Oral squamous cell carcinoma (OSCC) can arise anywhere in the oral cavity. OSCC's molecular pathogenesis is complex, resulting from a wide range of events that involve the interplay between genetic ...mutations and altered levels of transcripts, proteins, and metabolites. Platinum-based drugs are the first-line treatment for OSCC; however, severe side-effects and resistance are challenging issues. Thus, there is an urgent clinical need to develop novel and/or combinatory therapeutics. In this study, we investigated the cytotoxic effects of pharmacological concentrations of ascorbate on two human oral cell lines, the oral epidermoid carcinoma meng-1 (OECM-1) cell and the Smulow-Glickman (SG) human normal gingival epithelial cell. Our study examined the potential functional impact of pharmacological concentrations of ascorbates on the cell-cycle profiles, mitochondrial-membrane potential, oxidative response, the synergistic effect of cisplatin, and the differential responsiveness between OECM-1 and SG cells. Two forms of ascorbate, free and sodium forms, were applied to examine the cytotoxic effect and it was found that both forms had a similar higher sensitivity to OECM-1 cells than to SG cells. In addition, our study data suggest that the determinant factor of cell density is important for ascorbate-induced cytotoxicity in OECM-1 and SG cells. Our findings further revealed that the cytotoxic effect might be mediated through the induction of mitochondrial reactive oxygen species (ROS) generation and the reduction in cytosolic ROS generation. The combination index supported the agonistic effect between sodium ascorbate and cisplatin in OECM-1 cells, but not in SG cells. In summary, our current findings provide supporting evidence for ascorbate to serve as a sensitizer for platinum-based treatment of OSCC. Hence, our work provides not only repurposing of the drug, ascorbate, but also an opportunity to decrease the side-effects of, and risk of resistance to, platinum-based treatment for OSCC.
Density functional theory (DFT) has been carried out to investigate the electronic characteristics, UV–VIS–NIR absorption spectra, and nonlinear optical (NLO) properties of two series of zinc ...porphyrin analogs (FPD‐Nx and TPD‐Nx, x = 0–4) with donor‐π‐donor frameworks. The design of these analogs is based on previously synthesized furan‐linked zinc porphyrins (FPDs) and thiophene‐linked zinc porphyrins (TPDs). It is noted that their electro‐optical features are sensitive to the numbers of N‐coordination atoms and the attached groups. A dramatic enhancement of static first and second hyperpolarizabilities (β0 and γ0) occurs when two furan/thiophene rings are attached to the zinc porphyrin. Among the two series, FPD‐N3 and TPD‐N3 have the largest β0 values of about 7600 a.u. The static γ0 values of these complexes range from 0.41 × 106 to 1.79 × 106 a.u. The FPD‐Nx has a larger γ0 value than the corresponding TPD‐Nx, but the γ0 value of FPD‐N2 is close to that of TPD‐N2. In the dynamic NLO process, the electro‐optical Pockels effect, second harmonic generation, and electro‐optic Kerr effect can be enhanced at the wavelength of 1907 nm. This study provides a new strategy for the experimental design of high‐performance NLO materials.
The electronic and nonlinear optical properties of zinc porphyrins linked by furan/thiophene rings were investigated using density functional theory. The static first (β0) and second hyperpolarizability (γ0) are significantly enhanced when carbon atoms replace the coordinated N atoms of the porphyrin. In most cases, the β0/γ0 value of the complex with furan units is larger than that of the corresponding complex with thiophene rings.
The electronic and second‐order nonlinear optical (NLO) properties of small Agn clusters (n = 1 to 3) doped graphyne (GY) and pyrazine‐modified graphyne (pyGY) have been investigated employing ...(time‐dependent) density functional theory calculations. A large triangular hole of GY provides an efficient site to accommodate the Agn cluster, and an Ag atom prefers to be located in the center of the pyGY, interacting with the two pyridine N atoms. The silver clusters have strong interactions with GY/pyGY, and the intramolecular charge transfer is significant for determining NLO properties. The first hyperpolarizability (β0) values can be modulated by the introduction of silver clusters. The results show that the second‐order NLO response of Ag2/Ag3 doped pyGY complex is stronger than that of corresponding Ag2/Ag3 doped GY complex, while the β0 for single Ag doped GY is significantly higher than that of Ag@pyGY. Hence, the NLO responses of these complexes depend on the size of the clusters and the type of nanosheets. All complexes exhibit excellent transparency in the deep ultraviolet region, especially Ag3@GY/pyGY. These results suggest that these Agn clusters doped GY/pyGY are excellent candidates for potential applications in optical devices.
Small Agn clusters (n = 1–3) doped graphyne (GY) and pyrazine‐modified graphyne (pyGY) are constructed. By means of the density functional theory computations, the structures, electronic properties, and the first hyperpolarizabilities of these systems are investigated. The NLO responses of these complexes depend on the size of the clusters and the type of nanosheets. Ag@GY and Ag3@pyGY have the largest first hyperpolarizabilities in the two series.
Tumor necrosis factor-α (TNF-α) is a pro-inflammatory cytokine involved in pain processing and hypersensitivity. It regulates not only the expression of a variety of inflammatory mediators but also ...the functional activity of some ion channels. Acid-sensing ion channels (ASICs), as key sensors for extracellular protons, are expressed in nociceptive sensory neurons and contribute to pain signaling caused by tissue acidosis. It is still unclear whether TNF-α has an effect on functional activity of ASICs. Herein, we reported that a brief exposure of TNF-α acutely sensitized ASICs in rat dorsal root ganglion (DRG) neurons.
Electrophysiological experiments on rat DRG neurons were performed in vitro and acetic acid induced nociceptive behavior quantified in vitro.
A brief (5min) application of TNF-α rapidly enhanced ASIC-mediated currents in rat DRG neurons. TNF-α (0.1-10 ng/ml) dose-dependently increased the proton-evoked ASIC currents with an EC
value of 0.12 ± 0.01 nM. TNF-α shifted the concentration-response curve of proton upwards with a maximal current response increase of 42.34 ± 7.89%. In current-clamp recording, an acute application of TNF-α also significantly increased acid-evoked firing in rat DRG neurons. The rapid enhancement of ASIC-mediated electrophysiological activity by TNF-α was prevented by p38 mitogen-activated protein kinase (MAPK) inhibitor SB202190, but not by non-selective cyclooxygenase inhibitor indomethacin, suggesting that p38 MAPK is necessary for this enhancement. Behaviorally, TNF-α exacerbated acid-induced nociceptive behaviors in rats via activation of local p38 MAPK pathway.
These results suggest that TNF-α rapidly enhanced ASIC-mediated functional activity via a p38 MAPK pathway, which revealed a novel peripheral mechanism underlying TNF-α involvement in rapid hyperalgesia by sensitizing ASICs in primary sensory neurons.
Arsenicals have been widely used in the treatment of cancers such as leukemia and other tumors. However, their side effects limit their clinical application. Stiripentol, a second-line adjunctive ...treatment for epilepsy with a good safety profile, inhibits microsomal cytochrome-P450-family enzymes to extend the retention time of co-administration. Inspired by the metabolism of stiripentol, the 1,3-benzodioxole responsible for the inhibition and its metabolic derivatives were conjugated with arsenical precursors. The fabricated arsenicals were eliminated much slower in mice and maintained an efficient concentration in the blood for a longer time than that of the arsenical precursors. They also performed better in anti-proliferation by inhibiting the thioredoxin system to induce oxidative stress, and concomitantly to initiate apoptosis in vitro and in vivo. The fabricated arsenicals reversed the hemogram of tumor-bearing mice to normal and eliminated the tumor without causing damage to any organs, exhibiting a good design strategy and pre-clinical application for leukemia and other tumors.
The fouling of ultrafiltration (UF) and nanofiltration (NF) membranes during the treatment of surface waters continues to be of concern and the particular role of natural organic matter (NOM) ...requires further investigation. In this study the effect of pH and surface charge on membrane fouling during the treatment of samples of a representative surface water (Hyde Park recreational lake) were evaluated, together with the impact of pre-ozonation. While biopolymers in the surface water could be removed by the UF membrane, smaller molecular weight (MW) fractions of NOM were poorly removed, confirming the importance of membrane pore size. For NF membranes the removal of smaller MW fractions (800 Da–10 kDa) was less than expected from their pore size; however, nearly all of the hydrophobic, humic-type substances could be removed by the hydrophilic NF membranes for all MW distributions (greater than 90%). The results indicated the importance of the charge and hydrophilic nature of the NOM. Thus, the hydrophilic NF membrane could remove the hydrophobic organic matter, but not the hydrophilic substances. Increasing charge effects (more negative zeta potentials) with increasing solution pH were found to enhance organics removal and reduce fouling (flux decline), most likely through greater membrane surface repulsion. Pre-ozonation of the surface water increased the hydrophilic fraction and anionic charge of NOM and altered their size distributions. This resulted in a decreased fouling (less flux decline) for the UF and smaller pore NF, but a slight increase in fouling for the larger pore NF. The differences in the NF behavior are believed to relate to the relative sizes of ozonated organic fractions and the NF pores; a similar size of ozonated organic fractions and the NF pores causes significant membrane fouling.
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•Nearly all humic acid fractions could be removed by the hydrophilic NF membranes.•Hydrophilic NF membranes could not remove small MW hydrophilic NOM from surface water.•Higher pH or more negative zeta potentials of NOM were found to reduce fouling.•Membrane fouling depends on the comparative sizes of ozonated organic fractions and NF pores.
IL-1β mediates inflammation and regulates immune responses, cell proliferation, and differentiation. Dysregulation of IL-1β is linked to inflammatory and autoimmune diseases. Elevated IL-1β levels ...are found in patients with severe COVID-19, indicating its excessive production may worsen the disease. Also, dry eye disease patients show high IL-1β levels in tears and conjunctival epithelium. Therefore, IL-1β signaling is a potential therapeutic targeting for COVID-19 and aforementioned diseases. No small-molecule IL-1β inhibitor is clinically approved despite efforts. Developing such inhibitors is highly desirable. Herein, a docking-based strategy was used to screen the TCM (Traditional Chinese Medicine) database to identify possible IL-1β inhibitors with desirable pharmacological characteristics by targeting the IL-1β/IL-1R interface. Primarily, the docking-based screening was performed by selecting the crucial residues of IL-1β interface to retrieve the potential compounds. Afterwards, the compounds were shortlisted on the basis of binding scores and significant interactions with the crucial residues of IL-1β. Further, to gain insights into the dynamic behavior of the protein-ligand interactions, MD simulations were performed. The analysis suggests that four selected compounds were stabilized in an IL-1β pocket, possibly blocking the formation of an IL-1β/IL-1R complex. This indicates their potential to interfere with the immune response, making them potential therapeutic agents to investigate further.
A
bstract
I present a conjecture that all two-loop MHV amplitudes in planar
N
= 4 super-Yang-Mills theory possess an antipodal symmetry when evaluated on parity-even kinematics. The symmetry acts as ...a change of basis on the symbol letters, followed by the antipode operation associated with the Hopf algebra structure of multiple polylogarithms. At the symbol level, I provide the symmetry map explicitly for amplitudes with up to eight external particles, and also provide evidence at all multiplicities. Intriguingly, the map acts as an isomorphism on the normal fans of the Newton polytopes of the symbol letters. The conjectured symmetry is one of the rare known cases where the antipode map shows up in physically important examples.
•A new permeability model considering the matrix–fracture interaction is developed.•The influencing factors of internal swelling coefficient are discussed.•The effect of internal swelling coefficient ...on coal permeability is explored.
In this study, we develop a new permeability model that incorporates the matrix–fracture interactions. In addition, a newly defined internal swelling coefficient (f) has been introduced to quantify the contribution of adsorption-induced matrix deformation to fracture aperture and coal permeability. The model is independent of the boundary conditions and has been verified with the data tested under the conditions of uniaxial strain, constant external stress, constant effective stress, and constant pore pressure. Besides, a comparison between the commonly used models and our model shows that our model can cover most of the variation trends of the other models. The influencing factors and the mechanisms controlling the internal swelling coefficient have been comprehensively discussed. The results show that under the conditions of uniaxial strain and constant effective stress, f shows a downward trend with a reduction of the pore pressure, whereas under the constant external stress condition, f presents an opposite variation trend. The gas type has an effect on the internal swelling coefficient and f decreases in the order of N2, CH4, and CO2. In addition, the coal type also affects the internal swelling coefficient. All the factors indirectly affect the internal swelling coefficient by changing the effective stress and adsorption-induced matrix deformation. We have also investigated the controlling mechanism of the internal swelling coefficient on permeability, which indicated that the permeability shows an opposite variation trend with the internal swelling coefficient. It is suggested that the internal swelling coefficient can be set as a value in the range of 0–0.2 for the prediction of coal seam permeability during CBM recovery and CO2 geological sequestration.
Organic donor–acceptor systems have attracted much attention due to their various potential applications. However, the rational construction and modulation of highly ordered donor–acceptor systems ...could be a challenge due to the complicated self‐assembly process of donor and acceptor species. Considering the well‐defined arrangement of species at the molecule level, a crystalline host–guest system could be an ideal platform for the rational construction of donor–acceptor systems. Herein, it is shown how the rational construction of highly tunable donor–acceptor materials can be achieved based on a crystalline host–guest platform. Within the well‐established metal–organic framework NKU‐111 as the crystalline host enabled by the relatively stable coordination‐directed assembly, the introduction and arrangement of guest molecules in the crystals allow the rational construction of the NKU‐111⊃guest donor–acceptor system. The donor–acceptor interaction in the systems can be readily modulated with different guest molecules, which can be justified by the well‐demonstrated guest‐dependent characteristics. Accordingly, the NKU‐111⊃guest reveals highly tunable donor–acceptor properties such as charge‐transfer‐based emissions and electrical conductivity. This work indicates the potential of crystalline host–guest systems as an ideal platform for systematic investigations of donor–acceptor materials.
A donor–acceptor material based on a host–guest crystalline material platform is raised. As a proof of concept, a metal–organic framework (NKU‐111) is utilized as a host acceptor for the accommodation of aromatic donor guests. The resulting donor–acceptor system features highly tunable charge‐transfer‐based emissions and conductivity, indicating the rationality and efficiency of this strategy.
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