Inhibition of SARS-CoV-2 replication by zinc gluconate in combination with hinokitiol.

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic is currently the major challenge to global public health. Two proteases, papain-like protease (PLpro) and the 3-chymotrypsin-like protease (3CLpro or Mpro), are indispensable for SARS-CoV-2 replication, making them attractive targets for antiviral therapy development. Here we screened a panel of essential metal ions using a proteolytic assay and identified that zinc gluconate, a widely-used zinc supplement, strongly inhibited the proteolytic activities of the two proteases in vitro. Biochemical and crystallographic data reveal that zinc gluconate exhibited the inhibitory function via binding to the protease catalytic site residues. We further show that treatment of zinc gluconate in combination with a small molecule ionophore hinokitiol, could lead to elevated intracellular Zn2+ level and thereby significantly impaired the two protease activities in cellulo. Particularly, this approach could also be applied to rescue SARS-CoV-2 infected mammalian cells, indicative of potential application to combat coronavirus infections. Our studies provide the direct experimental evidence that elevated intracellular zinc concentration directly inhibits SARS-CoV-2 replication and suggest the potential benefits to use the zinc supplements for coronavirus disease 2019 (COVID-19) treatment.

Virtual Screening and Bioactivity Evaluation of Novel Androgen Receptor Antagonists From Anti-PCa Traditional Chinese Medicine Prescriptions.

Prostate cancer (PCa), a type of malignancy that arises in the prostate gland, is the most commonly diagnosed neoplasm and the second leading cause of cancer-related deaths in men. Acquisition of resistance to conventional therapy is a major problem for PCa patient treatment. Androgen receptor (AR) signaling pathway is necessary in the pathogenesis of prostate cancer, and there is a heightened interest in finding novel AR antagonists that target AR and its regulatory pathways. In our search for novel androgen receptor antagonists, we focus on the Traditional Chinese Medicine (TCM), which has been used for thousands of years to prove effective in the treatment of cancer. In this study, we collected 653 traditional Chinese medicine prescriptions that have certain therapeutic effect to prostate cancer, including the prescriptions and even the folk prescriptions. After summarizing the frequency of herbs and gathering the natural products contained in these prescriptions, we built a natural products database to do computer-aided virtual screening and drug-like evaluation to find potential AR antagonists. Totally 25 compounds were submitted to experimental biological activity tests. Through the MTT cell proliferation experiment, 5 chemicals were found to inhibit the proliferation of LNCaP cells in a concentration-dependent manner. Especially, MoL_11 was found to have good antagonistic activity and significantly inhibit fluorescence enzyme activity by the AR reporter gene experiment. Finally, the molecular dynamics simulation method was used to study the interaction between the most active compound MoL_11 and the wild-type and F876L mutant androgen receptor (WT/F876L AR), and it was found that F876L AR could not cause resistance to MoL_11.

Cancer-Targeting Functionalization of Selenium-Containing Ruthenium Conjugate with Tumor Microenvironment-Responsive Property to Enhance Theranostic Effects.

A mutifunctional ruthenium-based conjugate Ru-BSe was designed and synthesized. The Ru complex with favorable bioimaging function was covalently linked with a cancer-targeted molecule that could be effectively internalized by the tumor to realize enhanced theranostic effects. The pH-response of the Ru conjugate in tumor acidic microenvironment causes ligand substitution and release of therapeutic complex. This activated complex remains inert to the reducing biomolecule-glutathione and terminally locates in mitochondria, in which it triggers oxidative stress, and activates intrinsic apoptosis. Real-time monitoring reveals that this Ru conjugate could selectively accumulate in tumor tissue in vivo, which significantly suppresses tumor progression and alleviate the damage to normal organs, realizing the precise cancer theranosis.

Functionalized Selenium Nanosystem as Radiation Sensitizer of 125I Seeds for Precise Cancer Therapy.

Although radiotherapy has been extensively applied in cancer treatment, external beam radiation therapy is still unable to avoid damage to adjacent normal tissues in the process of delivering a sufficient radiation dose to the tumor sites of patients. To overcome this limitation, chemoradiotherapy, as a combination of chemotherapy and radiotherapy of a radioactive seed, has been proposed to decrease the damage to tumor-surrounding tissues and enhance the radiosensitivity of solid tumors. In this study, we designed and synthesized folic acid-conjugated selenium nanoparticles (FA@SeNPs) as a cancer-targeting agent that could be synergistically enhanced by radioactive 125I seeds to realize anticancer efficacy and inhibited colony formation ability. Interestingly, when compared with X-ray irradiation, 125I seeds demonstrate a larger synergistic effect with the FA@SeNPs, drastically increasing reactive oxygen species overproduction to trigger apoptosis and influencing the cell cycle distribution in human breast cancer cells, inducing DNA damage and activating the mitogen-activated protein kinase and p53 signaling pathways. Moreover, this combination treatment demonstrates better in vivo antitumor activity and lower systemic toxicity. Therefore, this study demonstrates a new strategy for using functionalized SeNPs as a radiation sensitizer for 125I seeds for cancer therapy.

Data on the characterization and anticancer action of iron(II) polypyridyl complexes.

This data article contains complementary figures and results related to the research article entitled, "Cellular localization of iron(II) polypyridyl complexes determines their anticancer action mechanisms" [1] (Chen et al., 2015). The characterization of Fe(II) complexes by ESI-MS, (1)H NMR, (13)C NMR spectroscopy, FT-IR spectra, UV-vis spectra was provided. Also,the data for the stability of Fe(II) complexes 1-5 in DMSO/Milli-Q water/ culture medium (without serum or phenol red) at 37 °C at different periods of time by UV-vis spectra and (1)H NMR was showed. At the same time, the anticancer efficacy, cellular distribution and ROS generation in MCF-7 cells of complexes are reported. In addition, we also show the cellular localization of complex 4, the relative fluorescence intensity of complex 1 and complex 3 pretreated with anti-TfR (2 µg/mL) in MCF-7 cells using flow cytometry. The compilation of this data provides an invaluable resource for the wider research community and the interpretation of these data could be found in the research article noted above.

Differential effects of amino acid surface decoration on the anticancer efficacy of selenium nanoparticles.

The use of selenium for anticancer therapy has been heavily explored during the last decade. Amino acids (AAs) play central roles both as building blocks of proteins and intermediates in metabolism. In the present study, AAs-modified selenium nanoparticles (SeNPs@AAs) have been successfully synthesized in a simple redox system. Typical neutral (valine), acidic (aspartic acid) and basic (lysine) amino acids were used to decorate SeNPs, and the stable and homodisperse nanoparticles were characterized by zeta potential and transmission electron microscope. The result of X-ray photoelectron spectra (XPS) showed that the interaction of -NH3(+) groups of the amino acids with negative-charged SeNPs could be a driving force for dispersion of the nanoparticles. The screening of in vitro anticancer activities demonstrated that SeNPs@AAs exhibited differential growth inhibitory effects on various human cancer cell lines. Among them, SeNPs decorated by Lys displayed higher anticancer efficacy than those of valine and aspartic acid. The studies on the in vitro cellular uptake mechanisms revealed that SeNPs@AAs were internalized by cancer cells through endocytosis. Flow cytometric analysis and the determination of caspase activity indicated that treatment of the MCF-7 breast adenocarcinoma cells with SeNPs@AAs led to a dose-dependent increase in apoptosis. Moreover, it was found that SeNPs@AAs-induced ROS overproduction could be the upstream signal of caspase activation and mitochondrial dysfunction in cancer cells. Taken together, our results suggest that these amino acid biocompatible nanoparticles might have potential application as chemopreventive and chemotherapeutic agents for human cancers.

[Simulation of SAR and temperature distribution for tumor RF thermotherapy with double-frequencies and double-plates].

The model establishment and numerical simulation of specific absorption rate (SAR) and the unsteady-state temperature distribution for radio frequency (RF) thermotherapy with double-frequencies and double-plates are presented in this paper. The model can correctly reflect the attenuation of electromagnetic wave in the biotissue. The variation of perfusion with temperature and the lower perfusion in tumor tissue are fully considered in the simulation of unsteady-state temperature profiles. Also presented are detailed analyses and discussions on the characteristics of SAR and temperature profiles, and the effects of the plates location and power as well as of the perfusion on the depth of effective treatment.

[The simulation of SAR and temperature distribution and parameters analysis for tumor RF thermotherapy].

In this paper are reported the model establishment and numerical simulation of specific absorption rate(SAR) and the unsteady temperature distribution for the non-invasive tumor RF thermotherapy. The model can correctly reflect the attenuation of electromagnetic wave in the biotissue, the variation of perfusion with temperature and lower perfusion of the tumor tissue are fully considered in the simulation. These measures made simulation results more close to the clinical results. Also presented in the paper are detailed analyses and discussions on the characteristics of SAR of electromagnetic energy and the temperature profiles, the effects of the frequency and the perfusion on the depth for effective treatment. The simulation results are of great significance for directing the clinical application of tumor RF thermotherapy.