly potent AMPK activators with anti-diabetic profiles.

Diabetes is a global healthcare problem that affects more than 400 million people worldwide. Treatment for type 1 and 2 diabetes is expected by targeting adenosine monophosphate activated protein kinase, AMPK, a well-known master regulator of glucose. Many pharmaceutical companies have tried to identify AMPK activators but few direct AMPK activators with high potency for the ß2-AMPK isoform, which is important for glucose homeostasis, have been found. In addition, their chemical structure is limited to benzimidazole or indole derivatives bearing an aromatic substituent at the C5 position of the core structure. We describe herein our efforts to identify novel benzimidazole derivatives that directly activate the ß2-AMPK isoform. Our newly designed activator 14d bearing a 1-amino indanyl moiety at the C5 position of the core exhibited high in vitro potency and good pharmacokinetic profiles. A single oral dosing of 14d showed dose-dependent activation of AMPK and blood-glucose-lowering effects was observed in a diabetic animal model. In addition, chronic AMPK activation with 14d led to dose-dependent reduction in HbA1c of the animal model.

CT Hounsfield Unit Is a Good Predictor of Growth in Meningiomas.

Predicting the growth rate of meningiomas is important in treatment planning. Although calcification may be an important sign of slow growth in meningiomas, the developmental process and its relation to the tumor growth pattern have not been elucidated. We retrospectively examined the location and degree of calcification in 150 meningiomas (131 asymptomatic tumors) using computed tomography (CT) scans and mean Hounsfield units (mHU). Tumor growth was evaluated using serial imaging studies wherein we calculated tumor doubling time (Td) and identified the growth curve pattern as exponential, intermediate, or decelerating. Tumors in women more frequently had calcification and showed higher mHU than those in men. The mHU was measured at least twice in 57 tumors. Tumors in women showed greater mHU increases than those in men. We found a significant correlation between Td and mHU (R = 0.49). Tumors in men and those in patients in the younger age group grew significantly faster. Multivariate analysis revealed that mHU was the only significant factor affecting Td (P <0.0001). The growth pattern was significantly related to calcification (n = 61, P = 0.0042). Tumors with decelerating growth more frequently showed calcification and had higher mHU than those with exponential growth. Receiver operating characteristic curve analysis revealed that mHU was a better predictor of growth pattern change compared with calcification on CT scan. Meningiomas with high mHU, even without calcification, were likely to show growth deceleration. Mean Hounsfield unit correlated with Td and may be a good quantitative indicator of the growth rate and pattern.

Cadmium activates extracellular signal-regulated kinase 5 in HK-2 human renal proximal tubular cells.

We examined the effects of cadmium chloride (CdCl(2)) exposure on the phosphorylation and functionality of extracellular signal-regulated kinase 5 (ERK5), a recently identified member of the mitogen-activated protein kinase (MAPK) family, in HK-2 human renal proximal tubular cells. Following exposure to CdCl(2), ERK5 phosphorylation increased markedly, but the level of total ERK5 was unchanged. ERK5 phosphorylation following CdCl(2) exposure was rapid and transient, similar to the time course of ERK1/2 phosphorylation. Treatment of HK-2 cells with the MAPK/ERK kinase 5 inhibitor, BIX02189, suppressed CdCl(2)-induced ERK5 but not ERK1/2 phosphorylation. The CdCl(2)-induced increase of phosphorylated cAMP response element-binding protein (CREB) and activating transcription factor-1 (ATF-1), as well as the accumulation of mobility-shifted c-Fos protein, were suppressed by BIX02189 treatment. Furthermore, BIX02189 treatment enhanced cleavage of poly(ADP-ribose) polymerase and increased the level of cytoplasmic nucleosomes in HK-2 cells exposed to CdCl(2). These findings suggest that ERK5 pathway activation by CdCl(2) exposure might induce the phosphorylation of cell survival-transcription factors, such as CREB, ATF-1, and c-Fos, and may exert a partial anti-apoptotic role in HK-2 cells.

Intracranial localized Castleman's disease. Case report.

A 68-year-old woman presented with generalized clonic seizure following a 2-month history of initiative loss, incoherent speech, headache, and left hemiparesis. No systemic signs or symptoms were seen and laboratory studies were within normal range. Computed tomography and magnetic resonance imaging demonstrated a well-delineated small mass with homogeneous enhancement in the right parietal convexity, associated with unusually extensive perifocal edema compared to the size of the mass. Cerebral angiography showed a faint stain fed by the middle meningeal artery. These imaging features were very similar to those of meningioma. Full recovery from the symptoms was achieved by total removal of the lesion and no recurrence was found after 3 years. Histological examination identified the hyaline-vascular type of angiofollicular lymph node hyperplasia (Castleman's disease). Castleman's disease involving the central nervous system is rare, with only 12 previous cases, but should be considered in the diagnosis of intracranial meningeal tumors. The treatment of choice for localized Castleman's disease is complete surgical resection, which is curative in most of the cases.