Recycling facemasks into civil construction material to manage waste generated during COVID-19.

Growing plastic pollution in the context of COVID-19 has caused significant challenges, exacerbating this already out-of-control issue. The pandemic has considerably boosted the demand for personal protective equipment (PPE), such as facemasks and gloves, all over the globe, and mismanaging this growing plastic pollution has harmed the environment and wildlife significantly. To mitigate negative environmental impacts, it is necessary to develop and implement effective waste management strategies. This present study estimated the daily facemask generation throughout the pandemic in Iran based on the distribution of urban and rural populations and, likewise, the daily generation of hand gloves in the COVID-19 era and the amount of medical waste generated by COVID-19 patients were calculated. In the next step, the quantities of discarded facemasks dumped into the Caspian Sea, the Persian Gulf, and the Gulf of Oman from the coastal cities were determined. Finally, the innovative alternatives for repurposing discarded facemasks in civil construction materials such as concrete, pavement, and partition wall panel were discussed.

Novel 1,4 benzothiazine 3-one derivatives as anticonvulsant agents: Design, synthesis, biological evaluation and computational studies.

In this study, two series of novel 1,4-benzothiazine-3-one derivatives with alkyl substitution (series 1: 4a-4f) and aryl substitution (series 2: 4g-4l) were designed and synthesized based on the chemical scaffolds of perampanel, hydantoins, progabide and etifoxine as anti-convulsant agents. The chemical structures of the synthesized compounds were confirmed by FT-IR, 1H NMR and 13C NMR spectroscopy. Anti-convulsant effect of the compounds was examined through intraperitoneal pentylenetetrazol (i.p. PTZ) induced epilepsy mouse models. Compound 4h (4-(4-bromo-benzyl)- 4 H-benzo[b] [1,4] thiazin-3(4 H)-one) demonstrated a promising activity toward chemically-induced seizure experiment. Molecular dynamics simulation on GABA-Aergic receptors as a plausible mechanism were also done to achieve the binding and orientation of compounds in the active site of the target to evaluate the results of docking and experimental studies. The computational results were confirmed the biological activity. DFT study of 4c and 4h was performed on B3LYP/6-311 G** level of theory. Reactivity descriptors such as HOMO, LUMO, electron affinity, ionization potential, chemical potential, hardness and softness were studied in detail and show that 4h has higher activity than 4c. Also, the frequency calculations were performed on the same level of theory and the results are in line with experimental data. Moreover, in silico ADMET properties were done to establish a relationship between the physiochemical data of the designed compounds and their in-vivo activity. Appropriate plasma protein binding and high blood-brain barrier penetration are the main features of desired in-vivo performance.

Azolation of Benzylic C-H Bonds via Photoredox-Catalyzed Carbocation Generation.

A visible-light photoredox-catalyzed method is reported that enables the coupling between benzylic C-H substrates and N-H azoles. Classically, medicinally relevant N-benzyl azoles are produced via harsh substitution conditions between the azole and a benzyl electrophile in the presence of strong bases at high temperatures. Use of C-H bonds as the alkylating partner streamlines the preparation of these important motifs. In this work, we report the use of N-alkoxypyridinium salts as a critically enabling reagent for the development of a general C(sp3)-H azolation. The platform enables the alkylation of electron-deficient, -neutral, and -rich azoles with a range of C-H bonds, most notably secondary and tertiary partners. Moreover, the protocol is mild enough to tolerate benzyl electrophiles, thus offering an orthogonal approach to existing SN2 and cross-coupling methods.

Therapeutic potential of quinazoline derivatives for Alzheimer's disease: A comprehensive review.

Quinazolines are considered as a promising class of bioactive heterocyclic compounds with broad properties. Particularly, the quinazoline scaffold has an impressive role in the design and synthesis of new CNS-active drugs. The drug-like properties and pharmacological characteristics of quinazoline could lead to different drugs with various targets. Among CNS disorders, Alzheimer's disease (AD) is a progressive neurodegenerative disorder with memory loss, cognitive decline and language dysfunction. AD is a complex and multifactorial disease therefore, the need for finding multi-target drugs against this devastative disease is urgent. A literature survey revealed that quinazoline derivatives have diverse therapeutic potential for AD as modulators/inhibitors of ß-amyloid, tau protein, cholinesterases, monoamine oxidases, and phosphodiesterases as well as other protective effects. Thus, we describe here the most relevant and recent studies about anti-AD agents with quinazoline structure which can further aid the development and discovery of new anti-AD agents.

Carbamazepine removal from aqueous solution by synthesized reduced graphene oxide-nano zero valent iron (Fe0-rGO) composite: theory, process optimization, and coexisting drugs effects.

Synthesized Fe0-rGO nanocomposite with ratio of 1/1 (w/w) was prepared and has been used as adsorbent for the removal of Carbamazepine (CBZ) from aqueous solution. The adsorbent was characterized by various techniques such as Fourier-transform infrared spectroscopy (FTIR), energy-dispersive X-ray spectroscopy (EDX), X-ray diffraction (XRD), and Field Emission Scanning Electron Microscopy (FE-SEM) analyses. Linear experiments were performed to compare the best fitting isotherms and kinetics. The Freundlich isotherm (R2>0.90) and pseudo second order kinetic (R2>0.99) fitted well the experimental data. On the basis of the Langmuir isotherm, the maximum adsorption capacity of Fe0-rGO for CBZ was up to 50 mg g-1 at 30 °C. The pH, adsorbent dose, and initial concentration of CBZ were observed to be the leading parameters that affected the removal of CBZ considering the analysis of variance (ANOVA; p<0.05). The optimum process value of variables obtained by numerical optimization corresponds to pH 3.07, an adsorbent dose of 36.2 mg, an initial CBZ concentration of 5 mg L-1 and at 30.15 °C. The results of optimum conditions reveal that a maximum of 94% removal efficiency can be achieved; whereas, this phenomenon was independent of temperature (p-value>0.05). Moreover, Fe0-rGO can be used to remove diclofenac (DIC) and cetirizine (CTZ) simultaneously. To sum up, the Fe0-rGO is a promising adsorbent not only for the efficient removal of CBZ but also for the reduction of coexisting drugs in aqueous solution.

Docking, Synthesis and Evaluation of the Antifungal Activity of Pyrimido [4,5-b]quinolins.

In order to expand the application of Fe3O4@SiO2-SnCl4 in the synthesis of heterocyclic compounds, in this study, we wish to report the use of one-pot three component synthesis of pyrimido [4,5-b]quinolone derivatives ( D1-D16 ) through reaction of 6-amino-2-(methylthio)pyrimidin-4 (3H)-one, dimedone, or 1,3-cyclohexadione and aldehydes in the presence of Fe3O4@SiO2-SnCl4 as an efficient eco-friendly catalyst under ultrasound irradiation. The final aim of this study is evaluation of antifungal activity of resulted products. Synthesis of pyrimido [4,5-b]quinolin derivatives were done via three components coupling reaction of aldehyde, dimedone or 1,3-cyclohexadione and 6-amino-2-(methylthio)pyrimidin-4 (3H)-one in the presence of Fe3O4@SiO2-SnCl4 under ultrasonic irradiation in water at 60 °C. The products structure were studied by FT-IRI, 1H NMR,II and 13C NMRII. All the compounds were screened for antimicrobial activity by broth microdilution methods as recommended by CLSIIII. Considering our results showed that compound ( D13 ) had the most antifungal activity against C. dubliniensis, C. Albicans, C. Tropicalis, and C. Neoformance at concentrations ranging (MIC90) from 1-4 µg/mL. Compounds ( D9 ), ( D10 ), ( D14 ), and ( D15 ) had significant inhibitory activities against C. dubliniensis at concentrations ranging (MIC90) from 4-8 µg/mL, respectively. 5-(3,4-dihydroxyphenyl)-8,8-dimethyl-2-(methylthio)-5,8,9,10-tetrahydropyrimido[4,5-b]quinoline-4,6(3H,7H)-dione ( D13 ) exhibited inhibitory and fungicidal activities against the tested yeasts. The specific binding mode or the binding orientation of more efficient compounds to CYP51 active site, have been also performed by molecular modeling investigations and showed that there is a good correlation with biological test.

Extracellular NAD+ enhances PARP-dependent DNA repair capacity independently of CD73 activity.

Changes in nicotinamide adenine dinucleotide (NAD+) levels that compromise mitochondrial function trigger release of DNA damaging reactive oxygen species. NAD+ levels also affect DNA repair capacity as NAD+ is a substrate for PARP-enzymes (mono/poly-ADP-ribosylation) and sirtuins (deacetylation). The ecto-5'-nucleotidase CD73, an ectoenzyme highly expressed in cancer, is suggested to regulate intracellular NAD+ levels by processing NAD+ and its bio-precursor, nicotinamide mononucleotide (NMN), from tumor microenvironments, thereby enhancing tumor DNA repair capacity and chemotherapy resistance. We therefore investigated whether expression of CD73 impacts intracellular NAD+ content and NAD+-dependent DNA repair capacity. Reduced intracellular NAD+ levels suppressed recruitment of the DNA repair protein XRCC1 to sites of genomic DNA damage and impacted the amount of accumulated DNA damage. Further, decreased NAD+ reduced the capacity to repair DNA damage induced by DNA alkylating agents. Overall, reversal of these outcomes through NAD+ or NMN supplementation was independent of CD73. In opposition to its proposed role in extracellular NAD+ bioprocessing, we found that recombinant human CD73 only poorly processes NMN but not NAD+. A positive correlation between CD73 expression and intracellular NAD+ content could not be made as CD73 knockout human cells were efficient in generating intracellular NAD+ when supplemented with NAD+ or NMN.

Nano-SnCl4.SiO2, an efficient catalyst for synthesis of benzimidazole drivatives as antifungal and cytotoxic agents.

The concept of green chemistry has made significant impact on many frontages including the use of green solvents or sustainable catalyst materials. Benzimidazole ring is an important nitrogen-containing heterocyclic, which exhibits a broad spectrum of bioactivities and are widely utilized by the medicinal chemists for drug discovery. A simple and efficient method was developed for the synthesis of some benzimidazole derivatives via reaction of o-phenylenediamine and substituted aldehydes in the presence of nano-SnCl4/SiO2 as a mild catalyst. Ten 2-substituted benzimidazole compounds ( J1-J10 ) were synthesized. All compounds were evaluated against different species of yeasts and filament fungi using broth micro dilution method as recommended by clinical and laboratory standard institute. Among these compounds, the active ones were chosen for their cytotoxic activities evaluation against MCF-7 and A549 cell lines using MTT method. Compound J2 showed the best antifungal activity against all tested species. Compounds J5-J7 had also desirable antifungal activities. Our cytotoxic results were also similar to the antifungal activities except for J7 which had no cytotoxic activity.

High Cell Density Perfusion Culture has a Maintained Exoproteome and Metabolome.

The optimization of bioprocesses for biopharmaceutical manufacturing by Chinese hamster ovary (CHO) cells can be a challenging endeavor and, today, heavily relies on empirical methods treating the bioreactor process and the cells as black boxes. Multi-omics approaches have the potential to reveal otherwise unknown characteristics of these systems and identify culture parameters to more rationally optimize the cultivation process. Here, the authors have applied both metabolomic and proteomic profiling to a perfusion process, using CHO cells for antibody production, to explore how cell biology and reactor environment change as the cell density reaches ≥200 × 106 cells mL-1 . The extracellular metabolic composition obtained in perfusion mode shows a markedly more stable profile in comparison to fed-batch, despite a far larger range of viable cell densities in perfusion. This stable profile is confirmed in the extracellular proteosome. Furthermore, the proteomics data shows an increase of structural proteins as cell density increases, which could be due to a higher shear stress and explain the decrease in cell diameter at very high cell densities. Both proteomic and metabolic results shows signs of oxidative stress and changes in glutathione metabolism at very high cell densities. The authors suggest the methodology presented herein to be a powerful tool for optimizing processes of recombinant protein production.

UBE3B Is a Calmodulin-regulated, Mitochondrion-associated E3 Ubiquitin Ligase.

Recent genome-wide studies found that patients with hypotonia, developmental delay, intellectual disability, congenital anomalies, characteristic facial dysmorphic features, and low cholesterol levels suffer from Kaufman oculocerebrofacial syndrome (KOS, also reported as blepharophimosis-ptosis-intellectual disability syndrome). The primary cause of KOS is autosomal recessive mutations in the gene UBE3B However, to date, there are no studies that have determined the cellular or enzymatic function of UBE3B. Here, we report that UBE3B is a mitochondrion-associated protein with homologous to the E6-AP Cterminus (HECT) E3 ubiquitin ligase activity. Mutating the catalytic cysteine (C1036A) or deleting the entire HECT domain (amino acids 758-1068) results in loss of UBE3B's ubiquitylation activity. Knockdown of UBE3B in human cells induces changes in mitochondrial morphology and physiology, a decrease in mitochondrial volume, and a severe suppression of cellular proliferation. We also discovered that UBE3B interacts with calmodulin via its N-terminal isoleucine-glutamine (IQ) motif. Deletion of the IQ motif (amino acids 29-58) results in loss of calmodulin binding and a significant increase in the in vitro ubiquitylation activity of UBE3B. In addition, we found that changes in calcium levels in vitro disrupt the calmodulin-UBE3B interaction. These studies demonstrate that UBE3B is an E3 ubiquitin ligase and reveal that the enzyme is regulated by calmodulin. Furthermore, the modulation of UBE3B via calmodulin and calcium implicates a role for calcium signaling in mitochondrial protein ubiquitylation, protein turnover, and disease.

Conformational changes of 1-4-glucopyranosyl residues of a sulfated C-C linked hexasaccharide.

This work describes the structure of a fully sulfated maltotriose alpha-beta C-C linked dimer, where a central glycosidic bond was substituted by a non natural, hydrolase-resistant C-C bond. Such compound shows anti-metastatic properties being an inhibitor of the heparanase enzymatic activity and of P-selectin-mediated cell-cell interactions. NMR spectroscopy was applied to investigate the structure and conformational properties of this C-C linked hexasaccharide. The presence of sulfate substituents and the internal C-C bond drives the two internal rings in an unusual (1)C(4) chair conformation, while the external rings linked by glycosidic bonds retain the typical (4)C(1) conformation. The NMR results were confirmed by molecular mechanics calculations using structure corresponding di- and tetrasaccharides as models.

Discrimination among IgG1-kappa monoclonal antibodies produced by two cell lines using charge state distributions in nanoESI-TOF mass spectra.

Charge state distributions (CSDs) of proteins in nanoESI mass spectra are affected by the instrumental settings and experimental conditions, in addition to the conformations of the proteins in the analyzed solutions. In the presented study, instrumental and experimental parameters--the desolvation gas flow rate, temperature, pH, buffer (ammonium acetate), and organic modifier (methanol) concentrations--were optimized according to a reduced central composite face experimental design to maximize the separation of CSDs of monoclonal IgG1-kappa antibodies produced by two production systems (CHO and GS-NS0 cell lines). Principal component analysis and Fisher linear discriminant analysis were then used to reduce the dimensions of the acquired dataset and quantify the separation of the protein classes, respectively. The results show that the IgG1-kappa molecules produced by the two production systems can be clearly distinguished using the described approach, which could be readily applied to other proteins and production systems.

Conformational studies of a monoclonal antibody, IgG1, by chemical oxidation: structural analysis by ultrahigh-pressure LC-electrospray ionization time-of-flight MS and multivariate data analysis.

We describe the development of a method in which protein oxidation by H2O2 followed by ultrahigh-pressure liquid chromatography (UHPLC) coupled with electrospray ionization time-of-flight mass spectrometry (ESI-ToFMS) and multivariate analysis are used to detect alterations in conformational states of proteins. In the study reported here, an IgG1 monoclonal antibody in native and denatured conformational states was oxidized by treatment with hydrogen peroxide. Peptide fragments generated by tryptic digestion were then analyzed by UHPLC-ESI-ToFMS. After reducing noise and extracting peaks from the LC-MS data using MzExplorer, software developed in-house and based on Matlab, we were able to distinguish peptides arising from the native and denatured states of the oxidized protein by principal component analysis. Peptides containing residues, which are inclined to undergo oxidation, such as methionine, are founded to be particularly important in this approach. We believe that the methodology could facilitate attempts to characterize the conformational states of recombinant monoclonal antibodies and other proteins.

Metabolic fingerprinting of rat urine by LC/MS Part 2. Data pretreatment methods for handling of complex data.

Metabolic fingerprinting of biofluids like urine is a useful technique for detecting differences between individuals. With this approach, it might be possible to classify samples according to their biological relevance. In Part 1 of this work a method for the comprehensive screening of metabolites was described, using two different liquid chromatography (LC) column set-ups and detection by electrospray ionization mass spectrometry (ESI-MS). Data pretreatment of the resulting data described in is needed to reduce the complexity of the data and to obtain useful metabolic fingerprints. Three different approaches, i.e., reduced dimensionality (RD), MarkerLynx, and MS Resolver, were compared for the extraction of information. The pretreated data were then subjected to multivariate data analysis by partial least squares discriminant analysis (PLS-DA) for classification. By combining two different chromatographic procedures and data analysis, the detection of metabolites was enhanced as well as the finding of metabolic fingerprints that govern classification. Additional potential biomarkers or xenobiotic metabolites were detected in the fraction containing highly polar compounds that are normally discarded when using reversed-phase liquid chromatography.

Metabolic fingerprinting of rat urine by LC/MS Part 1. Analysis by hydrophilic interaction liquid chromatography-electrospray ionization mass spectrometry.

Complex biological samples, such as urine, contain a very large number of endogenous metabolites reflecting the metabolic state of an organism. Metabolite patterns can provide a comprehensive signature of the physiological state of an organism as well as insights into specific biochemical processes. Although the metabolites excreted in urine are commonly highly polar, the samples are generally analyzed using reversed-phase liquid chromatography mass spectrometry (RP-LC/MS). In Part 1 of this work, a method for detecting highly polar metabolites by hydrophilic interaction liquid chromatography-electrospray ionization mass spectrometry (HILIC/ESI-MS) is described as a complement to RP-LC/ESI-MS. In addition, in an accompanying paper (Part 2), different multivariate approaches to extracting information from the resulting complex data are described to enable metabolic fingerprints to be obtained. The coverage of the method for the screening of as many metabolites as possible is highly improved by analyzing the urine samples using both a C(18) column and a ZIC-HILIC column. The latter was found to be a good alternative when analyzing highly polar compounds, e.g., hydroxyproline and creatinine, to columns typically used for reversed-phase liquid chromatography.