Attenuation of Age-Related Metabolic Dysfunction in Mice With a Targeted Disruption of the Cβ Subunit of Protein Kinase A

The cyclic adenosine monophosphate–dependent protein kinase A (PKA) pathway helps regulate both cell growth and division, and triglyceride storage and metabolism in response to nutrient status. Studies in yeast show that disruption of this pathway promotes longevity in a manner similar to caloric restriction. Because PKA is highly conserved, it can be studied in mammalian systems. This report describes the metabolic phenotype of mice lacking the PKA catalytic subunit Cβ. We confirmed that Cβ has high levels of expression in the brain but also showed moderate levels in liver. Cβ-null animals had reduced basal PKA activity while appearing overtly normal when fed standard rodent chow. However, the absence of Cβ protected mice from diet-induced obesity, steatosis, dyslipoproteinemia, and insulin resistance, without any differences in caloric intake or locomotor activity. These findings have relevant pharmacological implications because aging in mammals is characterized by metabolic decline associated with obesity, altered body fat distribution, and insulin resistance

Aldisine alkaloids from the Philippine sponge Stylissa massa are potent inhibitors of mitogen-activated protein kinase kinase-1 (MEK-1)

Raf/MEK-1/MAPK cascade inhibitor activity-directed fractionation of the sponge Stylissa massa afforded eight known alkaloids:  aldisine (1), 2-bromoaldisine (2), 10Z-debromohymenialdisine (3), 10E-hymenialdisine (4), 10Z-hymenialdisine (5), hymenin (6), oroidin (7), and 4,5-dibromopyrrole-2-carbonamide (8). Both 4 and 5 showed significant enzyme inhibitory activity (IC50 3 and 6 nM, respectively). Secondary assays identified these compounds as potent MEK-1 inhibitors. Compounds 4 and 5 also inhibited the growth of human tumor LoVo cells

Microcionamides A and B, bioactive peptides from the Philippine sponge Clathria (Thalysias) abietina

Microcionamides A (1) and B (2) have been isolated from the Philippine marine sponge Clathria (Thalysias) abietina. These new linear peptides are cyclized via a cystine moiety and have their C-terminus blocked by a 2-phenylethylenamine group. Their total structures, including absolute stereochemistry, were determined by a combination of spectral and chemical methods. Compound 1 was shown to slowly isomerize about the C-36/C-37 double bond when stored in DMSO. Microcionamides A (1) and B (2) exhibited significant cytotoxicity against the human breast tumor cells lines MCF-7 and SKBR-3 and displayed inhibitory activity against Mycobacterium tuberculosis H37Ra