Discovery of CN0 as a novel proteolysis-targeting chimera (PROTAC) degrader of PARP1 that can activate the cGAS/STING immunity pathway combined with daunorubicin.

Poly ADP-ribose polymerase 1 (PARP1) plays an essential role in DNA repair signaling, rendering it an attractive target for cancer treatment. Despite the success of PARP1 inhibitors (PARPis), only a few patients can currently benefit from PARPis. Moreover, drug resistance to PARPis occurs during clinical treatment. Natural and acquired resistance to PARPis has forced us to seek new therapeutic approaches that target PARP1. Here, we synthesized a series of compounds by proteolysis-targeting chimera (PROTAC) technology to directly degrade the PARP1 protein. We found that CN0 (compound 3) with no polyethylene glycol (PEG) linker can degrade the PARP1 protein through the proteasome pathway. More importantly, CN0 could inhibit DNA damage repair, resulting in highly efficient accumulation of cytosolic DNA fragments due to unresolved unrepaired DNA lesions when combined with daunorubicin (DNR). Therefore, CN0 can activate the cyclic GMP-AMP synthase/stimulator of the interferon gene (cGAS/STING) pathway of innate immunity and then spread the resulting inflammatory signals, thereby reshaping the tumor microenvironment, which may eventually enhance T cell killing of tumor cells.

Knockdown of GPRC5B alleviates the high glucose-induced inflammation and extracellular matrix deposition of podocyte through inhibiting NF-κB pathway.

BACKGROUND: Diabetes is a serious disease that could greatly increase the risk of cardiovascular complications, whereas the underlying pathology of DN is still unknown. GPRC5B is a member of the RAIG subfamily of type 3 (family C) GPCR, and its role in DN is still unclear. OBJECTIVE: To unveil the role of GPRC5B in diabetic nephropathy (DN) progression and investigate the potential signaling pathway. MATERIALS AND METHODS: Podocytes were stimulated with high glucose and expression of GPRC5B was analyzed by qPCR and western blot. Then the level of GPRC5B was depleted by siRNA transfection and inflammatory cytokine level was monitored by ELISA assay. The ECM depostion and the activation of NF-κB pathway were detected by Immunoblot. RESULTS: We investigated the possible role of GPRC5B in the pathology of diabetic nephropathy. We found GPRC5B was highly expressed in high glocuse (HG) induced podocytes. The depletion of GPRC5B inhibited HG induced cell inflammation. In addition, the ablation of GPRC5B suppressed the HG induced ECM deposition. We further found GPRC5B could alleviate the inflammation and extracellular matrix deposition of HG-induced podocytes through NF-κB pathway. CONCLUSION: We therefore thought GPRC5B could serve as a promising target for the treatment of diabetic nephropathy. G-protein-coupled receptors.

Cathodic electrochemiluminescence at C/CxO(1-x) electrodes for the fabrication of label-free biosensors.

Cathodic electrochemiluminescence (ECL) is firstly observed at a carbon oxide covered glassy carbon (C/C(x)O(1-x)) electrode as a large cathodic pulse polarization is applied. This insulating carbon oxide (C(x)O(1-x)) film is constructed on a glassy carbon (GC) substrate by electrochemical oxidization in basic media. The film properties, such as the composition of carbon and oxygen, and the thickness as well, can be controlled by the potential and the duration in the oxidizing process. X-Ray photoelectron spectroscopy (XPS) studies show that carbonyl and carboxyl dominate at the oxidized surface, to which antibodies can be covalently bound. The specific immunoreaction between antigen (Ag) and antibody (Ab) resulted in a decrease in the ECL intensity, thus creating an interesting basis for the development of a label-free cathodic ECL immunosensor. As an example, human IgG (hIgG) was sensitively determined in the concentration range of 0.01-100 ng mL(-1), and the detection limit was ca. 1.0 pg mL (-1) (S/N = 3). In addition, the content of hIgG in human serum has been assayed by the developed immunosensor and a commercially available immune turbidimetry method, respectively, and consistent results were obtained. The prepared immunosensor provides a promising approach for the clinical determination of IgG levels in human serum, because it is simple, rapid, highly sensitive, specific, and without the need of tedious labeling operations.

Synthesis and characterization of three ytterbium coordination polymers featuring various cationic species and a luminescence study of a terbium analogue with open channels.

Four novel metal-organic frameworks with 4,4'-oxybis(benzoate) (OBA) ligands and suitable cationic species, [NH(3)(CH(2))(2)NH(3)](0.5)[Yb(OBA)(2)(H(2)O)] (1), (NH(4))[Yb(OBA)(2)(H(2)O)(2)] (2), Na[Yb(OBA)(2)] x 0.4 DMF x 1.5 H(2)O (3), and Na[Tb(OBA)(2)] x 0.4 DMF x 1.5 H(2)O (4), have been synthesized and structurally characterized. The two-dimensional structure of 1 possesses open channels filled with ethylenediamine cations. The two-dimensional structure of 2 contains the network featuring organic ligands with uncoordinated functional RCO(2) groups suspended within the windows. The three-dimensional structure of 3, in which Na(+) cations replaced the NH(4)(+) cations of 2 and the presence of DMF molecules, adopts an open framework with large rhombic channels. The evacuated phase "Na[Yb(OBA)(2)]" in 3 retained rigidity and crystallinity to a high temperature. Framework 4, a terbium analogue of 3, has the potential sensing ability; it exhibited gradually increasing luminescence intensities when dispersed sequentially in water, methanol, and ethanol as suspensions.

Hydro-ecological controls on riverine organic carbon dynamics in the tropical monsoon region.

Transport fluxes and properties of riverine organic carbon in the tropical monsoon region were the vital parameters in the global riverine organic carbon fluxes budget. The study focused on the riverine organic carbon in the Changhuajiang River (CHJR), locating at the mid-west of the Hainan Island, China. Dissolved organic carbon (DOC) concentrations in the CHJR ranged from 0.22 mg/L to 11.75 mg/L with an average of 1.75 mg/L, which was lower than the average of global rivers and had a significantly temporal and spatial variation. Output flux of riverine DOC was calculated as 0.55 t/km2/y, which could be revised up to 1.03 t/km2/y, considering that the riverine discharge before dam construction. A linear model of riverine DOC flux suitable in CHJR basin was established, which involved the factors, such as soil organic carbon, runoff depth and slope, etc. There was a large variation of POC concentrations in the CHJR where the average POC concentration in the dry season was 2.41 times of the wet season. Riverine POC flux in CHJR basin was calculated as 1.78 t/km2/y, higher than the average of global rivers and far lower than those in other domestic larger rivers. About 8.28 × 103 t POC were exported yearly in CHJR, of which, 7.15 × 103 t originated from terrestrial ecosystem and 1.13 × 103 t stemmed from aquatic ecosystem. Meanwhile, about 87.74% of terrestrial source happened in the wet season and 12.26% in the dry season. This research revealed that the riverine organic carbon mainly stemmed from the surface erosion processes in the drainage basin during the wet season.

Preparation and characterization of N-(2-carboxybenzyl)chitosan as a potential pH-sensitive hydrogel for drug delivery.

A novel water-soluble chitosan derivative [N-(2-carboxybenzyl)chitosan, CBCS] was synthesized. The chemical structure of CBCS was characterized by FTIR, (1)H NMR and UV spectroscopies. The degree of substitution (DS) of N-2-carboxybenzyl was determined by colloid titration. In different pH buffer solutions, the swelling characteristics of hydrogels based on CBCS (CBCSG) prepared by crosslinking with glutaraldehyde have been studied. Results showed that the swelling ratio (SR) of CBCSG decreased with an increase of the amount of glutaraldehyde, and that CBCSG swelled more significantly in alkaline solution than in acidic medium, showing the lowest SR at pH5.0. The SR of CBCSG increased with the raising of the DS of the N-2-carboxybenzyl group in alkaline solution, but no significant change was observed in an acidic environment. CBCSG showed swelling reversibility when alternately soaked in pH1.0 and 7.4 buffer solutions. Release profiles of fluorouracil (5-FU), a poorly water-soluble drug, from CBCSG were studied under both simulated gastric and intestinal pHconditions. The release was much quicker in pH7.4 buffer than in pH1.0 solution. Results indicated that CBCS could be a potential pH-sensitive carrier for colon-specific drug delivery system.

A new supramolecular gel via host-guest complexation with cucurbit[8]uril and N-(4-diethylaminobenzyl)chitosan.

A novel supramolecular gel has been prepared via host-guest interaction between cucurbit[8]uril (Q[8]) and N-(4-diethylaminobenzyl)chitosan (EBCS). The structure of supramolecular gel has been characterized. The spectrum of (1)H NMR demonstrated the benzene ring of EBCS is reside inside the hydrophobic cavity of Q[8] and the host-guest interaction between Q[8] and EBCS was the main driving force for the formation of the supramolecular gel. The network structure of the xerogel of Q[8]/EBCS gel was observed by SEM. The Q[8]/EBCS gel system showed thermosensitive and pH-sensitive properties. The physical characterization by SEM, DSC, TG demonstrated the distinguished characters, which proved the formation of supramolecular gel instead of physical blending. The in vitro release study of the 5-fluorouracil-loaded supramolecular gel showed that sustained release profile in acidic condition, suggesting that Q[8]/EBCS gel could be a potential carrier for pH-sensitive drug controlled release system.