Investigating potential inhibitory effect of Uncaria tomentosa (Cat's Claw) against the main protease 3CL pro of SARS-CoV-2 by molecular modeling

COVID-19 is a disease caused by severe acute respiratory syndrome coronavirus 2. Presently, there is no effective treatment for COVID-19. As part of the worldwide efforts to find efficient therapies and preventions, it has been reported the crystalline structure of the SARS-CoV-2 main protease M pro (also called 3CL pro) bound to a synthetic inhibitor, which represents a major druggable target. The druggability of M pro could be used for discovering drugs to treat COVID-19. A multilevel computational study was carried out to evaluate the potential antiviral properties of the components of the medicinal herb Uncaria tomentosa (Cat's claw), focusing on the inhibition of M pro. The in silico approach starts with protein-ligand docking of 26 Cat's claw key components, followed by ligand pathway calculations, molecular dynamics simulations, and MM-GBSA calculation of the free energy of binding for the best docked candidates. The structural bioinformatics approaches led to identification of three bioactive compounds of Uncaria tomentosa (speciophylline, cadambine, and proanthocyanidin B2) with potential therapeutic effects by strong interaction with 3CL pro. Additionally, in silico drug-likeness indices for these components were calculated and showed good predicted therapeutic profiles of these phytochemicals. Our findings suggest the potential effectiveness of Cat's claw as complementary and/or alternative medicine for COVID-19 treatment

Galaxy cluster mass bias from projected mass maps: The Three Hundred-NIKA2 LPSZ twin samples

The determination of the mass of galaxy clusters from observations is subject to systematic uncertainties. Beyond the errors due to instrumental and observational systematic effects, in this work we investigate the bias introduced by modelling assumptions. In particular, we consider the reconstruction of the mass of galaxy clusters from convergence maps employing spherical mass density models. We make use of The Three Hundred simulations, selecting clusters in the same redshift and mass range as the NIKA2 Sunyaev-Zel'dovich Large Program sample: $3 \leq M_{500}/ 10^{14} \mathrm{M}_{\odot} \leq 10$ and $0.5 \leq z \leq 0.9$. We study different modelling and intrinsic uncertainties that should be accounted for when using the single cluster mass estimates for scaling relations. We confirm that the orientation of clusters and the radial ranges considered for the fit have an important impact on the mass bias. The effect of the projection adds uncertainties to the order of $10\%$ to $14\%$ to the mass estimates. We also find that the scatter from cluster to cluster in the mass bias when using spherical mass models is less than $20\%$ of the true mass of the clusters

Colorectal Cancer Chemoprevention by <i>S</i>-Allyl Cysteine–Caffeic Acid Hybrids: In Vitro Biological Activity and In Silico Studies

Conventional chemotherapy for colorectal cancer (CRC) gives only a small increase in patient survival, since it is often diagnosed at late stages, when the tumor has disseminated to other organs. Moreover, it is common to observe that malignant cells may acquire resistance to conventional chemotherapies through different mechanisms, including reducing drug activation or accumulation (by enhancing efflux), inducing alterations in molecular targets, and inhibiting the DNA damage response, among other strategies. Considering these facts, the discovery of new molecules with therapeutic potential has become an invaluable tool in chemoprevention. In this context, we previously evaluated two hybrids (SAC-CAFA-MET and SAC-CAFA-PENT) that exhibited selective cytotoxicity against SW480 cells, with better results than the conventional chemotherapeutic agent (5-fluorouracil; 5-FU). Here, we investigated the possible mechanisms of these molecules in greater depth, to identify whether they could be valuable therapeutic scaffolds in the search for new molecules with chemopreventive potential for the treatment of CRC. Both compounds reduced ROS formation, which could be related to antioxidant effects. Further evaluations showed that SAC-CAFA-MET induces cell death independent of caspases and the tumor-suppressor protein p53, but probably mediated by the negative regulation of the pro-apoptotic Bcl-2. In addition, the lack of activation of caspase-8 and the positive regulation of caspase-3 induced by SAC-CAFA-PENT suggest that this compound acts through an apoptotic mechanism, probably initiated by intrinsic pathways. Furthermore, the downregulation of IL-6 by SAC-CAFA-PENT suggests that it also induces a significant anti-inflammatory process. In addition, docking studies would suggest caspase-3 modulation as the primary mechanism by which SAC-CAFA-PENT elicits apoptosis in SW480human colorectal adenocarcinoma cells. Meanwhile, density functional theory (DFT) calculations suggest that both hybrids would produce effects in the modulation of ROS in SW480 cells via the hydrogen atom transfer (HAT) pathway. The present work notes that SAC-CAFA-MET and SAC-CAFA-PENT could be potential candidates for further investigations in the search for potential chemopreventive agents

Galaxy cluster mass bias from projected mass maps: The Three Hundred-NIKA2 LPSZ twin samples

International audienceThe determination of the mass of galaxy clusters from observations is subject to systematic uncertainties. Beyond the errors due to instrumental and observational systematic effects, in this work we investigate the bias introduced by modelling assumptions. In particular, we consider the reconstruction of the mass of galaxy clusters from convergence maps employing spherical mass density models. We make use of The Three Hundred simulations, selecting clusters in the same redshift and mass range as the NIKA2 Sunyaev-Zel'dovich Large Program sample: $3 \leq M_{500}/ 10^{14} \mathrm{M}_{\odot} \leq 10$ and $0.5 \leq z \leq 0.9$. We study different modelling and intrinsic uncertainties that should be accounted for when using the single cluster mass estimates for scaling relations. We confirm that the orientation of clusters and the radial ranges considered for the fit have an important impact on the mass bias. The effect of the projection adds uncertainties to the order of $10\%$ to $14\%$ to the mass estimates. We also find that the scatter from cluster to cluster in the mass bias when using spherical mass models is less than $20\%$ of the true mass of the clusters

Galaxy cluster mass bias from projected mass maps: The Three Hundred-NIKA2 LPSZ twin samples

International audienceThe determination of the mass of galaxy clusters from observations is subject to systematic uncertainties. Beyond the errors due to instrumental and observational systematic effects, in this work we investigate the bias introduced by modelling assumptions. In particular, we consider the reconstruction of the mass of galaxy clusters from convergence maps employing spherical mass density models. We make use of The Three Hundred simulations, selecting clusters in the same redshift and mass range as the NIKA2 Sunyaev-Zel'dovich Large Program sample: $3 \leq M_{500}/ 10^{14} \mathrm{M}_{\odot} \leq 10$ and $0.5 \leq z \leq 0.9$. We study different modelling and intrinsic uncertainties that should be accounted for when using the single cluster mass estimates for scaling relations. We confirm that the orientation of clusters and the radial ranges considered for the fit have an important impact on the mass bias. The effect of the projection adds uncertainties to the order of $10\%$ to $14\%$ to the mass estimates. We also find that the scatter from cluster to cluster in the mass bias when using spherical mass models is less than $20\%$ of the true mass of the clusters

Carvacrol: An In Silico Approach of a Candidate Drug on HER2, PI3Kα, mTOR, hER-α, PR, and EGFR Receptors in the Breast Cancer

Carvacrol is a phenol monoterpene found in aromatic plants specially in Lamiaceae family, which has been evaluated in an experimental model of breast cancer. However, any proposed mechanism based on its antitumor effect has not been reported. In our previous study, carvacrol showed a protective effect on 7,12-dimethylbenz[α]anthracene- (DMBA-) induced breast cancer in female rats. The main objective in this research was to evaluate by using in silico study the carvacrol on HER2, PI3Kα, mTOR, hER-α, PR, and EGFR receptors involved in breast cancer progression by docking analysis, molecular dynamic, and drug-likeness evaluation. A multilevel computational study to evaluate the antitumor potential of carvacrol focusing on the main targets involved in the breast cancer was carried out. The in silico study starts with protein-ligand docking of carvacrol followed by ligand pathway calculations, molecular dynamic simulations, and molecular mechanics energies combined with the Poisson–Boltzmann (MM/PBSA) calculation of the free energy of binding for carvacrol. As result, the in silico study led to the identification of carvacrol with strong binding affinity on mTOR receptor. Additionally, in silico drug-likeness index for carvacrol showed a good predicted therapeutic profile of druggability. Our findings suggest that mTOR signaling pathway could be responsible for its preventive effect in the breast cancer

The impact of surgical delay on resectability of colorectal cancer: An international prospective cohort study

AimThe SARS-CoV-2 pandemic has provided a unique opportunity to explore the impact of surgical delays on cancer resectability. This study aimed to compare resectability for colorectal cancer patients undergoing delayed versus non-delayed surgery.MethodsThis was an international prospective cohort study of consecutive colorectal cancer patients with a decision for curative surgery (January-April 2020). Surgical delay was defined as an operation taking place more than 4 weeks after treatment decision, in a patient who did not receive neoadjuvant therapy. A subgroup analysis explored the effects of delay in elective patients only. The impact of longer delays was explored in a sensitivity analysis. The primary outcome was complete resection, defined as curative resection with an R0 margin.ResultsOverall, 5453 patients from 304 hospitals in 47 countries were included, of whom 6.6% (358/5453) did not receive their planned operation. Of the 4304 operated patients without neoadjuvant therapy, 40.5% (1744/4304) were delayed beyond 4 weeks. Delayed patients were more likely to be older, men, more comorbid, have higher body mass index and have rectal cancer and early stage disease. Delayed patients had higher unadjusted rates of complete resection (93.7% vs. 91.9%, P = 0.032) and lower rates of emergency surgery (4.5% vs. 22.5%, P ConclusionOne in 15 colorectal cancer patients did not receive their planned operation during the first wave of COVID-19. Surgical delay did not appear to compromise resectability, raising the hypothesis that any reduction in long-term survival attributable to delays is likely to be due to micro-metastatic disease