Lipid nephrotoxicity mediated by HIF-1α activation accelerates tubular injury in diabetic nephropathy.

This study is intended to explore the effect of hypoxia-inducible factor-1α (HIF-1α) activation on lipid accumulation in the diabetic kidney. A type 1 diabetic rat model was established by STZ intraperitoneal injection. Cobalt chloride (CoCl2) and YC-1 were used as the HIF-1α activator and antagonist, respectively. CoCl2 treatment significantly increased HIF-1α expression, accelerated lipid deposition, and accelerated tubular injury in diabetic kidneys. In vitro, CoCl2 effectively stabilized HIF-1α and increased its transportation from the cytoplasm to the nucleus, which was accompanied by significantly increased lipid accumulation in HK-2 cells. Furthermore, results obtained in vivo showed that HIF-1α protein expression in the renal tubules of diabetic rats was significantly downregulated by YC-1 treatment. Meanwhile, lipid accumulation in the tubules of the DM + YC-1 group was markedly decreased in comparison to the DM + DMSO group. Accordingly, PAS staining revealed that the pathological injury caused to the tubular epithelial cells was alleviated by YC-1 treatment. Furthermore, the blood glucose level, urine albumin creatinine ratio, and NAG creatinine ratio in the DM + YC-1 group were significantly decreased compared to the DM + DMSO group. Moreover, the protein expression levels of transforming growth factor ß1 (TGF-ß1) and connective tissue growth factor (CTGF) in diabetic kidneys were decreased by YC-1 treatment. Our findings demonstrate that the activation of HIF-1α contributed to interstitial injury in a rat model of diabetic nephropathy and that the underlying mechanism involved the induction of lipid accumulation.

Role of sPD-1 and sPD-Ls in the pathogenesis of connective tissue disease. / sPD-1和sPD-Lsåœ¨ç»“ç¼”ç»„ç»‡ç— å‘ç— æœºåˆ¶ä¸­çš„ä½œç”¨.

Membrane-bound programmed cell death-1 (mPD-1) and membrane-bound programmed cell death-ligands (mPD-Ls) have soluble forms, which are soluble programmed cell death-1 (sPD-1) and soluble programmed cell death-ligands (sPD-Ls) [including soluble programmed cell death-ligand 1 (sPD-L1) and soluble programmed cell death-ligand 2 (sPD-L2)]. sPD-1 and sPD-L2 are mainly produced by alternative splicing isoforms of PD-1 mRNA, while sPD-L1 is produced by matrix metalloproteinases (MMPs) cutting membrane-bound programmed cell death-ligand 1 (mPD-L1). sPD-1 and sPD-Ls play an important role in autoimmune regulation via blocking the mPD-1 /mPD-L1 pathway, while connective tissue disease (CTD) is a kind of disease caused by autoimmune reaction, and abnormal function of mPD-1/mPD-L1 can occur in the occurrence and development of many autoimmune diseases. Therefore, sPD-1 and sPD-Ls play an important role in the pathogenesis of CTD caused by autoimmune reaction via blocking the mPD-1 /mPD-L1 pathway. It is of great practical significance to understand clinical value of sPD-1 and sPD-Ls in various CTDs for improving the quality of life of patients and the underlying mechanism.

Peripheral loss of EphA4 ameliorates TBI-induced neuroinflammation and tissue damage.

BACKGROUND: The continuum of pro- and anti-inflammatory response elicited by traumatic brain injury (TBI) is suggested to play a key role in the outcome of TBI; however, the underlying mechanisms remain ill -defined. METHODS: Here, we demonstrate that using bone marrow chimeric mice and systemic inhibition of EphA4 receptor shifts the pro-inflammatory milieu to pro-resolving following acute TBI. RESULTS: EphA4 expression is increased in the injured cortex as early as 2 h post-TBI and on CX3CR1gfp-positive cells in the peri-lesion. Systemic inhibition or genetic deletion of EphA4 significantly reduced cortical lesion volume and shifted the inflammatory profile of peripheral-derived immune cells to pro-resolving in the damaged cortex. These findings were consistent with in vitro studies showing EphA4 inhibition or deletion altered the inflammatory state of LPS-stimulated monocyte/macrophages towards anti-inflammatory. Phosphoarray analysis revealed that EphA4 may regulate pro-inflammatory gene expression by suppressing the mTOR, Akt, and NF-κB pathways. Our human metadata analysis further demonstrates increased EPHA4 and pro-inflammatory gene expression, which correlates with reduced AKT concurrent with increased brain injury severity in patients. CONCLUSIONS: Overall, these findings implicate EphA4 as a novel mediator of cortical tissue damage and neuroinflammation following TBI.

Hydrogels composed of hyaluronic acid and dendritic ELPs: hierarchical structure and physical properties.

Hydrogels that mimic the native extracellular matrix were prepared from hyaluronic acid (HA) and amine-terminated dendritic elastin-like peptides (denELPs) of generations 1, 2, and 3 (G1, 2, and 3) as crosslinking units. The physical properties of the hydrogels were investigated by rheology, scanning electron microscopy, swelling tests, small-angle X-ray scattering (SAXS), and model drug loading and release assays. Hydrogel properties depended on the generation number of the denELP, which contained structural segments based on the repeating GLPGL pentamer. Hydrogels with higher generation denELPs (G2 and 3) showed similar properties, but those prepared from G1 denELPs were rheologically weaker, had a larger mesh size, absorbed less model drug, and released the drug more quickly. Interestingly, most of the HA_denELP hydrogels studied here remained transparent upon gelation, but after lyophilization and addition of water retained opaque, "solid-like" regions for up to 4 d during rehydration. This rehydration process was carefully evaluated through time-course SAXS studies, and the phenomenon was attributed to the formation of pre-coacervates in the gel-forming step, which slowly swelled in water during rehydration. These findings provide important insights into the behavior of ELP-based hydrogels, in which physical crosslinking of the ELP domains can be controlled to tune mechanical properties, highlighting the potential of HA_denELP hydrogels as biomaterials.

Dendritic Elastin-like Peptides: The Effect of Branching on Thermoresponsiveness.

Elastin-like peptides (ELPs) have been used widely to confer thermoresponsive characteristics onto various materials, but to this point mostly linear ELPs have been studied. A class of linear and dendritic (branched) ELPs based on the GLPGL pentamer repeat unit was synthesized using an on-resin divergent strategy. The effect of peptide topology on the transition temperature (Tt) was examined using circular dichroism to study the peptide secondary structure transition and turbidity to measure the macroscopic phase transition (coacervation). Secondary structure transitions showed no dependence on topology, but a higher Tt was observed for dendritic peptides than for linear peptides with the same number of GLPGL repeats. The data support a phase transition model that consists of two neighboring processes: a secondary structure transition, related to intramolecular interactions, followed by coacervation, associated with intermolecular interactions.

Network Pharmacology-Based and Molecular Docking-Based Analysis of Cornus Officinalis for the Treatment of Spinal Cord Injury.

PURPOSE: Based on network pharmacology and molecular docking, this study aimed to screen out the active ingredients existing in Cornus officinalis for the treatment of spinal cord injury (SCI) and explore their potential mechanisms. METHODS: We collected the active ingredients of Cornus officinalis and its corresponding target proteins. The target proteins corresponding to Cornus officinalis active ingredients were obtained by the Uniport. The SCI genes were obtained through the GeneCards. The active ingredient-acting target network and the interaction between action targets and a target protein interaction network were built by the String and the CytoScape 3.7.2. The core targets were analyzed by the Metascape. The active components and core targets were verified by the AutoDock. RESULTS: We collected eighteen active ingredients, including tetrahydroalstonine. 390 targets, 50 targets related to SCI were obtained. The Key targrts were AKT1, MAPK1, TNF. Four major signaling pathways are involved, including MAPK pathway. The active components of Cornus officinalis have good affinity with the core targets of SCI. CONCLUSION: Our study summarized the active ingredients of Cornus officinalis and the mechanism of action in the treatment of SCI, providing implications for the development of the active ingredients of Cornus officinalis in the treatment of SCI.

Boosting the electro-oxidation of 5-hydroxymethyl-furfural on a Co-CoS x heterojunction by intensified spin polarization.

The conversion of biomass-derived platform molecules (e.g., 5-hydroxymethyl furfural (HMF)) represents a sustainable route to produce value-added chemicals. Here we report the fabrication of an N-doped carbon nanotube assembled yolk-shell polyhedron with embedded Co-CoS x nanoparticles (NPs) (Y-Co-CoS x @CN) for efficient HMF electrooxidation. DFT calculations demonstrate that the formation of the heterojunction could intensify spin polarization in Co-CoS2, thus achieving effective d-p coupling between the catalyst and reactant/intermediate. As expected, Y-Co-CoS x @CN exhibits excellent HMF electro-oxidation activity at a low applied potential of 1.29 V vs. RHE at 10 mA cm-2 in 0.1 M KOH with 5 mM HMF, affording an FDCA yield of 96% and FE of 93.5%. This work not only sheds light on the catalytic nature of the heterojunction and the underlying mechanisms for the enhancement of HMF electro-oxidation activity, but would also provide a descriptor for the rational design of advanced electro-catalysts.

Experimental Investigation on the Breaching Process of Landslide Dams with Differing Materials under Different Inflow Conditions.

Landslide dams are dangerous because the outburst floods produced by dam failures seriously threaten life and property downstream. In this study, a series of physical flume tests were conducted to investigate the breaching process of landslide dams with fine-grained, well graded, and coarse-grained material under different inflow conditions. The effects of dam material and inflow discharge on the breach development, outflow discharge and erosion characteristics were studied. The erosion resistance of materials and lateral collapses were also discussed. Experimental results reveal that the whole breaching process is determined by the water-sediment interaction. For the fine-grained dams, a general constant downstream slope angle is maintained during the breaching process. For the well-graded dams, a step-pool structure is generated due to the scarp erosion. For the coarse-grained dams, they can remain stable under normal circumstances but fail by overtopping in a short duration under the extreme inflow condition. The final breach of the dam with higher fine content or larger inflow discharge is deeper and narrower. In addition, many fluctuations are observed in the changing curve of the erosion rates along the flow direction for the well-graded and coarse-grained dams. The erosion resistance of materials increases along the flow direction, which needs to be further considered in physically based breach models. Furthermore, the lateral collapse is affected by the dam material instead of inflow discharge. The lower fine content causes more lateral collapses with smaller volumes.

Thermotropic organization of hydrogen-bond-bridged bolaform amphiphiles.

A series of quaternary ammonium amphiphiles (A-n) bearing carboxylic acid groups were designed and synthesized. The branched bolaform structures can be constructed by dimerizations of carboxylic acid groups through intermolecular hydrogen bonding, as demonstrated by the Fourier transform infrared (FT-IR) spectra and the temperature-dependent FT-IR spectra. The thermotropic organizations of branched bolaform ammonium dimer complexes were characterized by differential scanning calorimetry, polarized optical microscopy, and X-ray diffraction. We investigated the influence of the spacer between the cationic group and the benzene ring on the thermotropic organization. A-6 with short lateral alkyl chains formed a simple layered structure at room temperature and exhibited smectic A mesophase above 145 °C, whereas A-8 with intermediate lateral chain length organized into smectic A phase over a wide temperature range. A further increase of the length (n = 10, 12) of the lateral chains resulted in the formation of lamellar structure with in-plane layered periodicity, which is rare in the organization of ionic compounds. A packing model of the quasi-2D lamellar was proposed on the basis of the experimental data of X-ray diffraction results. Notably, the quasi-2D lamellar structure could evolve into a simple layer with the increase of temperature. The present results showed a direct relationship in which the branched architecture can be applied to tune the self-assembly behavior of ionic amphiphiles and is allowed to construct new layered superstructure.

Elastase-triggered H2S delivery from polymer hydrogels.

We report an elastase-responsive, H2S-releasing hydrogel prepared by covalently crosslinking a mixture of carboxymethylcellulose and poly(ethylene glycol) with an elastase-degradable peptide functionalized with an H2S-releasing S-aroylthiooxime (SATO) unit. Addition of elastase triggered a gel-to-sol transition, which exposed SATOs, leading to more and longer H2S release compared to untriggered gels.

H2S-releasing amphiphilic dipeptide hydrogels are potent S. aureus biofilm disruptors.

As a gasotransmitter, hydrogen sulfide (H2S) has been studied to treat wounds and inflammation, but its potential antimicrobial effects in this context have not been evaluated. An H2S-releasing dipeptide hydrogel (S-FE), and several non-H2S-releasing control dipeptides, (C-FE, C-GE, FBA-FE, and FE where S = S-aroylthiooxime, an H2S donor; C = control, an oxime incapable of H2S release; FBA = 4-formylbenzamide, also incapable of H2S release; and E, F, G = glutamic acid, phenylalanine, and glycine, respectively), were studied to correlate differences in their chemical structures and H2S-releasing abilities with their antimicrobial effects on Staphylococcus aureus bacteria. Dipeptides with Phe (S-FE, C-FE, and FE) self-assembled into nanoribbons in water and displayed ß-sheet formation and enhanced fluorescence, while the other two dipeptides (FBA-FE and C-GE) did not form assemblies in water. In vitro experiments with Staphylococcus aureus, which is a commonly found bacterium associated with wounds, showed significant antimicrobial effects from some of the dipeptides. Dipeptide S-FE inhibited bacterial growth more effectively than any of the controls, thereby limiting biofilm formation or disrupting established biofilms. These antimicrobial H2S-releasing dipeptide hydrogels provide a promising new approach to treat wound infections.

Functional N-Substituted N-Thiocarboxyanhydrides as Modular Tools for Constructing H2S Donor Conjugates.

We report a synthetic route toward a family of functional COS/H2S-releasing N-substituted N-thiocarboxyanhydrides (NTAs) with functionalities to accommodate popular conjugation reactions, including olefin cross metathesis, thiol-ene, and copper-catalyzed azide-alkyne cycloaddition. The N-substituted NTAs were attached to small molecules, polymers, and a protein to synthesize novel H2S donors convergently. All conjugates showed sustained H2S release kinetics.

Multi-scale characterization of thermoresponsive dendritic elastin-like peptides.

Elastin like peptides (ELPs)-polypeptides based on the protein elastin-are used widely as thermoresponsive components in biomaterials due to the presence of a sharp soluble-to-insoluble phase change at a characteristic transition temperature (Tt). While linear ELPs have been thoroughly studied, few investigations into branched ELPs have been carried out. Using lysine amino acids as branching and terminal units with 1-3 pentameric repeats between each branch, ELP dendrimers were prepared by solid-phase peptide synthesis with molecular weights as high as 14kDa. A conformation change from random coil to ß-turn upon heating through the Tt, typical of ELPs, was observed by circular dichroism spectroscopy for all peptides. The high molecular weights of these peptides enabled the use of characterization techniques typically reserved for polymers. Variable-temperature small-angle X-ray scattering measurements in dilute solution revealed an increase in size and fractal dimension upon heating, even well below the Tt. These results were corroborated by cryogenic transmission electron microscopy, which confirmed the presence of aggregates below the Tt, and micro differential scanning calorimetry, which showed a broad endothermic peak below the Tt. These results collectively indicate the presence of a pre-coacervation step in the phase transition of ELP dendrimers.

Transfer Charge and Energy of Ag@CdSe QDs-rGO Core-Shell Plasmonic Photocatalyst for Enhanced Visible Light Photocatalytic Activity.

Plasmonic heteronanostructures in semiconductor type display extraordinary photocatalytic efficiency induced by the plasmonic energy that operates in the Ag@CdSe-rGO hybrid ternary composites. The obtained plasmonic photocatalysts in nanoscale were fabricated by using a one-step hydrothermal method, during which the in situ nucleation of Ag@CdSe core-shell nanoparticles and the reduction of GO to rGO occurred simultaneously. Three different roles of Ag core and the junction of synergistic properties arising from the introduced rGO jointly enhanced the optical properties of CdSe. Localized plasmon resonance (LPR) effects of plasmonic Ag contribute to the separation of photogenerated e(-)/h(+) pairs via the electrons and resonant energy transfer. Electrochemical investigations have further confirmed the enhanced separation of the photogenerated e(-)/h(+) pairs. From comparative photocatalytic experiments of Ag@CdSe-rGO and Ag/CdSe-rGO, the plasmonic effect of the Ag core in the Ag@CdSe-rGO nanostructure serves to prolong the charge separation under visible light beyond common attached trimers.