Therapeutic Applications of Physalins: Powerful Natural Weapons

Abstract

Physalins, or 16,24-cyclo-13,14-seco steroids, are compounds belonging to the class of withanolides that can be found in plants of Solanaceae family, mainly in species belonging to the genus Physalis spp., which are annual herbaceous plants widely distributed in tropical and subtropical regions of the world. Physalins are versatile molecules that act in several cell signaling pathways and activate different mechanisms of cell death or immunomodulation. A number of studies have shown a variety of actions of these compounds, including anticancer, anti-inflammatory, antiparasitic, antimicrobial, antinociceptive, and antiviral activities. Here we reviewed the main findings related to the anticancer, immunomodulatory, and antiparasitic activities of physalins and its mechanisms of action, highlighting the \challenges and future directions in the pharmacological application of physalins.

Keywords: Physalis; Solanaceae; Withanolides; pharmacological properties; physalins.

FIGURE 1

The two subclasses of physalins. Physalins (Type I), in which C-14 is linked to C-17 through oxygen to form an acetal bridge, and neophysalins (Type II), in which C-14 is linked to C-16, while esterization of C-15/C-17 forms a lactone. The main differences between the two types are highlighted in blue.

FIGURE 2

Chemical structure of the physalins A, B, D, F, G, and H. The epoxy group of physalin F and the double bond for physalin B, which may contribute to the potent cytotoxic effect of these physalins, are highlighted in blue.

FIGURE 3

Main anti-inflammatory effects of physalins. In general, physalins suppress phosphorylation of iκB proteins and impair NF-κB translocation to the nucleus. NF-κB is involved in the regulation of several pro-inflammatory genes, and thus suppression of its activity by physalins results in inhibition of pro-inflammatory mediators, such as interleukins (IL)-1β, IL-6, IL-12, nitric oxide (NO), prostaglandin E₂ (PGE₂), and tumor necrosis factor (TNF). In addition, some physalins (such as physalin F and H) increase the production of IL-10, a well-known anti-inflammatory cytokine.

FIGURE 4

Cell death by apoptosis is induced by physalins through different pathways related to mitogen-activated protein kinase (MAPK). Physalins increase the phosphorylation levels of ERK1/2, JNK, and p38 MAPK. ERK1/2 activation induces mitochondrial ROS (mTOR) production, leading to the release of cytochrome c and activation of caspases 3, 6, and 9, triggering apoptosis. JNK activation promotes the phosphorylation of c-Jun, which leads to the formation of activator protein 1 (AP-1), a protein that regulates the transcription of pro-apoptotic factors and leads to apoptosis. P38 activation results in increase of ROS levels, which leads to p53 activation, which in turn increases the transcription of pro-apoptotic proteins, such as Noxa, BAX, and BAK, and decreases the transcription of the anti-apoptotic BCL-2 protein, leading to apoptosis through the mitochondrial pathway.

FIGURE 5

Mechanisms of action of physalins A, F, and H in aberrant signaling pathways. Physalin F inhibits Wnt/β-catenin signaling, accelerating the degradation of β-catenin and promoting the binding of YAP to the Axin, APC, CK1 and GSK-3β destruction complex. β-catenin phosphorylation facilitates its recognition by β-TrCP, leading to its degradation by the ubiquitin-dependent proteasome pathway. Physalin A inhibits the phosphorylation of the JAK receptor and the STAT3 protein, inhibiting their translocation to the nucleus and downstream Bcl-2 and XIAP transcription. Physalin H inhibits the Hedgehog pathway by suppressing Hh protein expression, impeding its binding to Hh-related proteins (PTCH) and inhibiting smoothened (SMO), which in turn allows the SUFU-containing GLI processing complex to generate transcriptional repressors, disrupting binding of GLI1 to its DNA binding domain and the non-expression of PTCH and Bcl-2.