Estrogen receptor-mediated health benefits of phytochemicals: a review.

Estrogen receptors (ERs) are transcription factors with two subtypes: estrogen receptor alpha (ERα) and estrogen receptor beta (ERß), which are essential for the maintenance of human health and play a regulatory role in common diseases such as breast cancer, osteoporosis, neurodegenerative disorders, liver injuries and lung cancers. A number of phytochemicals extracted from various fruits and vegetables have been demonstrated to exhibit estrogenic effects and are termed phytoestrogens. As modulators of ERs, phytoestrogens can be involved in the prevention and treatment of multiple diseases as complementary or alternative therapeutic agents and have a variety of health benefits for humans. This article reviews the health benefits of phytoestrogens in clinical and epidemiologic studies for several diseases and also provides a detailed description of the molecular mechanisms of their action. A brief comparison of the advantages and disadvantages of natural phytochemicals compared to synthetic drugs is also presented. The role of phytoestrogens in the treatment of diseases and human health requires further research to fully realize their therapeutic potential.

Nuclear Receptors-Mediated Endocrine Disrupting Effects of Non-Phthalate Plasticizers: A Review.

In 2021, the global market for non-phthalate plasticizers reached $3.1 billion, and it is projected to grow by 25.8% by 2025. These plasticizers have gained substantial attention as substitutes for phthalates in various industrial applications due to their potential health and environmental risks, particularly in agroecosystems where they have emerged as contaminants. Furthermore, recent studies have demonstrated that non-phthalate plasticizers can exert endocrine-disrupting effects through mechanisms mediated by nuclear receptors. This review aims to summarize the present understanding of the molecular mechanisms by which non-phthalate plasticizers modulate the activity of nuclear receptors, including estrogen receptor, androgen receptor, glucocorticoid receptor, and peroxisome proliferator-activated receptors. Furthermore, the potential health impacts of exposure to conventional phthalate plasticizers are discussed, with a particular emphasis on developmental and reproductive toxicity, metabolic disorders, and carcinogenesis. Overall, this review underscores the significance of evaluating the endocrine-disrupting effects of non-phthalate plasticizers and lays the foundation for the development of safer alternatives within the plastic industry.

In vitro and in silico assessment of endocrine disrupting effects of food contaminants through pregnane X receptor.

As a promiscuous xenobiotic receptor, pregnane X receptor (PXR) has been confirmed to participate in numerous physiological process. In addition to the conventional estrogen/androgen receptor, PXR also serves as an alternative target for environmental chemical contaminants. In this work, the PXR-mediated endocrine disrupting effects of typical food contaminants were explored. Firstly, the time-resolved fluorescence resonance energy transfer assays confirmed the PXR binding affinities of 2,2',4,4',5,5'-hexachlorobiphenyl, bis(2-ethylhexyl) phthalate, dibutyl phthalate, chlorpyrifos, bisphenol A, and zearalenone, with IC50 values ranging from 1.88 to 4284.00 nM. Then their PXR agonist activities were assessed by PXR-mediated CYP3A4 reporter gene assays. Subsequently, the regulation of gene expressions of PXR and its targets CYP3A4, UGT1A1, and MDR1 by these compounds was further investigated. Intriguingly, all the tested compounds interfered with these gene expressions, confirming their endocrine disrupting effects via PXR-mediated signaling. The compound-PXR-LBD binding interactions were explored by molecular docking and molecular dynamics simulations to unravel the structural basis of their PXR binding capacities. The weak intermolecular interactions are key players in stabilizing these compound-PXR-LBD complexes. During the simulation process, 2,2',4,4',5,5'-hexachlorobiphenyl remained stable while the other 5 compounds underwent relatively severe disturbances. In conclusion, these food contaminants might exhibit endocrine disrupting effects via PXR.

Characterization of tangeretin as an activator of nuclear factor erythroid 2-related factor 2/antioxidant response element pathway in HEK293T cells.

Numerous studies have reported that tangeretin is a polymethoxylated flavone with a variety of biological activates, but little research has been done on the antioxidant mechanism of tangeretin. Hence, we investigated the effect of tangeretin on the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway and its potential molecular mechanisms by in vitro and in silico research. The results of molecular docking suggested that tangeretin bound at the top of the central pore of Kelch-like ECH-associated protein 1 (Keap1) Kelch domain, and the hydrophobic and hydrogen bond interactions contributed to their stable binding. Herein, the regulation of Nrf2-ARE pathway by tangeretin was explored in the human embryonic kidney cell line HEK293T, which is relatively easy to be transfected. Upon binding to tangeretin, Nrf2 translocated to the nucleus of HEK293T cells, which in turn activated the Nrf2-ARE pathway. Luciferase reporter gene analysis showed that tangeretin significantly induced ARE-mediated transcriptional activation. Real-time PCR and Western blot assays showed that tangeretin induced the gene and protein expressions of Nrf2-mediated targets, including heme oxygenase 1 (HO-1), nicotinamide adenine dinucleotide phosphate (NADPH) quinone dehydrogenase 1 (NQO1), and glutamate-cysteine ligase (GCLM). In addition, tangeretin could effectively scavenge 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radicals. In summary, tangeretin may be a potential antioxidant via activating the Nrf2-ARE pathway.

Spatiotemporally Targeted Polypeptide Nanoantidotes Improve Chemotherapy Tolerance of Cisplatin.

The toxicity of drugs causes various adverse effects in patients. While antidotes that neutralize drug toxicity help reduce systemic damage during clinical therapy, these antidotes are generally accompanied by the loss of drug efficacy. Herein, the spatiotemporally targeted polycystine-based nanoantidotes were designed as a neutralizer of cisplatin (CDDP) to decrease its toxicity without affecting its anticancer efficacy. The nanoantidotes administered before CDDP selectively accumulated in the liver and kidney and then firmly bound to CDDP through the highly stable Pt-S bond during subsequent chemotherapy. This two-step administration strategy reduced the level of Pt in normal organs, shortened the half-life of CDDP in plasma, and increased the tolerance to CDDP. More importantly, the nanoantidotes maintained the anticancer efficacy of CDDP after reducing systemic toxicity, indicating its great potential in expanding the clinical application of CDDP.

Recent advances in nuclear receptors-mediated health benefits of blueberry.

BACKGROUND: Blueberry is rich in bioactive substances and has anti-oxidant, anti-inflammatory, anti-obesity, anti-cancer, neuroprotective, and other activities. Blueberry has been shown to treat diseases by mediating the transcription of nuclear receptors. However, evidence for nuclear receptor-mediated health benefits of blueberry has not been systematically reviewed. PURPOSE: This review aims to summarize the nuclear receptor-mediated health benefits of blueberry. METHODS: This study reviews all relevant literature published in NCBI PubMed, Scopus, Web of Science, and Google Scholar by January 2022. The relevant literature was extracted from the databases with the following keyword combinations: "biological activities" OR "nuclear receptors" OR "phytochemicals" AND "blueberry" OR "Vaccinium corymbosum" as well as free-text words. RESULTS: In vivo and in vitro experimental results and clinical evidence have demonstrated that blueberry has health-promoting effects. Supplementing blueberry is beneficial to the treatment of cancer, the alleviation of metabolic syndrome, and liver protection. Blueberry can regulate the transcription of PPARs, ERs, AR, GR, MR, LXRs, and FXR and mediate the expressions of Akt, CYP 1Al, p53, and Bcl-2. CONCLUSION: Blueberry can be targeted to treat various diseases by mediating the transcription of nuclear receptors. Nevertheless, further human research is needed.

Identification of 20(S)-Ginsenoside Rh2 as a Potential EGFR Tyrosine Kinase Inhibitor.

As the main active ingredients of Panax ginseng, ginsenosides possess numerous bioactivities. Epidermal growth factor receptor (EGFR) was widely used as a valid target in anticancer therapy. Herein, the EGFR targeting activities of 20(S)-ginsenoside Rh2 (20(S)-Rh2) and the relationship of their structure-activity were investigated. Homogeneous time-resolved fluorescence assay showed that 20(S)-Rh2 significantly inhibited the activity against EGFR kinase. 20(S)-Rh2 was confirmed to effectively inhibited cell proliferation in a dose-dependent manner by MTT assay. Furthermore, quantitative real-time PCR and western blotting analysis revealed that 20(S)-Rh2 inhibited A549 cells growth via the EGFR-MAPK pathway. Meanwhile, 20(S)-Rh2 could promote cell apoptosis, block cell cycle, and reduce cell migration of A549 cells, respectively. In silico, the result suggested that both hydrophobic interactions and hydrogen-bonding interactions could contribute to stabilize their binding. Molecular dynamics simulation showed that the side chain sugar moiety of 20(S)-Rh2 was too flexible to be fixed at the active site of EGFR. Collectively, these findings suggested that 20(S)-Rh2 might serve as a potential EGFR tyrosine kinase inhibitor.

In vitro and in silico evaluation of EGFR targeting activities of curcumin and its derivatives.

As polyphenols from Curcuma longa, curcumin and its derivatives possess numerous bioactivities. Herein, the epidermal growth factor receptor (EGFR) targeting activities of curcumin and its derivatives, as well as their structure-activity relationship were investigated. All of the tested compounds exhibited significant inhibition activities against EGFR kinase in homogeneous time-resolved fluorescence assay. Then their antiproliferative activities against Caco-2 were confirmed. The expressions of EGFR and phospho-EGFR proteins were regulated by curcumin and its derivatives. The 3,5-dione and methoxyl groups exerted significant influence on their electrostatic interactions with EGFR. Both hydrogen bonds and hydrophobic contacts were crucial for their binding with EGFR. Interestingly, their EGFR targeting activities were structure-dependent. The binding stabilities of curcumin and its derivatives were different from each other due to their structural diversity. This work indicated that curcumin and its derivatives were potential tyrosine kinase inhibitors that target EGFR.

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

BACKGROUND: Quercetin is a natural flavonoid, which widely exists in nature, such as tea, coffee, apples, and onions. Numerous studies have showed that quercetin has multiple biological activities such as anti-oxidation, anti-inflammatory, and anti-aging. Hence, quercetin has a significant therapeutic effect on cancers, obesity, diabetes, and other diseases. In the past decades, a large number of studies have shown that quercetin combined with other agents can significantly improve the overall therapeutic effect, compared to single use. PURPOSE: This work reviews the pharmacological activities of quercetin and its derivatives. In addition, this work also summarizes both in vivo and in vitro experimental evidence for the synergistic effect of quercetin against cancers and metabolic diseases. METHODS: An extensive systematic search for pharmacological activities and synergistic effect of quercetin was performed considering all the relevant literatures published until August 2021 through the databases including NCBI PubMed, Scopus, Web of Science, and Google Scholar. The relevant literatures were extracted from the databases with following keyword combinations: "pharmacological activities" OR "biological activities" OR "synergistic effect" OR "combined" OR "combination" AND "quercetin" as well as free-text words. RESULTS: Quercetin and its derivatives possess multiple pharmacological activities including anti-cancer, anti-oxidant, anti-inflammatory, anti-cardiovascular, anti-aging, and neuroprotective activities. In addition, the synergistic effect of quercetin with small molecule agents against cancers and metabolic diseases has also been confirmed. CONCLUSION: Quercetin cooperates with agents to improve the therapeutic effect by regulating signal molecules and blocking cell cycle. Synergistic therapy can reduce the dose of agents and avoid the possible toxic and side effects in the treatment process. Although quercetin treatment has some potential side effects, it is safe under the expected use conditions. Hence, quercetin has application value and potential strength as a clinical drug. Furthermore, quercetin, as the main effective therapeutic ingredient in traditional Chinese medicine, may effectively treat and prevent coronavirus disease 2019 (COVID-19).

Inhibitory activities of 20(R, S)-protopanaxatriol against epidermal growth factor receptor tyrosine kinase.

As major metabolites of protopanaxatriol-type ginsenosides, 20(R, S)-protopanaxatriol [20(R, S)-PPT] display multiple bioactivities. This work aimed to investigate the inhibitory activities of 20(R, S)-PPT against epidermal growth factor receptor tyrosine kinase and the potential mechanism. 20(R, S)-PPT inhibited the proliferation of HepG2 cells in a dose-dependent manner and blocked cell cycle progression at G1/G0 phase. Then 20(R, S)-PPT were found to influence the protein expressions involved in epidermal growth factor receptor (EGFR)-mitogen-activated protein kinase (MAPK) signaling pathway. Molecular docking suggested that 20(R, S)-PPT could bind to the active sites of all target proteins in EGFR-MAPK pathway. It is worth noting that 20(R, S)-PPT showed stronger binding capacities with EGFR, compared with other proteins. Hence, this work further investigated the binding interactions and binding stabilities between 20(R, S)-PPT and EGFR. Both hydrophobic interactions and hydrogen bonds contributed to the 20(R, S)-PPT-EGFR binding. In addition, the in vitro inhibitory activities of 20(R, S)-PPT against EGFR tyrosine kinase were observed in a homogeneous time-resolved fluorescence assay, with the IC50 values of 24.10 ± 0.17 and 33.19 ± 0.19 µM respectively. Taken together with the above results, both of 20(R)-PPT and 20(S)-PPT might serve as potential EGFR tyrosine kinase inhibitors.

GR-mediated anti-inflammation of α-boswellic acid: Insights from in vitro and in silico studies.

Although multiple bioactivities of α-boswellic acid have been reported, the molecular mechanism of its anti-inflammatory action is not yet clear. Hence, glucocorticoid receptor (GR)-mediated anti-inflammation of α-boswellic acid was investigated in this work. Fluorescence polarization assay suggested that α-boswellic acid bound to GR with IC50 value of 658.00 ± 0.21 µM. Upon binding to α-boswellic acid, GR translocated from cytoplasm into nucleus of HeLa cells, facilitating sequential transcriptional regulation of GR-related genes. Luciferase reporter assay suggested that α-boswellic acid lacked GR transcriptional activity, indicating its potential as a dissociative GR ligand. Interestingly, α-boswellic acid selectively modulated the anti-inflammatory gene CBG (marker for GR transrepression), while leaving the "side-effect" gene TAT (marker for GR transactivation) unaffected in HepG2 cells. Furthermore, α-boswellic acid inhibited lipopolysaccharide-stimulated cytokines production in U937 macrophages, confirming its anti-inflammation property in vitro. Molecular docking showed that both hydrogen-bonding and hydrophobic interactions helped to stabilize α-boswellic acid-GR binding. Their binding stability was further confirmed in a 70-ns dynamics simulation. In summary, α-boswellic acid could bind to and translocate GR but did not induce glucocorticoid response element-mediated transcription. Since α-boswellic acid showed the dissociated characteristic that separated transrepression from transactivation, it might be a selective GR modulator against inflammatory disorders.

BiVO4/Fe3O4@polydopamine superparticles for tumor multimodal imaging and synergistic therapy.

BACKGROUND: Despite tremendous progress has been achieved in tumor theranostic over the past decade, accurate identification and complete eradication of tumor cells remain a great challenge owing to the limitation of single imaging modality and therapeutic strategy. RESULTS: Herein, we successfully design and construct BiVO4/Fe3O4@polydopamine (PDA) superparticles (SPs) for computed tomography (CT)/photoacoustic (PA)/magnetic resonance (MR) multimodal imaging and radiotherapy (RT)/photothermal therapy (PTT) synergistic therapy toward oral epithelial carcinoma. On the one hand, BiVO4 NPs endow BiVO4/Fe3O4@PDA SPs with impressive X-ray absorption capability due to the high X-ray attenuation coefficient of Bi, which is beneficial for their utilization as radiosensitizers for CT imaging and RT. On the other hand, Fe3O4 NPs impart BiVO4/Fe3O4@PDA SPs with the superparamagnetic property as a T2-weighted contrast agent for MR imaging. Importantly, the aggregation of Fe3O4 NPs in SPs and the presence of PDA shell greatly improve the photothermal conversion capability of SPs, making BiVO4/Fe3O4@PDA SPs as an ideal photothermal transducer for PA imaging and PTT. By integrating advantages of various imaging modalities (CT/PA/MR) and therapeutic strategies (RT/PTT), our BiVO4/Fe3O4@PDA SPs exhibit the sensitive multimodal imaging feature and superior synergistic therapeutic efficacy on tumors. CONCLUSIONS: Since there are many kinds of building blocks with unique properties appropriating for self-assembly, our work may largely enrich the library of nanomateirals for tumor diagnosis and treatment.

Poly(l-glutamic acid)-cisplatin nanoformulations with detachable PEGylation for prolonged circulation half-life and enhanced cell internalization.

PEGylation has been widely applied to prolong the circulation times of nanomedicines via the steric shielding effect, which consequently improves the intratumoral accumulation. However, cell uptake of PEGylated nanoformulations is always blocked by the steric repulsion of PEG, which limits their therapeutic effect. To this end, we designed and prepared two kinds of poly(l-glutamic acid)-cisplatin (PLG-CDDP) nanoformulations with detachable PEG, which is responsive to specific tumor tissue microenvironments for prolonged circulation time and enhanced cell internalization. The extracellular pH (pHe)-responsive cleavage 2-propionic-3-methylmaleic anhydride (CDM)-derived amide bond and matrix metalloproteinases-2/9 (MMP-2/9)-sensitive degradable peptide PLGLAG were utilized to link PLG and PEG, yielding pHe-responsive PEG-pH e-PLG and MMP-sensitive PEG-MMP-PLG. The corresponding smart nanoformulations PEG-pH e-PLG-Pt and PEG-MMP-PLG-Pt were then prepared by the complexation of polypeptides and cisplatin (CDDP). The circulation half-lives of PEG-pH e-PLG-Pt and PEG-MMP-PLG-Pt were about 4.6 and 4.2 times higher than that of the control PLG-Pt, respectively. Upon reaching tumor tissue, PEG on the surface of nanomedicines was detached as triggered by pHe or MMP, which increased intratumoral CDDP retention, enhanced cell uptake, and improved antitumor efficacy toward a fatal high-grade serous ovarian cancer (HGSOC) mouse model, indicating the promising prospects for clinical application of detachable PEGylated nanoformulations.

BiVO4@Bi2S3 Heterojunction Nanorods with Enhanced Charge Separation Efficiency for Multimodal Imaging and Synergy Therapy of Tumor.

Despite malignant tumors being one of the most serious diseases threatening human health and living quality, exploring theranostic agents for highly effective tumor diagnosis and treatment is still full of challenges. Herein, we demonstrate the design and preparation of Tween-20-modified BiVO4@Bi2S3 heterojunction nanorods (HNRs) for multimodal computed tomography (CT)/photoacoustic (PA) imaging and radiotherapy (RT)/radiodynamic therapy (RDT)/photothermal therapy (PTT) synergistic therapy. Benefiting from the high X-ray attenuation coefficient of Bi, BiVO4@Bi2S3 HNRs exhibit a sensitive CT imaging capacity and radiation enhancement effect during RT. Meanwhile, the strong NIR absorption of Bi2S3 endows BiVO4@Bi2S3 HNRs with an excellent PA imaging and photothermal transformation capacity. More importantly, by taking advantage of the type II band alignment between BiVO4 and Bi2S3, an extra internal electric field is established to accelerate the separation of X-ray-induced electrons and holes in BiVO4@Bi2S3 HNRs, resulting in the realization of highly effective X-ray-induced RDT. Because the in vitro and in vivo experiments have verified that the RT/RDT/PTT synergistic therapeutic efficacy is greatly superior to any single treatment, it is believed that our BiVO4@Bi2S3 HNRs can be used as the multifunctional nanotheranostic platform for malignant tumor theranostics.

Cucurbitacin IIa interferes with EGFR-MAPK signaling pathway leads to proliferation inhibition in A549 cells.

Cucurbitacin IIa (CuIIa), a tetracyclic triterpenoid harboring anticancer activity, was investigated in A549 cells to reveal its mechanism of targeting on epidermal growth factor receptor (EGFR) signaling pathway. Results showed that CuIIa was capable of inducing apoptosis and cell cycle arrest at G2/M phase. The transcription of EGFR pathway genes and their proteins accumulation was inconsistently influenced by CuIIa. Notably, transcription of Raf1 was significantly upregulated, nevertheless, MEK1 and ERK1 were significantly downregulated. On the other hand, the accumulation of the total and phosphorylated proteins of the most members in EGFR-mitogen-activated protein kinase (MAPK) pathway, as well as CylclinB1 and survivin were also shifted by CuIIa treatment. Remarkably, total MEK remained constant but survivin completely degraded. Moreover, phosphorylated BRAF continuously increased while Raf1 and MEK decreased continuously. CuIIa was further confirmed to be a tyrosine kinase inhibitor (TKI) of EGFR by kinase inhibition assay. The results of molecular simulation showed that the long side chain of CuIIa occupied the binding pocket of EGFR and the ligand was stabilized at the active site of EGFR. In view of the results above, it is suggested that CuIIa inhibits cell proliferation by interfering the EGFR-MAPK signaling pathway.