Miracle-dz/UniFAR-FTUs huggingface dataset:
Cytochrome P450 3A Time-Dependent Inhibition Assays Are Too Sensitive for Identification of Drugs Causing Clinically Significant Drug-Drug Interactions: A Comparison of Human Liver Microsomes and Hepatocytes and Definition of Boundaries for Inactivation Rate Constants

Time-dependent inhibition (TDI) of CYP3A is an important mechanism underlying numerous drug-drug interactions (DDIs), and assays to measure this are done to support early drug research efforts. However, measuring TDI of CYP3A in human liver microsomes (HLMs) frequently yields overestimations of clinical DDIs and thus can lead to the erroneous elimination of many viable drug candidates from further development. In this investigation, 50 drugs were evaluated for TDI in HLMs and suspended human hepatocytes (HHEPs) to define appropriate boundary lines for the TDI parameter rate constant for inhibition (kobs) at a concentration of 30 µM. In HLMs, a kobs value of 0.002 minute−1 was statistically distinguishable from control; however, many drugs show kobs greater than this but do not cause DDI. A boundary line defined by the drug with the lowest kobs that causes a DDI (diltiazem) was established at 0.01 minute−1. Even with this boundary, of the 33 drugs above this value, only 61% cause a DDI (true positive rate). A corresponding analysis was done using HHEPs; kobs of 0.0015 minute−1 was statistically distinguishable from control, and the boundary was established at 0.006 minute−1. Values of kobs in HHEPs were almost always lower than those in HLMs. These findings offer a practical guide to the use of TDI data for CYP3A in early drug-discovery research. Significance Statement Time-dependent inhibition of CYP3A is responsible for many drug interactions. In vitro assays are employed in early drug research to identify and remove CYP3A time-dependent inhibitors from further consideration. This analysis demonstrates suitable boundaries for inactivation rates to better delineate drug candidates for their potential to cause clinically significant drug interactions.
Repurposing of approved drug molecules for viral infectious diseases: a molecular modelling approach

Abstract The identification of new viral drugs has become a task of paramount significance due to the frequent occurrence of viral infections and especially during the current pandemic. Despite the recent advancements, the development of antiviral drugs has not made parallel progress. Reduction of time frame and cost of the drug development process is the major advantage of drug repurposing. Therefore, in this study, a drug repurposing strategy using molecular modelling techniques, i.e. biological activity prediction, virtual screening, and molecular dynamics simulation was employed to find promising repurposing candidates for viral infectious diseases. The biological activities of non-redundant (4171) drug molecules were predicted using PASS analysis, and 1401 drug molecules were selected which showed antiviral activities in the analysis. These drug molecules were subjected to virtual screening against the selected non-structural viral proteins. A series of filters, i.e. top 10 drug molecules based on binding affinity, mean value of binding affinity, visual inspection of protein-drug complexes, and number of H-bond between protein and drug molecules were used to narrow down the drug molecules. Molecular dynamics simulation analysis was carried out to validate the intrinsic atomic interactions and binding conformations of protein-drug complexes. The binding free energies of drug molecules were assessed by employing MMPBSA analysis. Finally, nine drug molecules were prioritized, as promising repurposing candidates with the potential to inhibit the selected non-structural viral proteins. Communicated by Ramaswamy H. Sarma
Metabolite Profiling and Characterization of LW6, a Novel HIF-1α Inhibitor, as an Antitumor Drug Candidate in Mice

A novel HIF (hypoxia-inducible factor)-1α inhibitor, the (aryloxyacetylamino)benzoic acid derivative LW6, is an anticancer agent that inhibits the accumulation of HIF-1α. The aim of this study was to characterize and determine the structures of the metabolites of LW6 in ICR mice. Metabolite identification was performed using a predictive multiple reaction monitoring-information dependent acquisition-enhanced product ion (pMRM-IDA-EPI) method in negative ion mode on a hybrid triple quadrupole-linear ion trap mass spectrometer (QTRAP). A total of 12 metabolites were characterized based on their MS/MS spectra, and the retention times were compared with those of the parent compound. The metabolites were divided into five structural classes based on biotransformation reactions: amide hydrolysis, ester hydrolysis, mono-oxidation, glucuronidation, and a combination of these reactions. From this study, 2-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)acetic acid (APA, M7), the metabolite produced via amide hydrolysis, was found to be a major circulating metabolite of LW6 in mice. The results of this study can be used to improve the pharmacokinetic profile by lowering the clearance and increasing the exposure relative to LW6.
5-O-methylcneorumchromone K Exerts Antinociceptive Effects in Mice via Interaction with GABAA Receptors

The proper pharmacological control of pain is a continuous challenge for patients and health care providers. Even the most widely used medications for pain treatment are still ineffective or unsafe for some patients, especially for those who suffer from chronic pain. Substances containing the chromone scaffold have shown a variety of biological activities, including analgesic effects. This work presents for the first time the centrally mediated antinociceptive activity of 5-O-methylcneorumchromone K (5-CK). Cold plate and tail flick tests in mice showed that the 5-CK-induced antinociception was dose-dependent, longer-lasting, and more efficacious than that induced by morphine. The 5-CK-induced antinociception was not reversed by the opioid antagonist naloxone. Topological descriptors (fingerprints) were employed to narrow the antagonist selection to further investigate 5-CK’s mechanism of action. Next, based on the results of fingerprints analysis, functional antagonist assays were conducted on nociceptive tests. The effect of 5-CK was completely reversed in both cold plate and tail-flick tests by GABAA receptor antagonist bicuculline, but not by atropine or glibenclamide. Molecular docking studies suggest that 5-CK binds to the orthosteric binding site, with a similar binding profile to that observed for bicuculline and GABA. These results evidence that 5-CK has a centrally mediated antinociceptive effect, probably involving the activation of GABAergic pathways.
Gold-Based Nanoplataform for the Treatment of Anaplastic Thyroid Carcinoma: A Step Forward

Simple Summary Anaplastic thyroid carcinoma (ATC) is a subtype of thyroid cancer that generally does not respond to the available treatments, making it one of the most lethal cancers known. As an alternative, Photothermal Therapy (PTT) can be considered a promising strategy. In this case, gold nanoparticles (AuNPs) are activated when irradiated by light, enhancing the local temperature, resulting in cell death. Thus, this study aims to formulate AuNPs specifically for targeting PTT to ATC. For this, biocompatible AuNPs were designed and functionalized with ATC-specific ligands (holo-transferrin, epidermal growth factor (EGF), and lapatinib), showing optimal physicochemical properties. Safety, efficacy, and ATC specificity were determined in vitro. Holo-transferrin functionalized-AuNPs were the most effective for PTT against ATC. Safety and biodistribution were studied in vivo, proving that the formulation was safe for intratumoural administration. So, taking these results all together, AuNPs-mediated-PTT seems to be a promising hint to find a viable treatment for ATC. Abstract Anaplastic thyroid carcinoma (ATC) is a very rare subtype of thyroid carcinoma and one of the most lethal malignancies. Poor prognosis is mainly associated with its undifferentiated nature, inoperability, and failing to respond to the typically used therapies for thyroid cancer. Photothermal Therapy (PTT) entails using light to increase tissues’ temperature, leading to hyperthermia-mediated cell death. Tumours are more susceptible to heat as they are unable to dissipate it. By using functionalized gold nanoparticles (AuNPs) that transform light energy into heat, it is possible to target the heat to the tumour. This study aims to formulate ATC-targeted AuNPs able to convert near-infrared light into heat, for PTT of ATC. Different AuNPs were synthetized and coated. Size, morphology, and surface plasmon resonances band were determined. The optimized coated-AuNPs were then functionalized with ligands to assess ATC’s specificity. Safety, efficacy, and selectivity were assessed in vitro. The formulations were deemed safe when not irradiated (>70% cell viability) and selective for ATC. However, when irradiated, holo-transferrin-AuNPs were the most cytotoxic (22% of cell viability). The biodistribution and safety of this formulation was assessed in vivo. Overall, this novel formulation appears to be a highly promising approach to evaluate in a very near future.
Exploring Factors Associated with Functional Change and Predictors of Participation Improvement—A Two Years Follow-Up on People with Depression

The purpose of this study is to understand the functional status distribution and to explore the factors associated with changes in functional status and social participation in people with depression using two-year follow-up data. Subjects were selected from the Taiwan Databank of Persons with Disabilities (TDPD) if they had an evaluation date between July 2012 and 31 December 2017. We used data for 1138 individuals with multiple evaluation records and who were diagnosed with depression. The WHO Disability Assessment Schedule 2.0 (WHODAS 2.0) was the primary functional status measure. Other factors selected from the TDPD included social demographic data, living situation, employment status, economic status, and educational level. The results show scores in all dimensions of the WHODAS 2.0 declined over two years, especially in the domains of cognition, household activities, social participation, and total WHODAS 2.0 score. Aging groups showed poor recovery in cognition, getting along with others, and household activities. People living in suburban areas showed poorer recovery than people living in rural and urban areas in cognition, self-care, and general function (total score of WHODAS 2.0). Employment was also strongly associated with functional recovery in household activities, social participation, and general function. The original scores for cognition and getting along with others showed a significant negative relationship with social participation improvement. Our results can be used by policy makers to provide resources and conduct investigations, and by clinicians when making rehabilitation plans.
Modeling the Invasion of the Large Hive Beetle, Oplostomus fuligineus, into North Africa and South Europe under a Changing Climate

Simple Summary Large Hive Beetles (LHBs) are common pests of honeybee colonies, especially in the African continent. The ability of this pest to invade new regions in North Africa and Europe is highlighted in the present study using a species distribution modeling technique in current and future climate change scenarios in 2050 and 2070. In brief, this pest will be a new burden on the beekeeping sector outside Africa, and therefore the development of early monitoring strategies is recommended. Abstract Some beetle species can attack honeybee colonies, causing severe damage to beekeeping. These pests include Oplostomus fuligineus, which is also known as the Large Hive Beetle (LHB). This beetle is native to Sub-Saharan Africa and has recently also been recorded in some parts of North Africa. It feeds mainly on young bee larvae and stored food within the colonies, causing severe damage to weak colonies. The present work sheds light on the current and future distribution (from 2050 to 2070) of this beetle in Africa and South Europe using species distribution modeling. Maxent was used to model the invasion of LHB. The Shared Socioeconomic Pathways (SSPs) 126 and 585 were used to model the future distribution of LHB. The Maxent models showed satisfactory results with a high Area Under Curve (AUC) value (0.85 ± 0.02). Furthermore, the True Skill Statistics (TSS) value was equal to 0.87. The current and future maps showed a high risk of invasion because of temperature variation in most of the parts of North Africa and South Europe. The maps also predicted the future invasion of LHB into other countries, mainly through southern Europe. These predictive risk maps will help quarantine authorities in highly relevant countries to prevent the expansion of this pest outside of its natural range.
Induction of Phlorotannins and Gene Expression in the Brown Macroalga Fucus vesiculosus in Response to the Herbivore Littorina littorea

Mechanisms related to the induction of phlorotannin biosynthesis in marine brown algae remain poorly known. Several studies undertaken on fucoid species have shown that phlorotannins accumulate in the algae for several days or weeks after being exposed to grazing, and this is measured by direct quantification of soluble phenolic compounds. In order to investigate earlier inducible responses involved in phlorotannin metabolism, Fucus vesiculosus was studied between 6 and 72 h of grazing by the sea snail Littorina littorea. In this study, the quantification of soluble phenolic compounds was complemented by a Quantitative real-time PCR (qRT-PCR) approach applied on genes that are potentially involved in either the phlorotannin metabolism or stress responses. Soluble phlorotannin levels remained stable during the kinetics and increased significantly only after 12 h in the presence of grazers, compared to the control, before decreasing to the initial steady state for the rest of the kinetics. Under grazing conditions, the expression of vbpo, cyp450 and ast6 genes was upregulated, respectively, at 6 h, 12 h and 24 h, and cyp450 gene was downregulated after 72 h. Interestingly, the pksIII gene involved in the synthesis of phloroglucinol was overexpressed under grazing conditions after 24 h and 72 h. This study supports the hypothesis that phlorotannins are able to provide an inducible chemical defense under grazing activity, which is regulated at different stages of the stress response.
Recent Advances of Taxol-Loaded Biocompatible Nanocarriers Embedded in Natural Polymer-Based Hydrogels

The discovery of paclitaxel (PTX) has been a milestone in anti-cancer therapy and has promoted the development and marketing of various formulations that have revolutionized the therapeutic approach towards several malignancies. Despite its peculiar anti-cancer activity, the physico-chemical properties of PTX compromise the administration of the compound in polar media. Because of this, since the development of the first Food and Drug Administration (FDA)-approved formulation (Taxol®), consistent efforts have been made to obtain suitable delivery systems able to preserve/increase PTX efficacy and to overcome the side effects correlated to the presence of some excipients. The exploitation of natural polymers as potential materials for drug delivery purposes has favored the modulation of the bioavailability and the pharmacokinetic profiles of the drug, and in this regard, several formulations have been developed that allow the controlled release of the active compound. In this mini-review, the recent advances concerning the design and applications of natural polymer-based hydrogels containing PTX-loaded biocompatible nanocarriers are discussed. The technological features of these formulations as well as the therapeutic outcome achieved following their administration will be described, demonstrating their potential role as innovative systems to be used in anti-tumor therapy.
l-Aspartate: An Essential Metabolite for Plant Growth and Stress Acclimation

L-aspartate (Asp) serves as a central building block, in addition to being a constituent of proteins, for many metabolic processes in most organisms, such as biosynthesis of other amino acids, nucleotides, nicotinamide adenine dinucleotide (NAD), the tricarboxylic acid (TCA) cycle and glycolysis pathway intermediates, and hormones, which are vital for growth and defense. In animals and humans, lines of data have proved that Asp is indispensable for cell proliferation. However, in plants, despite the extensive study of the Asp family amino acid pathway, little attention has been paid to the function of Asp through the other numerous pathways. This review aims to elucidate the most important aspects of Asp in plants, from biosynthesis to catabolism and the role of Asp and its metabolic derivatives in response to changing environmental conditions. It considers the distribution of Asp in various cell compartments and the change of Asp level, and its significance in the whole plant under various stresses. Moreover, it provides evidence of the interconnection between Asp and phytohormones, which have prominent functions in plant growth, development, and defense. The updated information will help improve our understanding of the physiological role of Asp and Asp-borne metabolic fluxes, supporting the modular operation of these networks.
Refractive‐Index Dispersion of Tellurite Glasses in the Region from 0.40 to 1.71 μm

The refractive index of binary tellurite glasses with various modifiers was measured down to the fifth decimal place in the wavelength range of 0.40-1.71 μm using the minimum-deviation method. An empirical equation based on the single-oscillator Drud-Voigt dispersion equation, n d 2 =A. Nfλ 0 2 +B, is obtained, where n d is the refractive index at 0.5876 μm, N is the number of molecules in a unit volume, f is the average oscillator strength, λ 0 is the average resonance wavelength, and A and B are constants. The refractive index n d of tellurite glasses is substantially determined by the resonance wavelength at the ultraviolet region, which is affected by the main constituent, TeO 2
Metagenomic Analysis of the Respiratory Microbiome of a Broiler Flock from Hatching to Processing

Elucidating the complex microbial interactions in biological environments requires the identification and characterization of not only the bacterial component but also the eukaryotic viruses, bacteriophage, and fungi. In a proof of concept experiment, next generation sequencing approaches, accompanied by the development of novel computational and bioinformatics tools, were utilized to examine the evolution of the microbial ecology of the avian trachea during the growth of a healthy commercial broiler flock. The flock was sampled weekly, beginning at placement and concluding at 49 days, the day before processing. Metagenomic sequencing of DNA and RNA was utilized to examine the bacteria, virus, bacteriophage, and fungal components during flock growth. The utility of using a metagenomic approach to study the avian respiratory virome was confirmed by detecting the dysbiosis in the avian respiratory virome of broiler chickens diagnosed with infection with infectious laryngotracheitis virus. This study provides the first comprehensive analysis of the ecology of the avian respiratory microbiome and demonstrates the feasibility for the use of this approach in future investigations of avian respiratory diseases.
Structural Features and Properties’ Characterization of Polylactic Acid/Natural Rubber Blends with Epoxidized Soybean Oil

Because of the effort to preserve petroleum resources and promote the development of eco-friendly materials, bio-based polymers produced from sustainable resources have attracted great attention. Among them, polylactide (PLA) and natural rubber (NR) present prominent polymers with unique barrier and mechanical features. A series of samples with improved phase compatibility were obtained by blending PLA and NR using a double-rotor mixer. A plasticizing and enhancing effect on the polymers’ compatibility was achieved by using epoxidized soybean oil (ESO) as a natural plasticizer and compatibilizer. ESO compounding in the PLA-NR blends increased the mobility of the biopolymer’s molecular chains and improved the thermal stability of the novel material. The size of the NR domains embedded in the continuous PLA matrix decreased with the ESO content increment. The combination of thermal analysis and scanning electron microscopy enabled the authors to determine the features of potential packaging material and the optimal content of PLA-NR-ESO for the best mechanical properties.
Subnormothermic Ex Vivo Lung Perfusion Temperature Improves Graft Preservation in Lung Transplantation

Abstract: Background Normothermic machine perfusion is clinically used to assess the quality of marginal donor lungs. Although subnormothermic temperatures have proven beneficial for other solid organ transplants, subnormothermia-related benefits of ex vivo lung perfusion (EVLP) still need to be investigated. Material and Methods: In a rat model, we evaluated the effects of 28 °C temperature on 4-h EVLPs with subsequent left lung transplantation. The recipients were observed for 2 h postoperatively. Lung physiology data were recorded and metabolic parameters were assessed. Results: During the 4-h subnormothermic EVLP, the lung oxygenation was significantly higher (p < 0.001), pulmonary vascular resistance (PVR) lower and dynamic compliance (Cdyn) higher when compared to the 37 °C EVLP. During an end-of-EVLP stress test, we recorded significantly higher flow (p < 0.05), lower PVR (p < 0.05) and higher Cdyn (p < 0.01) in the 28 °C group when compared to the 37 °C group. After the left lung transplantation, Cdyn and oxygenation improved in the 28 °C group, which were comparable to the 37 °C group. Chemokines RANTES, MIP-3α, MIP-1α MCP-1 GRO/KC and pro-inflammatory mediators GM-CSF, G-CSF and TNFα were significantly lower after the 28 °C EVLP and remained low in the plasma of the recipient rats after transplantation. The lungs of the 28 °C group showed significantly lowered myeloperoxidase activity and lowered levels of TNFα and IL-1β. Conclusions: Compared to the normothermic perfusion, the 28 °C EVLP improved Cdyn and PVR and reduced both the release of pro-inflammatory cytokines and myeloperoxidase activity in lung tissue. These observations were also observed after the left lung transplantation in the subnormothermic group. The 28 °C EVLP significantly improved biochemical, physiological and inflammatory parameters in lung donors.