The Fenton system in the presence of nitrilotriacetate (NTA) ligand is studied by DFT approach. The calculations show that complexation of Fe(II) with NTA significantly facilitates the H2O2 ...activation. The ferric‐hydroperoxo intermediate NTAFe(III)OOH predominantly decays via the disproportionation into NTAFe(II)OH2 and NTAFe(IV)O involving the formation of a μ‐1,2‐hydroperoxo‐bridged biferric intermediate. In this mechanism, the bridged hydroperoxo is reduced by hydroperoxo ligand rather than by Fe(III). On the one hand, the NTAFe(III)OOH is sluggish to undergo hydrogen ion; on the other hand, it is a good nucleophile that may perform aldehyde deformylation. The present calculations suggest that both ˙OH and Fe(IV)O are generated in the NTA‐assisted Fenton system. However, the polycarboxylate ligand provides a favorable environment for H2O2 to accumulate around iron ion through hydrogen bonding. This promotes the quenching of Fe(IV)O by H2O2, rationalizing why the Fe(IV)O species is hardly detected in the NTA‐assisted Fenton system.
The NTA/Fe/H2O2 Fenton system has been investigated by DFT calculations. The FeIII/FeII recycling is accomplished by the disproportionation of FeIIIOOH into FeIIOH2 and FeIVO via the formation of μ‐1,2‐hydroperoxo‐bridged biferric intermediate. Although both ˙OH and FeIVO are generated, the polycarboxylate environment results in accumulation of H2O2 around iron ion and thus promotes the quenching of FeIVO by H2O2.
A novel and practical fluoroalkyl radical-initiated cascade reaction was developed to access diverse 2-fluoroalkylbenzothiazoles by reacting various fluoroalkyl radical sources, including ...perfluoroalkyl iodide (IC n F2n+1, n = 3–8, 10), ICF(CF3)2, ICF2COOEt, ICF2CF2Cl, or ICF2CF2Br, tetramethylethane-1,2-diamine (TMEDA), and 2-isocyanoaryl thioethers in tetrahydrofuran under nitrogen atmosphere and blue-light irradiation conditions. Furthermore, this one-pot protocol could well be expanded to access various 2-fluoroalkylbenzoselenazoles starting from (2-isocyanophenyl)(methyl)selane, perfluoroalkyl iodides (IC n F2n+1, n = 3–8) or ICF2COOEt and TMEDA.
PURPOSE
To evaluate the effectiveness on reducing anxiety of a diaphragmatic breathing relaxation (DBR) training program.
DESIGN AND METHODS
This experimental, pre‐test–post‐test randomized ...controlled trial with repeated measures collected data using the Beck Anxiety Inventory and biofeedback tests for skin conductivity, peripheral blood flow, heart rate, and breathing rate.
FINDINGS
The experimental group achieved significant reductions in Beck Anxiety Inventory scores (p < .05), peripheral temperature (p = .026), heart rate (p = .005), and breathing rate (p = .004) over the 8‐week training period. The experimental group further achieved a significant reduction in breathing rate (p < .001).
PRACTICE IMPLICATIONS
The findings provide guidance for providing quality care that effectively reduces the anxiety level of care recipients in clinical and community settings.
The transcription factor MYC is deregulated in almost all human cancers, especially in aggressive lymphomas, through chromosomal translocation, amplification, and transcription hyperactivation. Here, ...we report that high expression of tribbles homologue 3 (TRIB3) positively correlates with elevated MYC expression in lymphoma specimens; TRIB3 deletion attenuates the initiation and progression of MYC-driven lymphoma by reducing MYC expression. Mechanistically, TRIB3 interacts with MYC to suppress E3 ubiquitin ligase UBE3B-mediated MYC ubiquitination and degradation, which enhances MYC transcriptional activity, causing high proliferation and self-renewal of lymphoma cells. Use of a peptide to disturb the TRIB3-MYC interaction together with doxorubicin reduces the tumor burden in Myc
mice and patient-derived xenografts. The pathophysiological relevance of UBE3B, TRIB3 and MYC is further demonstrated in human lymphoma. Our study highlights a key mechanism for controlling MYC expression and a potential therapeutic option for treating lymphomas with high TRIB3-MYC expression.
Parkinson's disease (PD) is a neurodegenerative disease characterized by motor deficits and marked neuroinflammation in various brain regions. The pathophysiology of PD is complex and mounting ...evidence has suggested an association with the dysregulation of microRNAs (miRNAs) and gut dysbiosis. Using a rotenone-induced PD mouse model, we observed that administration of
PS128 (PS128) significantly improved motor deficits in PD-like mice, accompanied by an increased level of dopamine, reduced dopaminergic neuron loss, reduced microglial activation, reduced levels of inflammatory factors, and enhanced expression of neurotrophic factor in the brain. Notably, the inflammation-related expression of miR-155-5p was significantly upregulated in the proximal colon, midbrain, and striatum of PD-like mice. PS128 reduced the level of miR-155-5p, whereas it increased the expression of suppressor of cytokine signaling 1 (SOCS1), a direct target of miR-155-5p and a critical inhibitor of the inflammatory response in the brain. Alteration of the fecal microbiota in PD-like mice was partially restored by PS128 administration. Among them,
,
_6,
, and
were statistically correlated with the improvement of rotenone-induced motor deficits and the expression of miR-155-5p and SOCS1. Our findings suggested that PS128 ameliorates motor deficits and exerts neuroprotective effects by regulating the gut microbiota and miR-155-5p/SOCS1 pathway in rotenone-induced PD-like mice.
Tau, an important pathological protein of Alzheimer's disease (AD), can mediate the toxicity of amyloid β (Aβ). Thus, reduction of Tau with chemical molecules may offer a novel strategy for treating ...AD. Here, we designed and synthesized a series of multifunctional molecules that contained Tau-recognition moieties and E3 ligase-binding moieties to enhance Tau degradation. Among these molecules, TH006 had the highest activity of inducing Tau degradation by increasing its poly-ubiquitination. The decrement in Tau induced by TH006 could decrease the cytotoxicity caused by Aβ. Furthermore, TH006 could regulate the Tau level in the brain of an AD mouse model. Therefore, partial reduction of Tau with such multifunctional peptides may open up a novel therapeutic strategy for AD treatment.
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•Synthesized multifunctional PROTACs peptide TH006 effectively induces Tau degradation•TH006 increases poly-ubiquitination of Tau depending on VHL E3 ligase•Decrement of Tau induced by TH006 reduces the cytotoxicity caused by Aβ•TH006 can promote Tau reduction in primary neuron cells and 3xTg-AD mice
Tau, involved in Alzheimer's disease, is an intrinsically disordered protein which is difficult to be regulated. Chu et al. design and synthesize a multifunctional PROTACs peptide, TH006, to induce intracellular Tau degraded by increasing its poly-ubiquitination. Partial reduction of Tau induced by TH006 prevents cytotoxicity caused by Aβ.
Biomaterial-based tissue culture platforms have emerged as useful tools to mimic in vivo physiological microenvironments in experimental cell biology and clinical studies. We describe herein a ...three-dimensional (3D) tissue culture platform using a polydimethylsiloxane (PDMS)-based hanging drop array (PDMS-HDA) methodology. Multicellular spheroids can be achieved within 24 h and further boosted by incorporating collagen fibrils in PDMS-HDA. In addition, the spheroids generated from different human tumor cells exhibited distinct sensitivities toward drug chemotherapeutic agents and radiation as compared with two-dimensional (2D) cultures that often lack in vivo-like biological insights. We also demonstrated that multicellular spheroids may enable key hallmarks of tissue-based bioassays, including drug screening, tumor dissemination, cell co-culture, and tumor invasion. Taken together, these results offer new opportunities not only to achieve the active control of 3D multicellular spheroids on demand, but also to establish a rapid and cost-effective platform to study anti-cancer therapeutics and tumor microenvironments.
A visible‐light‐induced dioxygenation of β,γ‐unsaturated oximes for the synthesis of diverse useful isoxazolines bearing a hydroxyl moiety was developed by employing graphitic carbon nitride (g‐C3N4) ...as a heterogeneous photocatalyst under an air atmosphere. Noted that, the eminent advantages of this metal‐free protocol include step economy, easy operation, a recyclable photocatalyst, external reductant‐/oxidant‐free and mild reaction conditions. Additionally, mechanistic studies indicated hydroxyl radical was generated under the photocatalysis of g‐C3N4.
Special delivery! An aptamer-directed anticancer drug was molecularly engineered to be delivered to target cells for efficient therapeutic application. The covalent conjugation of drug and aptamer ...creates alternative opportunities for targeted therapy, as multiple yet specific aptamers can be "generated" relatively easily by cell-SELEX for any target cells; this demonstrates the full potential of cell-SELEX as a molecular discovery tool for biomedical studies and drug development.The conjugation of antitumor drugs to targeting reagents such as antibodies is a promising method that can increase the efficacy of chemotherapy and reduce the overall toxicity of the drugs. In this study, we covalently link the antitumor agent doxorubicin (Dox) to the DNA aptamer sgc8c, which was selected by the cell-SELEX method. In doing so, we expected that this sgc8c-Dox conjugate would specifically kill the target CCRF-CEM (T-cell acute lymphoblastic leukemia, T-cell ALL) cells, but with minimal toxicity towards nontarget cells. The results demonstrated that the sgc8c-Dox conjugate possesses many of the properties of the sgc8c aptamer, including high binding affinity (Kd=2.0±0.2 nM) and the capability to be efficiently internalized by target cells. Moreover, due to the specific conjugation method, the acid-labile linkage connecting the sgc8c-Dox conjugate can be cleaved inside the acidic endosomal environment. Cell viability tests demonstrate that the sgc8c-Dox conjugates not only possess potency similar to unconjugated Dox, but also have the required molecular specificity that is lacking in most current targeted drug delivery strategies. Furthermore, we found that nonspecific uptake of membrane-permeable Dox to nontarget cell lines could also be inhibited by linking the drug with the aptamer; thus, the conjugates are selective for cells that express higher amounts of target proteins. Compared to the less effective Dox-immunoconjugates, these sgc8c-Dox conjugates make targeted chemotherapy more feasible with drugs having various potencies. When combined with the large number of recently created DNA aptamers that specifically target a wide variety of cancer cells, this drug-aptoconjugation method will have broad implications for targeted drug delivery.
Multivalent synthetic vaccines were obtained by solid‐phase synthesis of tumor‐associated MUC1 glycopeptide antigens and their coupling to a Pam3Cys lipopeptide through click reactions. These ...vaccines elicited immune responses in mice without the use of any external adjuvant. The vaccine containing four copies of a MUC1 sialyl‐TN antigen showed a significant cluster effect. It induced in mice prevailing IgG2a antibodies, which bind to MCF‐7 breast tumor cells and initiate the killing of these tumor cells by activation of the complement‐dependent cytotoxicity complex.
Multivalent vaccines containing a MUC1 glycopeptide bearing the STn antigen were chemically synthesized and immunologically evaluated. The induced immune responses in mice were dependent on the valence of the glycopeptide. The antisera exhibited strong binding to tumor cells which resulted in tumor cell death. This novel effect of clustered multivalent vaccines can be attributed to the altered pattern of the induced antibody isotypes.
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