Targeting mitochondria: Novel concepts for mechanisms underlying therapeutic effects of Cimicifuga racemosa and Petasites hybridus extracts

The Cimicifuga racemosa extract Ze 450 is produced by a standardized procedure and well-established in the treatment of menopausal complaints; however, the underlying mechanism of action has not been clarified. In a recent study, Ze 450 mediated beneficial effects on glucose tolerance, insulin sensitivity and weight gain in diabetic ob/ob mice and on weight gain in a clinical study investigating therapeutic effects of Ze 450 on climacteric symptoms in menopausal women. Therefore, it was of great interest to study the effects of Ze 450 on cell metabolism in more detail. To address this issue, Ze 450 was exposed to neuronal and liver cells alone, and in model systems of oxidative stress, since an imbalance in redox homeostasis was shown to be crucially involved in the pathogenesis of many age-related diseases, including, for example, diabetes mellitus type II, and further provides a molecular link towards menopause. In this context, a new concept of menopause is hypothesized, implying age-related metabolic disturbances rather than exclusively focusing on estrogen depletion. This study revealed that Ze 450 mediated remarkable effects on metabolism by reducing metabolic activity and the rate of cell proliferation in various cell types. Furthermore, it was demonstrated that Ze 450 provided protection against erastin- and glutamate-mediated oxidative cytotoxicity in neuronal and liver cells. Notably, the findings on liver cells clearly demonstrated, that Ze 450 is rather protective than causing hepatotoxicity. Additionally, Ze 450 preserved mitochondrial integrity and function, while under oxidative challenge, Ze 450 prevented mitochondrial impairments by protecting against erastin- and glutamate-mediated lipid-peroxidation, mitochondrial ROS formation, loss of mitochondrial membrane potential and ATP depletion. Ze 450 exerted beneficial effects by directly inhibiting mitochondrial respiration and, thereby, reducing mitochondrial superoxide production. Moreover, Ze 450 preserved the energy supply of the cell by metabolic reprogramming towards glycolysis. In this context, it was demonstrated that a regulation of HIF1α and cMyc most likely contributed to the metabolic shift by enhancing the protein expression of key glycolytic enzymes. Further, it was demonstrated that Ze 450 enhanced glucose uptake to maintain cellular energy homeostasis by promoting glycolysis. These results demonstrated that Ze 450 affects energy metabolism by direct inhibition of mitochondrial respiration and metabolic reprogramming towards glycolysis, supporting a novel therapeutic concept describing Ze 450 as a metabolic regulator. Ze 450 is a plant extract, which consists of many different components. In former studies, triterpene glycosides were identified as active ingredients, but in neuronal cells, the isolated components (actein, 23-epi-26-deoxyactein, cimiracemoside C) were not able to mediate effects comparable to Ze 450. Nevertheless, sub-fractions of Ze 450 were investigated and the EtOAc fraction turned out to act in a similar manner like Ze 450, but the effective concentrations were higher than contained in 100 µg/mL of Ze 450. Besides triterpene glycosides, Ze 450 also contains phenolic acids that mediate antioxidant effects. Indeed, Ze 450 showed moderate antioxidant properties compared to Trolox but this antioxidant effect is not mainly contributing to the observed protection by Ze 450. Taken together, Ze 450 offers promising therapeutic potential in diseases involving mitochondrial damage and increased ROS formation and provides first evidence for a novel mechanism of action involving metabolic reprogramming, which highlights a new perspective on menopausal transition. Besides Ze 450, a special extract of Petasites hybridus was investigated in the model systems of ferroptosis. Ze 339 is a CO2 extract obtained from leaves of Petasites hybridus and is used to treat seasonal allergic rhinitis. In this study, Ze 339 was investigated in order to specify its mechanism of action and assess its potential protective effects against oxidative damage in HT22 neuronal cells. Ze 339 induced mild ROS formation produced by lipid-peroxidation and by mitochondria but did not impair cell viability at concentrations up to 50 µg/mL of Ze 339. In the context of mitohormesis, Ze 339 might provide protection against mitochondrial impairment by a mild increase in ROS. Moreover, Ze 339 protected against erastin- mediated cytotoxicity and mitochondrial impairment in HT22 neuronal cells. In conclusion, it is hypothesized that Ze 339 provides mitochondrial resilience by a mild increase in ROS formation leading to beneficial metabolic adaptions or responses to allergens. In this study, it was demonstrated that (mito-) hormetic regulation processes might contribute to symptom relief of allergic rhinitis