The Effects of Artemisia Derived Natural Products on Adipogenesis

For the first time in human history, more people worldwide suffer from obesity than are undernourished. Numerous health complications are associated with obesity including cardiovascular disease, Type 2 Diabetes, cancers of reproductive tissues, stroke, depression, anxiety disorders, and Alzheimer’s disease. A deeper understanding of the anti-adipogenic effects and mechanism of action of sesquiterpene lactones may have pharmacological import in the continuing search for therapeutic modalities to ameliorate the effects of this global obesity epidemic. Dehydroleucodine (DhL), 11,13-dihydro-dehydroleucodine (DH-DhL), and dehydroparashin-B (DhP), sesquiterpene lactones extracted from or derived from compounds extracted from Artemisia douglasiana, were investigated for their anti-adipogenic effects on 3T1-L1 preadipocytes. Dehydroleucodine inhibited the expression of C/EBPa and PPARg, and also strongly blocked the expression of C/EBPβ, an early stage biomarker of early adipogenesis, in a concentration-dependent manner. Dehydroleucodine arrested the cell cycle at the G0/G1 phase, increased p27 and decreased both cyclins A and D and their partners (e.g., CDK2 and CDK4). Furthermore, DhL downregulated expression of histone demethylase JMJD2 as well as repressed the expression of histone methyltransferase MLL4, which in turn diminished the expression of C/EBPb and PPARg, respectively. 11,13-dihydro-dehydroleucodine blocked the accumulation of lipid droplets and inhibited the expression of PPARγ and C/EBPβ. Collectively, the results indicate that the inhibition of early stage preadipocyte differentiation by DH-DhL may be associated with cell cycle arrest at the G0/G1 phase. Dehydroparashin-B significantly decreased the accumulation of lipid content and downregulated the expression of CEBPβ, PPARγ and CEBPα as well as FAS. Interestingly, the addition of DhP inhibited the number as well as the size of the lipid droplets during the differentiation of 3T3-L1 preadipocytes. Taken together, this data suggests that DhP has an important inhibitory effect on cellular pathways regulating adipocyte differentiation

Visions of a Martian Future

As we look beyond our terrestrial boundary to a multi-planetary future for humankind, it becomes paramount to anticipate the challenges of various human factors on the most likely scenario for this future: permanent human settlement of Mars. Even if technical hurdles are circumvented to provide adequate resources for basic physiological and psychological needs, Homo sapiens will not survive on an alien planet if a dysfunctional psyche prohibits the utilization of these resources. No matter how far we soar into the stars, our psychologies for future generations will be forever tethered to the totality of our surroundings. By shaping our environment toward survival and welfare during the voyage to Mars and in a Martian colony, we indirectly shape our psyches and prepare them for a mission of unprecedented alienation and duration. Once on Mars, human factors such as leadership structure, social organization and code of conduct, group size, gender balance, developmental cycle, mobility, length of stay and the ecological settings and type and manner of subsistence, will create a novel Martian culture. The degree that settlers are severed from the Earth will affect how radically foreign this culture will be when compared with cultures on Earth

Biomedical properties of sesquiterpene lactones, with a focus on dehydroleucodine

Dehydroleucodine, a sesquiterpene lactone, belongs to the terpenoid class of secondary metabolites. Dehydroleucodine and other Artemisia-derivedphytochemicals evolved numerous biodefenses that were first co-opted for human pharmacological use by traditional cultures in the Middle East, Asia, Europeand the Americas. Later, these phytochemicals were modified through the use of medicinal chemical techniques to increase their potency. All sesquiterpenelactones contain an α-methylene-γ-lactone group, which confers thiol reactivity, which is responsible, in part, for their therapeutic effects. A wide range oftherapeutic uses of sequiterpene lactones has been found, including anti-adipogenic, cytoprotective, anti-microbial, anti-viral, anti-fungal, anti-malarial and,anti-migraine effects. Dehydroleucodine significantly inhibits differentiation of murine preadipocytes and also significantly decreases the accumulation oflipid content by a dramatic down regulation of adipogenic-specific transcriptional factors PPARγ and C-EBPα. Dehydroleucodine also inhibits secretion ofmatrix metalloprotease-2 (MMP-2), which is a known protease involved in migration and invasion of B16 cells. In addition to these anti-adipogenic and anticancereffects, dehydroleucodine effectively neutralizes several bacterial species, including Bacillus cereus, Staphylococcus aureus, Escherichia coli,Klebsiella pneumoniae, Helicobacter pylori, methicillin resistant Staphylococcus aueus (MRSA) and S. epidermis (MRSE). The compound also inhibits thegrowth and secretion of several toxins of Pseudomonas aeruginosa, possesses gastro-protective qualities and possesses anti-parasitic properties againstTrypanosoma cruzi, responsible for Chagas disease. Other sesquiterpene lactones, such as parthenolide, costunolide, and helanin, also possess significanttherapeutic utility.Fil: Abood, Steven. Florida International University; Estados UnidosFil: Mustafi, Sushmita. Florida International University; Estados UnidosFil: Veisaga, Maria-Luisa. Florida International University; Estados UnidosFil: Lopez, Luis Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Barbieri, Manuel Alejandro. Fairchild Tropical Botanic Garden; Estados Unido

Activation of G-proteins in brain by endogenous and exogenous cannabinoids

The biological response to cannabinoid agonist begins when the agonist-bound receptor activates G-protein Gα subunits, thus initiating a cascade of signal transduction pathways. For this reason, information about cannabinoid receptors/G-protein coupling is critical to understand both the acute and chronic actions of cannabinoids. This review focuses on these mechanisms, predominantly examining the ability of cannabinoid agonists to activate G-proteins in brain with agonist-stimulated [35S]guanylyl-5′-O-(γ-thio)-triphosphate ([35S]GTPγS) binding. Acute efficacies of cannabinoid agonists at the level of G-protein activation depend not only on the ability of the agonist to induce a high affinity state in Gα for GTP, but also to induce a low affinity for GDP. When several agonists are compared, it is clear that cannabinoid agonists differ considerably in their efficacy. Both WIN 55212-2 and levonantradol are full agonists, while Δ9 is a weak partial agonist. Of interest, anandamide and its stable analog methanand amide are partial agonists. Chronic treatment in vivo with cannabinoids produces significant tolerance to the physiological and behavioral effects of these drugs, and several studies have shown that this is accompanied by a significant loss in the ability of cannabinoid receptors to couple to G-proteins in brain. These effects vary across different brain regions and are usually (but not always) accompanied by loss of cannabinoid receptor binding. Although the relationship between cannabinoid receptor desensitization and tolerance has not yet been established, these mechanisms may represent events that lead to a loss of cannabinoid agonist response and development of tolerance