Thymoquinone: A Review of Pharmacological Importance, Oxidative Stress, COVID-19, and Radiotherapy

Widely consumed worldwide, Nigella sativa (NS) is a medicinal herb commonly used in various alternative medicine systems such as Unani and Tibb, Ayurveda, and Siddha. Recommended for regular use in Tibb-e-Nabwi (Prophetic Medicine), NS is considered one of the most notable forms of healing medicine in Islamic literature. Thymoquinone (TQ), the main component of the essential oil of NS, has been reported to have many properties such as antioxidant, anti-inflammatory, antiviral, and antineoplastic. Its chemical structure indicates antiviral potential against many viruses, including the hepatitis C virus, human immunodeficiency virus, and other coronavirus diseases. Interestingly, molecular docking studies have demonstrated that TQ can potentially inhibit the development of the coronavirus disease 2019 (COVID-19) by binding to the receptor site on the transmembrane serine proteinase 2 (the activator enzyme that attaches the virus to the cell). In addition, TQ has been shown to be effective against cancer cells due to its inhibitory effect by binding to the different regions of MDM2, according to the proposed molecular docking study. Detailed in this review is the origin of TQ, its significance in alternative medicine, pharmacological value, potential as a cancer anti-proliferative agent, use against the coronavirus disease 2019 (COVID-19), and treatment of other diseases.

Evaluating mitigation translocations for better biodiversity outcomes

<p>The expansion of urban areas and associated loss of natural areas due to development are greatly contributing to global biodiversity loss. Furthermore, development produces direct harm to wildlife and their habitat. In New Zealand, lizards and their habitat are legally protected and damage due to development of a natural area must be avoided or mitigated whenever possible. Mitigation translocations, the intentional relocation of individuals from the site to be developed to a receptor site, have become commonly used to meet legal obligations; however, mitigation translocations do not guarantee survival of individuals or population success at the receptor site. I aimed to evaluate the success of a mitigation translocation case study, proactively plan receptor sites for a mitigation translocation, and develop a framework for selecting and preparing receptor sites to provide better mitigation translocation outcomes, particularly for herpetofauna. I evaluated the short-term success of a mitigation translocation case study using results from post-release monitoring at receptor sites. This is one of the first studies to provide multiple post-release monitoring sessions and detail recapture rates and body condition changes of lizards at receptor sites with and without resident populations following mitigation translocation. I expanded upon commonly used receptor site selection criteria and translocation data management systems by proactively studying and preparing receptor sites in regional parks, including conducting pilot surveys to evaluate resident populations. Recapture rates were similar between receptor sites (9% and 11.8%) and the limited number of recaptured individuals showed an increase in body condition from the time of salvage to intervals of one- and two-years post-release. Presence of residents was not found to have an effect on recapture rates or body condition changes. Implementation of enhanced site selection criteria resulted in approval of six sites within three protected areas for future mitigation translocations. These sites had low numbers of resident lizards present, if at all. A geodatabase was developed to store results from receptor site evaluations before and after translocation. Together, the improved criteria and geodatabase fit into a framework for selecting and preparing receptor sites to improve outcomes of mitigation translocations of herpetofauna. The framework produced has potential to be used at a national level, in collaboration with ecologists, iwi, and community groups, and for a variety of species. Mitigation translocations should be re-evaluated as the go-to method to mitigate damage to lizards due to development; however, if they must continue, it is essential that best practices are used, and results are published so that outcomes can improve for biodiversity.</p>

Evaluating mitigation translocations for better biodiversity outcomes

<p>The expansion of urban areas and associated loss of natural areas due to development are greatly contributing to global biodiversity loss. Furthermore, development produces direct harm to wildlife and their habitat. In New Zealand, lizards and their habitat are legally protected and damage due to development of a natural area must be avoided or mitigated whenever possible. Mitigation translocations, the intentional relocation of individuals from the site to be developed to a receptor site, have become commonly used to meet legal obligations; however, mitigation translocations do not guarantee survival of individuals or population success at the receptor site. I aimed to evaluate the success of a mitigation translocation case study, proactively plan receptor sites for a mitigation translocation, and develop a framework for selecting and preparing receptor sites to provide better mitigation translocation outcomes, particularly for herpetofauna. I evaluated the short-term success of a mitigation translocation case study using results from post-release monitoring at receptor sites. This is one of the first studies to provide multiple post-release monitoring sessions and detail recapture rates and body condition changes of lizards at receptor sites with and without resident populations following mitigation translocation. I expanded upon commonly used receptor site selection criteria and translocation data management systems by proactively studying and preparing receptor sites in regional parks, including conducting pilot surveys to evaluate resident populations. Recapture rates were similar between receptor sites (9% and 11.8%) and the limited number of recaptured individuals showed an increase in body condition from the time of salvage to intervals of one- and two-years post-release. Presence of residents was not found to have an effect on recapture rates or body condition changes. Implementation of enhanced site selection criteria resulted in approval of six sites within three protected areas for future mitigation translocations. These sites had low numbers of resident lizards present, if at all. A geodatabase was developed to store results from receptor site evaluations before and after translocation. Together, the improved criteria and geodatabase fit into a framework for selecting and preparing receptor sites to improve outcomes of mitigation translocations of herpetofauna. The framework produced has potential to be used at a national level, in collaboration with ecologists, iwi, and community groups, and for a variety of species. Mitigation translocations should be re-evaluated as the go-to method to mitigate damage to lizards due to development; however, if they must continue, it is essential that best practices are used, and results are published so that outcomes can improve for biodiversity.</p>

A Novel Spider Toxin Inhibits Fast Inactivation of the Nav1.9 Channel by Binding to Domain III and Domain IV Voltage Sensors

Venomous animals have evolved to produce peptide toxins that modulate the activity of voltage-gated sodium (Nav) channels. These specific modulators are powerful probes for investigating the structural and functional features of Nav channels. Here, we report the isolation and characterization of δ-theraphotoxin-Gr4b (Gr4b), a novel peptide toxin from the venom of the spider Grammostola rosea. Gr4b contains 37-amino acid residues with six cysteines forming three disulfide bonds. Patch-clamp analysis confirmed that Gr4b markedly slows the fast inactivation of Nav1.9 and inhibits the currents of Nav1.4 and Nav1.7, but does not affect Nav1.8. It was also found that Gr4b significantly shifts the steady-state activation and inactivation curves of Nav1.9 to the depolarization direction and increases the window current, which is consistent with the change in the ramp current. Furthermore, analysis of Nav1.9/Nav1.8 chimeric channels revealed that Gr4b preferentially binds to the voltage-sensor of domain III (DIII VSD) and has additional interactions with the DIV VSD. The site-directed mutagenesis analysis indicated that N1139 and L1143 in DIII S3-S4 linker participate in toxin binding. In sum, this study reports a novel spider peptide toxin that may slow the fast inactivation of Nav1.9 by binding to the new neurotoxin receptor site-DIII VSD. Taken together, these findings provide insight into the functional role of the Nav channel DIII VSD in fast inactivation and activation.

Combined Pharmacophore and Grid-Independent Molecular Descriptors (GRIND) Analysis to Probe 3D Features of Inositol 1,4,5-Trisphosphate Receptor (IP3R) Inhibitors in Cancer

Inositol 1, 4, 5-trisphosphate receptor (IP3R)-mediated Ca2+ signaling plays a pivotal role in different cellular processes, including cell proliferation and cell death. Remodeling Ca2+ signals by targeting the downstream effectors is considered an important hallmark in cancer progression. Despite recent structural analyses, no binding hypothesis for antagonists within the IP3-binding core (IBC) has been proposed yet. Therefore, to elucidate the 3D structural features of IP3R modulators, we used combined pharmacoinformatic approaches, including ligand-based pharmacophore models and grid-independent molecular descriptor (GRIND)-based models. Our pharmacophore model illuminates the existence of two hydrogen-bond acceptors (2.62 Å and 4.79 Å) and two hydrogen-bond donors (5.56 Å and 7.68 Å), respectively, from a hydrophobic group within the chemical scaffold, which may enhance the liability (IC50) of a compound for IP3R inhibition. Moreover, our GRIND model (PLS: Q2 = 0.70 and R2 = 0.72) further strengthens the identified pharmacophore features of IP3R modulators by probing the presence of complementary hydrogen-bond donor and hydrogen-bond acceptor hotspots at a distance of 7.6–8.0 Å and 6.8–7.2 Å, respectively, from a hydrophobic hotspot at the virtual receptor site (VRS). The identified 3D structural features of IP3R modulators were used to screen (virtual screening) 735,735 compounds from the ChemBridge database, 265,242 compounds from the National Cancer Institute (NCI) database, and 885 natural compounds from the ZINC database. After the application of filters, four compounds from ChemBridge, one compound from ZINC, and three compounds from NCI were shortlisted as potential hits (antagonists) against IP3R. The identified hits could further assist in the design and optimization of lead structures for the targeting and remodeling of Ca2+ signals in cancer.

Identification of potential inhibitors of SARS-CoV-2 S protein–ACE2 interaction by in silico drug repurposing

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a new coronavirus discovered that appeared in Wuhan, China, in December 2019, causes COVID-19 disease which have resulted in cases similar to SARS-atypical pneumonia. Worldwide, around 116 million cases and 2.57 million deaths are reported with new cases and increasing mortality every day. To date, there is no specific commercial treatment to control the infection. Repurpose drugs targeting the angiotensin-converting enzyme 2 (ACE2) receptor represents an alternative strategy to block the binding of SARS-CoV-2 protein S and forestall virus adhesion, internalization, and replication in the host cell. Methods: We performed a rigid molecular docking using the receptor binding domain of the S1 subunit of S protein (RBD S1)-ACE2 (PDB ID: 6VW1) interaction site and 1,283 drugs FDA approved. The docking score, frequency of the drug in receptor site, and interactions at the binding site residues were used as analyzing criteria. Results: This research yielded 40 drugs identified as a potential inhibitor of RBD S1-ACE2 interaction. Among the inhibitors, compounds such as ipratropium, formoterol, and fexofenadine can be found. Specialists employ these drugs as therapies to treat chronic obstructive pulmonary disease, asthma and virtually any respiratory infection. Conclusions: Our results will serve as the basis for in vitro and in vivo studies to evaluate the potential use of those drugs to generate affordable and convenient therapies to treat COVID-19.

Offline analysis of the chemical composition and hygroscopicity of sub-micrometer aerosol at an Asian outflow receptor site and comparison with online measurements

Filter-based offline analysis of atmospheric aerosol hygroscopicity coupled to composition analysis provides information complementary to that obtained from online analysis. However, its application itself and comparison to online analysis have remained limited to date. In this study, daily submicrometer aerosol particles (PM0.95, 50 % cutoff diameter: 0.95 μm) were collected onto quartz fiber filters in Okinawa Island, a receptor of East Asian outflow, in the autumn of 2015. The chemical composition of water-soluble matter (WSM) in PM0.95 and PM0.95 itself, and their respective hygroscopicities were characterized through the offline use of an aerosol mass spectrometer and a hygroscopicity tandem differential mobility analyzer. Thereafter, results were compared with those obtained from online analyses. Sulfate dominated the WSM mass (60 %), followed by water-soluble organic matter (WSOM, 20 %) and ammonium (13 %). WSOM accounted for most (93 %) of the mass of extracted organic matter (EOM) and the atomic O to C ratios (O : C) of WSOM and EOM were high (mean ± standard deviation were, respectively, 0.84 ± 0.08 and 0.79 ± 0.08), both of which indicate highly aged characteristics of the observed aerosol. The hygroscopic growth curves showed clear hysteresis for most samples. At 85 % RH, the calculated hygroscopicity parameter κ of the WSM (κWSM), WSOM, EOM, and PM0.95 (κPM0.95) were, respectively, 0.50 ± 0.03, 0.22 ± 0.12, 0.20 ± 0.11, and 0.47 ± 0.03. An analysis using the thermodynamic E-AIM model shows, on average, that inorganic salts and WSOM respectively contributed 88 % and 12 % of the κWSM (or κPM0.95). High similarities were found between offline and online analysis for chemical compositions that are related to particle hygroscopicity (the mass fractions and O : C of organics, and the degree of neutralization), and also for aerosol hygroscopicity. As possible factors governing the variation of κWSM, the influences of WSOM abundance and the neutralization of inorganic salts were assessed. At high RH (70–90 %), the hygroscopicity of WSM and PM0.95 was affected considerably by the presence of organic components; at low RH (20–50 %), the degree of neutralization could be important. This study not only characterized aerosol hygroscopicity at the receptor site of East Asian outflow, but also shows that the offline hygroscopicity analysis is an appropriate method, at least for aerosols of the studied type. The results encourage further applications to other environments and to more in-depth hygroscopicity analysis, in particular for organic fractions.

Carrying G allele in rs786204926 involved in alternative splicing of PTEN is associated with chemosensitivity in breast cancer

Background Chemoresistance is still the main reason for the failure of breast cancer treatment and is the main cause of death of breast cancer patients. Although many studies have shown the association between genetic polymorphisms of PTEN and chemoresistance, the molecular mechanism of breast cancer chemotherapy has not been further studied. This study aims to investigate the potential association between novel PTEN gene polymorphism and breast chemoresistance in Chinese population, and explore whether alternative splicing of the PTEN gene is affected by the gene polymorphism. Methods The study included 234 patients with breast cancer chemotherapy, 157 chemosensitive cases and 77 chemoresistant case. rs786204926, rs701848, rs12402181, rs35770269 were analysed using Sanger sequence and Sequenom MassArray typing technology. Silicon analysis was used to predict whether and how the polymorphism affects alternative splicing. Semi-quantitative RT-PCR and Western blot were further used to validate the silicon analysis. Results It is showed that there was a significant association between rs786204926 polymorphism and breast cancer chemoresistance. Carrying G allele or AG genotype will increase the risk of chemosensitivity in breast cancer. Additionally, Logistic multivariate regression analysis showed that age, lymph node metastasis and rs786204926 genotype are risk factors for breast cancer chemoresistance. Furthermore, Silico analysis showed that carrying G allele or AG genotype in chemosensitivity samples produced a new receptor site of alternative splicing, which increases the possibility of a new mutant PTEN isoform production. Interestingly, further experiments also verify this possibility. Conclusion We speculate that the mechanism of breast cancer chemosensitivity might be caused by a change in alternative splicing caused by the rs786204926 of PTEN gene. Thus, our study might provide theoretical guidance for the individualized treatment of clinical breast cancer patients.