Docetaxel (DTX) is the treatment of choice for metastatic castration-resistant prostate cancer. However, developing drug resistance is a significant challenge for achieving effective therapy. This study evaluated the anticancer and synergistic effects on DTX of four natural compounds (calebin A, 3[']-hydroxypterostilbene, hispolon, and tetrahydrocurcumin) using PC-3 androgen-resistant human prostate cancer cells. We utilized the CellTiter-Glo[®] luminescent cell viability assay and human PC-3 androgen-independent prostate cancer cells to determine the antiproliferative effects of the four compounds alone and combined with DTX. Cytotoxicity to normal human prostate epithelial cells was tested in parallel using normal immortalized human prostate epithelial cells (RWPE-1). We used cell imaging and quantitative caspase-3 activity to determine whether these compounds induce apoptosis. We also measured the capacity of each drug to inhibit TNF-α-induced NF-kB using a colorimetric assay. Our results showed that all four natural compounds significantly augmented the toxicity of DTX to androgen-resistant PC-3 prostate cancer cells at IC50. Interestingly, when used alone, each of the four compounds had a higher cytotoxic activity to PC-3 than DTX. Mechanistically, these compounds induced apoptosis, which we confirmed by cell imaging and caspase-3 colorimetric assays. Further, when used either alone or combined with DTX, the four test compounds inhibited TNF-α-induced NF-kB production. More significantly, the cytotoxic effects on normal immortalized human prostate epithelial cells were minimal and non-significant, suggesting prostate cancer-specific effects. In conclusion, the combination of DTX with the four test compounds could effectively enhance the anti-prostate cancer activity of DTX. This combination has the added value of reducing the DTX effective concentration. We surmise that calebin A, 3[']-hydroxypterostilbene, hispolon, and tetrahydrocurcumin were all excellent drug candidates that produced significant antiproliferative activity when used alone and synergistically enhanced the anticancer effect of DTX. Further in vivo studies using animal models of prostate cancer are needed to confirm our in vitro findings.

Death receptor 5 (DR5) is an apoptosis-inducing membrane receptor that mediates cell death in several life-threatening conditions. There is a crucial need for the discovery of DR5 antagonists for the therapeutic intervention of conditions in which the overactivation of DR5 underlies the pathophysiology. DR5 activation mediates cell death in non-alcoholic fatty liver disease (NAFLD) and neurodegenerative processes including amyloid-beta (Aβ) accumulation, spinal cord injury (SCI), and brain ischemia. In the current work, we used fluorescence resonance energy transfer (FRET) to monitor the conformational dynamics of DR5 that mediate death signaling. We used a time-resolved FRET screening platform to screen the Selleck library of 2863 U.S. Food and Drug Administration (FDA)-approved compounds. The high-throughput screen (HTS) identified 13 compounds that modulated the FRET between DR5 monomers beyond 5 median absolute deviations (MADs) from the DMSO controls. Of these 13 compounds, indirubin was identified to specifically inhibit tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced caspase-8 activity without modulating DR5 surface expression or TRAIL binding. Indirubin inhibited Fas-associated death domain (FADD) oligomerization and increased cellular FLICE-inhibitory protein (c-FLIP) expression; both are molecular mechanisms involved in inhibiting the DR5 signaling cascade. This study has elucidated previously unknown properties of indirubin that make it a promising candidate for therapeutic investigation of diseases in which overactivation of DR5 underlies pathology.

Phytochemicals from the genus, Fagonia, have been attracting increasing attention due to their potential beneficial effects on human health. Fagonia species contain various types of phytochemicals such as flavonoids, alkaloids, saponins, terpenoids, coumarins and tannins. In this study, we investigated the phytochemical composition of unhydrolyzed and acid-hydrolyzed extracts of Fagonia indica and their bioactivity toward breast cancer MCF-7 cells in vitro. The results revealed that F. indica contains phytochemicals consistent with the reported phytochemical composition of this Fagonia species, with greater amounts of aglycones detected in the hydrolyzed extract. The crude extract of F. indica without acid hydrolysis was found to be ineffective in inhibiting the growth of MCF-7 cells at doses below 1000 μg/mL. However, after acid hydrolysis (to mimic gastro-intestinal hydrolysis), the F. indica extract became growth-inhibitory to MCF-7 cells as low as 10 μg/mL and the cytotoxicity increased with increasing dose and time of treatment. The results suggest that F. indica extracts contain phytochemicals in glycosidic forms whose aglycones are active as anti-proliferative agents toward breast cancer cells in vitro.

SARS-CoV-2 spike protein-induced heart inflammation may originate from either COVID-19 infection or the administration of COVID-19 mRNA vaccines. As pyrroloquinoline quinone (PQQ) is a scavenger of free radicals, redox cofactor, and antioxidant which supports cognitive and mitochondrial functions, supplementation with PQQ could have a positive effect to reduce heart inflammation after COVID-19 mRNA vaccines. However, there is no evidence yet for this opportunity in the literature. Cellular and animal model results are missing. Similarly, no clinical trials have been conducted. While it is recommended to measure the levels of the cardiac biomarkers before and after COVID-19 vaccination, no recommendation can be made about supplementation with PQQ, which, however, we note has no contraindication.

Objective: To predict the mechanism of Shengmai Injection (SMI) in the acute treatment of COVID-19 by network pharmacology and molecular docking. Methods: Search the compounds in the Traditional Chinese Medicine Systems Pharmacology (TCMSP), and screen them by Drug-like properties (DL) and Oral bioavailability (OB); Using PharmMapper database and GeneCards database to collect compounds targets and COVID-19 targets, and using UniProt database to standardize the names of target genes; Using DAVID database for KEGG pathway annotation and GO bioinformatics analysis; Using Cytoscape 3.8.2 software and STRING 10.5 database to construct "Component-Target-Pathway" network and Protein-Protein Interaction network (PPI); Using molecular docking to predict the binding ability of key compounds and key proteins. Results: A total of 34 active components, 38 core targets and 180 signaling pathways were screened out. The results of molecular docking showed that Schisantherin A and Moupinamide have strong binding with EGFR and MAPK1. Conclusion: The key active compounds of SMI in the treatment of COVID-19 may be Schisantherin A and Moupinamide, and the molecular mechanism may be related to key targets such as EGFR and MAPK1, and may be involved in the PI3K-Akt signaling pathway and MAPK signaling pathway.

Coronavirus disease 2019 (COVID-19) is an infection caused by a newly discovered coronavirus which was identified in Wuhan, China. The race is on globally to repurpose drugs for COVID-19 and develop a safe and effective vaccine against the disease. There is an urgent need to search for effective remedies against COVID-19 from the rich and extensive flora of Africa and the world. A literature search was conducted to obtain information on drugs with the potential for effectiveness in the treatment of COVID-19 based mostly on outcomes of preclinical studies and a few clinical investigations. This was considered important to this perspective as some of the identified mechanisms of action may be related to potential anti-COVID-19 actions of phytomedicines. The findings from the literature search were also used to establish the need for exploration of phytomedicines in the fight against COVID-19. This perspective identifies the need to preserve the rich tradition of herbal medicine in Africa, repositioning it by inculcating all aspects of discovery, development, and chemical evaluation of pharmaceuticals from medicinal plants for effective management of prevalent diseases. The identified mechanisms of action of current drugs under consideration for the treatment of COVID-19 include preventing fusion of SARS-CoV-2 with human cells; decrease acidity in endosomes, cell membrane-derived vesicles for transportation of the virus within the host cell and within which the virus can replicate; and blockade of the production of proinflammatory cytokines. Phytomedicines may possibly elicit either one or a combination of these effects. The case for the exploration of phytomedicines against COVID-19 is strengthened by the emergence of a number of conventional drugs from medicinal plants and the emergence of botanicals with proven efficacy for some medical conditions. Caution against indiscriminate use of medicinal plants in the guise of treating COVID-19 has been highlighted and the need for reliable preclinical and clinical studies.

Coronaviruses (CoVs) that cause infections such as severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome phylogenetically originate from bat CoVs. The coronaviral nonstructural protein 3 (nsp3) has been implicated in viral replication, polyprotein cleavage, and host immune interference. We report the structure of the C domain from the SARS-Unique Domain of bat CoV HKU4. The protein has a frataxin fold, consisting of 5 antiparallel β strands packed against 2 α helices. Bioinformatics analyses and nuclear magnetic resonance experiments were conducted to investigate the function of HKU4 C. The results showed that HKU4 C engages in protein-protein interactions with the nearby M domain of nsp3. The HKU4 C residues involved in protein-protein interactions are conserved in group 2c CoVs, indicating a conserved function.

We report relative bioactivities of extracts prepared from a large collection of plants from three national parks in Panama. Over 181 plants were collected, taxonomically identified and their detannified dichloromethane (DCM)-methanolic extracts were used for profiling selected bioactivities. Assays were performed to evaluate the antioxidant activity of the extracts for Antioxidant Response Element (ARE) induction, total non-enzymatic antioxidant potential, anti-inflammatory and anticancer properties. The high throughput analysis of 280 extracts resulted in identification of 57.5% of the extracts that could induce ARE at one or more concentrations tested, 93.5% that harbored total antioxidant capacity, and 2.1% of the extracts that showed lung cancer cell line-specific cytotoxicity. Data from our profiling experiments indicate that a large number of extracts could be a source for further isolation and chemical identification of compounds that could serve as leads for discovery of antioxidant, anticancer and anti-inflammatory agents to prevent or treat complex diseases like cancer and neurodegenerative disorders.

The human immunodeficiency virus (HIV-1 virus) exploits several host factors for assembly, infection, and replication within the infected cells. In this work, we describe the evidence for an interaction of the N-terminal domain of the HIV-1 capsid protein with human calmodulin. The precise role of this interaction within the life cycle of the HIV-1 virus is yet to be defined. Potential roles for this interaction in the viral capsid uncoating are discussed.

Activity-guided fractionation was used to isolate and identify two components of the Brazilian açaí berry (Euterpe oleracea Mart.) with the ability to induce antioxidant response element (ARE)-dependent gene transcription in human hepatoma (HepG2) cells. Using an ARE-Luciferase reporter construct in cultured HepG2 cells, a suite of fractions from dried and powdered açaí berries were evaluated for transcriptional up-regulation of the luciferase gene. Active fractions were further refined until several pure compounds were isolated and identified. These compounds belong to the pheophorbide class of molecules, and are composed of the methyl and ethyl esters of the parent pheophorbide A, all of which are classified as photosensitizers. Using standard pheophorbides, dose response studies were carried out, and ARE-activation could be observed at concentrations as low as 8.2 μM and 16.9 μM for pheophorbide A methyl ester and pheophorbide A, respectively. These studies not only suggest a possible source of antioxidant properties for the açaí berry, but may also explain the recently identified photosensitizing abilities of açaí products as well.

The antibiotic resistant threat is continuing to grow, due in part to the overuse of antibiotics in livestock feed. Many nations in Europe have banned the use of antibiotics in feed, leading to higher rates of infection in livestock animals and reduced productivity for the food market. Increasingly, researchers are looking into the efficacy of phytopreparations to replace antibiotics in feed, allowing for increased animal health without the development of resistance. Macleaya cordata, or Chinese plume poppy, shows promise as a food additive. To evaluate the antimicrobial efficacy of this plant, we tested in vitro activity of M. cordata extract, as well as pure compounds sanguinarine and chelerythrine against wild-type, methicillin-resistant, and multiply-resistant strains of Staphylococcus aureus (SA1199, AH1263, and IA116, respectively). Combination tests to evaluate synergy, additivity, and antagonism within the extract were also completed for the first time. Sanguinarine and chelerythrine showed complete growth inhibition of all strains of S. aureus at concentrations ranging from 3-10 µg/mL, and were equal in activity or were more potent than the reference compound chloramphenicol. Combination studies of pure sanguinarine and chelerythrine with M. cordata extract revealed additivity or indifference of mixture components with these compounds. Because sanguinarine and chelerythrine represent the major active constituents of M. cordata, the pooled amounts of these two compounds may be useful for establishing potency for quality control purposes. This is the first report of activity of chelerythrine and sanguinarine against methicillin-resistant S. aureus AH1263 and multiply-resistant S. aureus IA116, and illustrates the promise of M. cordata extract as an alternative to antibiotics in feed additives.

We describe BaMORC, a software package that performs 13C chemical shifts reference correction for either assigned or unassigned peak lists derived from protein NMR spectra. BaMORC provides an intuitive command line interface that allows non-NMR experts to detect and correct 13C chemical shift referencing errors of unassigned peak lists at the very beginning of NMR data analysis, further lowering the bar of expertise required for effective protein NMR analysis. Furthermore, BaMORC provides an application programming interface for integration into sophisticated protein NMR data analysis pipelines, both before and after the protein resonance assignment step.

Peptides designed to mimic the antiatherogenic and anti-inflammatory properties of apolipoprotein A-I show that although lipid association is required, not all lipid-associating peptides exhibit these properties. Our studies of a series of peptides showed that peptides with aromatic residues at the center of the nonpolar face were able to interact with inflammatory lipids and inhibited inflammation, which resulted in the amelioration of several lipid-mediated disorders such as lesion development, tumor formation, and Alzheimer's plaque formation. The pK a values determined using 13C nuclear magnetic resonance (NMR) spectroscopy of K residues located at the polar-nonpolar interface provided the first clue to the relative orientations of the peptide helices with respect to each other and around the edge of the lipid discoidal complexes. High-resolution 1H-NMR studies of peptide-lipid discoidal complex confirmed the amphipathic α-helical structure of the peptide, location of aromatic residues of the peptide closer to the polar-nonpolar interface, and head-to-tail arrangement of the peptide helices around the edge of the disc. Amphipathic α-helical structure and the location of aromatic residues (F, W, Y) closer to the polar-nonpolar interface in a lipid environment allow the peptide to strongly bind oxidized lipids resulting in its anti-inflammatory properties.

This review summarizes the chemical composition reported up to date on Laurus nobilis L. (Lauraceae), an evergreen shrub or tree cultivated for its aromatic leaves and ornamental interest. It has been focused on non-volatile phytochemicals such as sesquiterpene lactones, flavonoids and proanthocyanidins, among others. Moreover, biological activities of laurel extracts and pure compounds have also been reviewed.