As a promiscuous xenobiotic sensor, pregnane X receptor (PXR) plays a crucial role in drug metabolism. Since dietary phytochemicals exhibit the potential to modulate human PXR, this review aims to summarize the plant-derived PXR modulators, including agonists, partial agonists, and antagonists. The crystal structures of the apo and ligand-bound forms of PXR especially that of PXR complexed with binary mixtures are summarized, in order to provide the structural basis for PXR binding promiscuity and synergistic activation of PXR by composite ligands. Furthermore, this review summarizes the characterized agonists, partial agonists, and antagonists of human PXR from botanical source. Contrary to PXR agonists, there are only a few antagonists obtained from botanical source due to the promiscuity of PXR. It is worth noting that trans-resveratrol and a series of methylindoles have been identified as partial agonists of PXR, both in activating PXR function, but also inhibiting the effect of other PXR agonists. Since antagonizing PXR function plays a crucial role in the prevention of drug-drug interactions and improvement of therapeutic efficacy, further research is necessary to screen more plant-derived PXR antagonists in the future. In summary, this review may contribute to understanding the roles of phytochemicals in food-drug and herb-drug interactions.

Dietary phytochemicals as modulators of human pregnane X receptor

Drug resistance represents a major obstacle in cancer management, and the mechanisms underlying stress adaptation of cancer cells in response to therapy-induced hostile environment are largely unknown. As the central organelle for cellular energy supply, mitochondria can rapidly undergo dynamic changes and integrate cellular signaling pathways to provide bioenergetic and biosynthetic flexibility for cancer cells, which contributes to multiple aspects of tumor characteristics, including drug resistance. Therefore, targeting mitochondria for cancer therapy and overcoming drug resistance has attracted increasing attention for various types of cancer. Multiple mitochondrial adaptation processes, including mitochondrial dynamics, mitochondrial metabolism, and mitochondrial apoptotic regulatory machinery, have been demonstrated to be potential targets. However, recent increasing insights into mitochondria have revealed the complexity of mitochondrial structure and functions, the elusive functions of mitochondria in tumor biology, and the targeting inaccessibility of mitochondria, which have posed challenges for the clinical application of mitochondrial-based cancer therapeutic strategies. Therefore, discovery of both novel mitochondria-targeting agents and innovative mitochondria-targeting approaches is urgently required. Here, we review the most recent literature to summarize the molecular mechanisms underlying mitochondrial stress adaptation and their intricate connection with cancer drug resistance. In addition, an overview of the emerging strategies to target mitochondria for effectively overcoming chemoresistance is highlighted, with an emphasis on drug repositioning and mitochondrial drug delivery approaches, which may accelerate the application of mitochondria-targeting compounds for cancer therapy. 

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Mitochondrial adaptation in cancer drug resistance: prevalence, mechanisms, and management

As a natural dietary ingredient, berberine possesses multiple biological activities including anti-inflammatory effects. In this work, glucocorticoid receptor (GR)-mediated alleviation of inflammation by berberine was investigated by a combination of in vitro, in silico, and in vivo approaches. The fluorescence polarization assay showed that berberine bound to GR with an IC50 value of 9.14 ± 0.16 pM. Molecular docking and molecular dynamics simulation suggested that berberine bound stably to the active site of GR via hydrogen bonding and hydrophobic interactions. Berberine induced GR nuclear translocation but did not activate the glucocorticoid response element in HeLa cells. Furthermore, both gene and protein expressions of PEPCK were significantly attenuated by berberine in HepG2 cells. Interestingly, berberine downregulated CBG mRNA and protein levels without up-regulating TAT mRNA and protein levels in HepG2 cells, demonstrating its dissociated characteristics that could separate transrepression from transactivation. In addition, the in vitro and in vivo anti-inflammatory effects of berberine were confirmed in lipopolysaccharide-induced RAW 264.7 cells and in a mouse model of allergic contact dermatitis, respectively. In conclusion, berberine might serve as a potential selective GR modulator.

Glucocorticoid receptor-mediated alleviation of inflammation by berberine: in vitro, in silico and in vivo investigations.

Synergism of ellagic acid in combination with radiotherapy and chemotherapy for cancer treatment.

Ischemic stroke (IS) is characterized by high recurrence and disability; however, its therapies are very limited. As one of the effective methods of treating acute attacks of IS, intravenous thrombolysis has a clear time window. Quercetin, a flavonoid widely found in vegetables and fruits, inhibits immune cells from secreting inflammatory cytokines, thereby reducing platelet aggregation and limiting inflammatory thrombosis. In pre-clinical studies, it has been shown to exhibit neuroprotective effects in patients with ischemic brain injury. However, its specific mechanism of action remains unknown. Therefore, this review aims to use published data to elucidate the potential value of quercetin in patients with ischemic brain injury. This article also reviews the plant sources, pharmacological effects, and metabolic processes of quercetin in vivo, thus focusing on its mechanism in inhibiting immune cell activation and inflammatory thrombosis as well as promoting neuroprotection against ischemic brain injury.

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Rajamanikkam Kamaraj

Papers

A review on pharmacological activities and synergistic effect of quercetin with small molecule agents.

Dietary phytochemicals as modulators of human pregnane X receptor