AMPK Activation by Cimicifuga racemosa Extract Ze 450 Is Associated with Metabolic Effects and Cellular Resilience against Age-Related Pathologies in Different Tissue Cell Types.

Cimicifuga racemosa extracts (CREs) have gained well-established use for the treatment of menopausal symptoms such as hot flushes and excessive sweating, and weight gain. While the clinical effects of CREs have been well documented, the mechanisms underlying these effects are largely unknown. More recently, the metabolic effects of the CRE Ze 450 were demonstrated in cultured cells in vitro and in mouse models of obesity in vivo. At the molecular level, metabolic regulation, enhanced insulin sensitivity, and increased glucose uptake were linked to the activation of AMP-activated protein kinase (AMPK). Therefore, we tested the effects of Ze 450 on AMPK phosphorylation and thus activation in cells from different tissues, i.e., murine C2C12 myoblast cells, human HEPG2 liver cells, mouse HT22 neuronal cells, and in murine 3T3L1 adipocytes. Using a FRET-based HTRF-assay, we found that Ze 450 induced AMPK phosphorylation and the activation of this key enzyme of metabolic regulation in cells from various different tissues including C2C12 (muscle), HEPG2 (liver), HT22 (hippocampal), and 3T3-L1 (adipocyte) cells. In C2C12 muscle cells, enhanced AMPK activation was accompanied by reduced mitochondrial respiration and enhanced glucose uptake. Further, Ze 450 enhanced the resilience of the cells against oxidative death induced by ferroptosis inducers erastin or RSL3. Our findings suggest a general effect of Cimicifuga racemosa on AMPK activation in different tissues and across species. This may have a significant impact on expanded therapeutic applications of Ze 450, since AMPK activation and the related metabolic effects have been previously associated with anti-aging effects and the prevention of the metabolic syndrome.

Novel anti-viral therapy: drugs that block HIV entry at different target sites.

Drugs that block the entry of human immunodeficiency virus type 1 (HIV-1) into host cells abrogate the establishment of a productive infection and should ideally diminish the chances of HIV-1 developing resistance. This review will give an overview of the mechanism by which the envelope glycoprotein mediates HIV-1 entry and will summarize current drug developments.

Modulation of catecholamine release from rat striatal slices by the fixed combination of aspirin, paracetamol and caffeine.

The fixed combination of aspirin, paracetamol (acetaminophen) and caffeine has been used successfully to treat different kinds of pain including migraine attacks. Even when this formulation has been marketed for a long time, the exact molecular mechanisms underlying its therapeutic effectiveness have not been completely elucidated. In the present investigation, we have studied the effects of the fixed combination of aspirin, paracetamol and caffeine (APC) on the release of dopamine and noradrenaline from rat striatal slices in an attempt to find potential new mechanisms of action of this widely used analgesic combination. We found that APC produced a significant reduction in extracellular dopamine and a dramatic increase in norepinephrine release from the slices incubated with different concentrations of APC (dose relationship 1:1:0.2, corresponding to the dose-relationship of Thomapyrin). These findings suggest that the modulation of catecholaminergic neurotransmission is a new pharmacological effect of APC which could explain the mechanism of action of this formulation, considering that the independent effect of either compound alone does not explain the potent antinociceptive properties when observed in combination.

Quantitative measurement of depolarization-induced anandamide release in human and rat neocortex.

It has been suggested that the endocannabinoid anandamide is released from central neurons upon depolarization of the cell membrane. In order to determine whether anandamide levels were increased after K(+) depolarization of fresh human and rat brain slices, we developed a rapid and sensitive method for the isolation and quantitation of anandamide. This included solvent extraction, solid phase separation, and reversed phase high performance liquid chromatography (HPLC) with fluorometric detection. Compared with basal levels, K(+) stimulation enhanced the neocortical anandamide concentration in both species (70.5 vs. 21.1 pmol/g tissue in humans, 14.3 vs. 3.2 pmol/g tissue in rats). Basal anandamide levels in the rat hippocampus (11.1 pmol/g) were significantly higher than in the neocortex. Anandamide was also detected in the human amygdala (67.8 pmol/g). In conclusion, our data provide evidence for the depolarization-induced synthesis of anandamide, supporting the hypothesis of a neuromodulatory action of this endocannabinoid. Furthermore, the presence of anandamide in the limbic system suggests participation in cognition, behavior or reward.