Abstract The present study was to demonstrate the effects of goblet cell-targeting nanoparticles on the oral absorption of insulin in vitro , ex vivo and in vivo , and identify the targeting ...mechanism as well as the influence of mucus. The insulin loaded nanoparticles were prepared using trimethyl chitosan chloride (TMC) modified with a CSKSSDYQC (CSK) targeting peptide. Compared with unmodified nanoparticles, the CSK peptide modification could facilitate the uptake of nanoparticles in villi, enhance the permeation of drugs across the epithelium, meanwhile, induce a significantly higher internalization of drugs via clathrin and caveolae mediated endocytosis on goblet cell-like HT29-MTX cells. In transport studies across Caco-2/HT29-MTX co-cultured cell monolayer (simulating intestinal epithelium), the CSK peptide modification also showed enhanced transport ability, even if the targeting recognition was partially affected by mucus. Moreover, it was found the existence of mucus was propitious to the transport of insulin from both modified and unmodified nanoparticles. In the pharmacological and pharmacokinetic studies in diabetic rats, the orally administrated CSK peptide modified nanoparticles produced a better hypoglycemic effect with a 1.5-fold higher relative bioavailability compared with unmodified ones. In conclusion, CSK peptide modified TMC nanoparticles showed sufficient effectiveness as goblet cell-targeting nanocarriers for oral delivery of insulin.
A convenient and effective protocol for the ruthenium‐catalyzed C–H selenylations of benzamide was achieved under mild reaction conditions. The robust ruthenium catalyst tolerated a wide range of ...functional groups and set the stage for the preparation for diversely decorated benzamides. The amide directing group could be transferred to carboxylic acid, aldehyde and tetrazoles. Preliminary mechanistic study indicated a base‐assisted electrophilic‐type substitution C–H activation event.
The easily transformable amide directing groups assisted ortho‐C–H selenylations of arenes with 1,2‐diphenyldiselane by robust ruthenium catalyst were achieved with ample scope under mild reaction conditions. This general approach offered a straightforward access to various functional group substituted diarylselenide containing compounds. The plausible mechanism was proposed after the detailed mechanistic studies.
The first palladium(II)‐catalyzed direct ortho‐C(sp2)–H chalcogenations of N‐arylsulfonamide via weak coordination have been achieved, affording the corresponding mono‐chalocgenated products in good ...to excellent yields. This strategy features ligand/additive‐free conditions, broad substrate scope with excellent functional group tolerance and a high position selectivity.
The first palladium(II)‐catalyzed direct ortho‐C(sp2)–H chalcogenations of N‐arylsulfonamide via weak coordination have been achieved. This strategy features ligand/additive‐free conditions, broad substrate scope with excellent functional group tolerance and a high position selectivity.
A new perovskite-type oxide, CaCu3Cr2Nb2O12, has been synthesized at 10 GPa and 1100 °C. The compound crystallizes in space group Im3¯ with 1:3 ordered Ca and Cu cations at the A sites and disordered ...Cr and Nb cations at the octahedral B sites. CaCu3Cr2Nb2O12 exhibits a paramagnetic–ferrimagnetic transition at around 192.3 K and the Arrott plots manifest this transition is a second-order transition. We investigate the critical behavior of CaCu3Cr2Nb2O12 using the modified Arrott plots, Kouvel–Fisher plot, and the scale theory. The estimated critical exponents β, γ and δ, which yield β = 0.465 ± 0.006, γ = 1.312 ± 0.019 and δ = 3.833 ± 0.019 with TC = 197 K, fall within the predicted values from the mean-field model and three-dimensional Heisenberg model. The renormalization group analysis suggests that the exchange interaction decays as J(r)∼ r−4.871, indicating the magnetic interactions may be long-range coupling in CaCu3Cr2Nb2O12.
It's always a challenge to crosslink different polysiloxane oligomers through a common organic reaction to obtain high performance silicone materials. This paper reported a new type of silicone ...rubber (VPSR) that α,ω-aminopropyl polydimethylsiloxane (A-PDMS) was reinforced with vinyl carbonate functional polyhedral oligomeric silsesquioxane (VEC-POSS) and crosslinked by primary ammonia and cyclic carbonate reaction. VEC-POSS was synthesized from γ-mercaptopropyl polyhedral oligomeric silsesquioxane (SH-POSS) and vinyl carbonate (VEC) via the common thiol-ene click reaction. The silicones with high thermal stability, hydrophobicity and good tensile properties was obtained. FTIR confirmed the crosslinked network was formed by the combination of non-covalent bond and covalent bond. The enhancement effect of VEC-POSS was systematically studied by the experimental and molecular dynamics (MD) simulation. The results revealed that the increase of VEC-POSS contents enhanced the tensile strength and the contact angle to 3.35 MPa and 122.7°, respectively. The glass transition temperature (Tg) and the number of hydrogen bonds (H-bonds) increased with the increase of VEC-POSS contents, while the mean square displacement (MSD) and the free volume fraction (FFV) decreased gradually. Moreover, compared with the experimental results, the simulated Tg was consistent with the experimental Tan δ values, which proved the rationality of the model.
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•A type of silicones strengthened and crosslinked by VEC-POSS was prepared.•The silicones with high thermal stability and good tensile properties was obtained.•The strengthened structure included the microphase separation and POSS reinforcement.•The crosslinking network was formed by non-covalent and covalent bonds.•The strengthened and crosslinked network of silicones was simulated by MS.
A multitude of evidence suggests that iodinated contrast material causes nephrotoxicity; however, there have been no previous studies that use arterial spin labeling (ASL) blood flow functional ...magnetic resonance imaging (fMRI) to investigate the alterations in effective renal plasma flow between normointensive and hypertensive rats following injection of contrast media. We hypothesized that FAIR-SSFSE arterial spin labeling MRI may enable noninvasive and quantitative assessment of regional renal blood flow abnormalities and correlate with disease severity as assessed by histological methods. Renal blood flow (RBF) values of the cortex and medulla of rat kidneys were obtained from ASL images postprocessed at ADW4.3 workstation 0.3, 24, 48, and 72 h before and after injection of iodinated contrast media (6 ml/kg). The H&E method for morphometric measurements was used to confirm the MRI findings. The RBF values of the outer medulla were lower than those of the cortex and the inner medulla as reported previously. Iodinated contrast media treatment resulted in decreases in RBF in the outer medulla and cortex in spontaneously hypertensive rats (SHR), but only in the outer medulla in normotensive rats. The iodinated contrast agent significantly decreased the RBF value in the outer medulla and the cortex in SHR compared with normotensive rats after injection of the iodinated contrast media. Histological observations of kidney morphology were also consistent with ASL perfusion changes. These results demonstrate that the RBF value can reflect changes of renal perfusion in the cortex and medulla. ASL-MRI is a feasible and accurate method for evaluating nephrotoxic drugs-induced kidney damage.
Radiotherapy for head and neck tumors can lead to a severe complication known as radiation-induced brain injury (RIBI). However, the underlying mechanism of RIBI development remains unclear, and ...limited prevention and treatment options are available. Neuroactive steroids have shown potential in treating neurological disorders. 5α-Androst-3β, 5, 6β-triol (TRIOL), a synthetic neuroprotective steroid, holds promise as a treatment candidate for RIBI patients. However, the neuroprotective effects and underlying mechanism of TRIOL on RIBI treatment are yet to be elucidated. In the present study, our findings demonstrate TRIOL’s potential as a neuroprotective agent against RIBI. In gamma knife irradiation mouse model, TRIOL treatment significantly reduced brain necrosis volume, microglial activation, and neuronal loss. RNA-sequencing, immunofluorescence, real-time quantitative polymerase chain reaction, siRNA transfection, and western blotting techniques revealed that TRIOL effectively decreased microglial activation, proinflammatory cytokine release, neuron loss, and guanylate-binding protein 5 (GBP5) expression, along with its downstream signaling pathways NF-κB and NLRP3 activation in vitro. In summary, TRIOL effectively alleviate RIBI by inhibiting the GBP5/NF-κB/NLRP3 signal axis, reducing microglia activation and pro-inflammation cytokines release, rescuing neuron loss. This study highlights the potential of TRIOL as a novel and promising therapy drug for RIBI treatment.
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Neuronal hyperexcitability is identified as a critical pathological basis of epileptic seizures. Cholestane-3β, 5α, 6β-triol (Triol) is a major metabolic oxysterol of cholesterol. Although its ...neuroprotective effect on ischemia-induced neuronal injury and negative modulation of voltage-gated sodium (Nav) channels were well established, the physical binding site of triol to sodium channels and its effects on neuronal hyperexcitability have not yet been explored. In this study, we utilized molecular docking and molecular dynamics simulation to investigate the interaction between triol and Nav Channels. Our results demonstrated that triol binds to the indole ring of Trp122 of the Nav Channel in silico with a high biological affinity. We further found that triol negatively modulates the action potentials bursts of hippocampal neurons by cell-attached patch recording. Moreover, triol significantly inhibits low Mg2+-induced hyperexcitability in vitro. In addition, triol attenuates pentylenetetrazole (PTZ)-induced convulsive-form behavioral deficits in vivo. Together, our results suggest that triol suppresses neuronal hyperexcitability via binding to Nav channel, indicating that triol might be an attractive lead compound for the treatment of neuronal hyperexcitability-related neurological disorders, especially epileptic seizures.
•Triol binds to the indole ring of Trp122 of voltage-gated sodium channel with a high affinity.•Triol negatively modulates action potential bursts of hippocampal neurons.•Triol inhibits low Mg2+–induced hyperexcitability in acute preparation of hippocampal slices.•Triol attenuates PTZ-induced epileptic seizures.
In this paper, we extend Mumford-Shah energy, the most general model for image segmentation on the assumption that all visible surface patches have intensity which is slowly varying plus noise, to ...unsupervised texture segmentation by considering multiple channels including both colors and Gabor wavelets representations. The Mumford-Shah energy in the paper thus formalizes a tradeoff between region homogeneity in color and texture field and edge compactness. Numerical results are presented for synthesized and real images to reveal the validity of the proposed algorithm.
