Genetic and pharmacological inhibition of GRPR protects against acute kidney injury via attenuating renal inflammation and necroptosis.

Gastrin-releasing peptide (GRP) binds to its receptor (GRP receptor [GRPR]) to regulate multiple biological processes, but the function of GRP/GRPR axis in acute kidney injury (AKI) remains unknown. In the present study, GRPR is highly expressed by tubular epithelial cells (TECs) in patients or mice with AKI, while histone deacetylase 8 may lead to the transcriptional activation of GRPR. Functionally, we uncovered that GRPR was pathogenic in AKI, as genetic deletion of GRPR was able to protect mice from cisplatin- and ischemia-induced AKI. This was further confirmed by specifically deleting the GRPR gene from TECs in GRPRFlox/Flox//KspCre mice. Mechanistically, we uncovered that GRPR was able to interact with Toll-like receptor 4 to activate STAT1 that bound the promoter of MLKL and CCL2 to induce TEC necroptosis, necroinflammation, and macrophages recruitment. This was further confirmed by overexpressing STAT1 to restore renal injury in GRPRFlox/Flox/KspCre mice. Concurrently, STAT1 induced GRP synthesis to enforce the GRP/GRPR/STAT1 positive feedback loop. Importantly, targeting GRPR by lentivirus-packaged small hairpin RNA or by treatment with a novel GRPR antagonist RH-1402 was able to inhibit cisplatin-induced AKI. In conclusion, GRPR is pathogenic in AKI and mediates AKI via the STAT1-dependent mechanism. Thus, targeting GRPR may be a novel therapeutic strategy for AKI.

Binding of Anionic Polyacrylamide with Amidase and Laccase under 298, 303, and 308 K: Docking and Molecular Dynamics Simulation Studies Combined with Experiments.

Amidase and laccase play a key role in the degradation process of anionic polyacrylamide (HPAM). However, the largest challenge of HPAM enzymatic degradation is whether the enzyme can bind with a substrate for a period of time. Here, the most suitable complexes, namely, Rh Amidase-HPAM-2 and Bacillus subtilis (B. subtilis) laccase-HPAM-3, were obtained by docking, and they were carried out for molecular dynamics simulation (MDS) under 298, 303, and 308 K. MDS result analysis showed that Rh Amidase-HPAM-2 was the most stable at 298 K mainly due to a salt bridge and a hydrogen bond, and B. subtilis laccase-HPAM-3 was the most stable at 298 K mainly due to two electrostatic and hydrogen bonds. The LYS96 in Rh Amidase-HPAM-2 and LYS135 in B. subtilis laccase-HPAM-3 had been the most important in their binding process. The binding of Rh Amidase-HPAM-2 and B. subtilis laccase-HPAM-3 was optimal at 303 and 298 K, respectively. HPAM was degraded by mixed bacteria, and the optimal conditions were determined to be 308 K, initial pH = 7, and an inoculated dosage of 2 mL. Under these conditions, the degradation ratio reached 39.24%. The effect of parameters on the HPAM degradation ratio followed a decreasing order of temperature > initial pH > inoculated dosage. The HPAM codegradation mechanism was supposed by mixed bacteria according to test data. The mixed bacteria secreted both amidase and laccase, and they interacted jointly with HPAM. These results lay a theoretical foundation to design and modify the enzyme through mutation experiments in the future.

Correction: Surface lanthanide activator doping for constructing highly efficient energy transfer-based nanoprobes for the on-site monitoring of atmospheric sulfur dioxide.

Correction for 'Surface lanthanide activator doping for constructing highly efficient energy transfer-based nanoprobes for the on-site monitoring of atmospheric sulfur dioxide' by Cuilan Zhang et al., Analyst, 2020, 145, 537-543, https://doi.org/10.1039/C9AN01725A.

Biodegradation of anionic polyacrylamide by manganese peroxidase: docking, virtual mutation based on affinity, QM/MM calculation and molecular dynamics simulation.

Manganese peroxidase (Mn P) is capable of effectively degrading anionic polyacrylamide (HPAM). However, the interaction of Mn P with HPAM at molecular level is lacking until now. Here, the HPAM model compounds, HPAM-2, HPAM-3, HPAM-4, and HPAM-5, were selected to reveal their binding mechanisms with Mn P. The results showed that the most suitable substrate for Mn P was HPAM-5, and the main reason for MnP-HPAM-5 with maximal affinity was strong hydrogen bond. LYS96 was the important key residue in all complexes, and the number of key residue was largest in MnP-HPAM-5. The optimal THR27ILE mutant may enhance the affinity of Mn P to HPAM-4. The stability of Mn P binding to HPAM-4 was the optimal. These results were helpful in designing highly efficient Mn P against HPAM to protect the ecological environment.

Discovery of a novel GRPR antagonist for protection against cisplatin-induced acute kidney injury.

The side effects of acute Kidney Injury (AKI) and nephrotoxicity limit the application of cisplatin in cancer treatment. Inflammation and oxidative stress paly important role in the pathogenesis of cisplatin-induced AKI. Gastrin-releasing peptide receptor (GRPR) plays an important role in inflammatory response. In this study, we designed 34 new Pd176252 analogs, most synthesized compounds could reduce cisplatin-induced HK2 cell death. Of these compounds, 9b had strong binding affinity with GRPR, and significantly increased HK2 cell viability. Compound 9b significantly downregulated the level of creatinine, blood urea nitrogen (BUN), and malondialdehyde (MDA), and recovered the glutathione (GSH) level in cisplatin-induced AKI model. It also decreased the level of kidney injury molecule-1(KIM-1) in vitro and vivo. In the further pathogenesis studies, 9b downregulated level of inflammatory factors (TNF-α, IL-1ß, IL-6 and MCP-1), suppressed the nuclear factor-kappa B (NF-kB) phosphorylation, and decreased GRPR level. The results suggested that ameliorating cisplatin-induced AKI actions of 9b was involved in downregulation of TNF-α, IL-1ß, IL-6, and MCP-1, inhibition of NF-kB activation, and reduction of GRPR and oxidative stress level.

Surface lanthanide activator doping for constructing highly efficient energy transfer-based nanoprobes for the on-site monitoring of atmospheric sulfur dioxide.

The sensitive and on-site detection of sulfur dioxide (SO2) is in great demand in the fields of food safety and environmental protection. Here, we developed a novel upconversion nanoprobe based on the luminescence energy transfer mechanism for monitoring the atmospheric SO2 concentrations. The lanthanide emitters, Tm3+ ions, were optimized to be doped on the surface layer of the upconversion nanoparticles to improve their energy transfer efficiency by minimizing the distance between the emitters and the surface quencher, a cyanine dye. As a proof-of-concept, the optimal nanoprobe was utilized to detect SO2 water derivatives, bisulfite ions, exhibiting a linear luminescence increase in the range of 1 nM to 10 nM. Furthermore, we assembled the cyanine-modified upconversion nanoparticles onto a test paper, and used a smartphone-based detection platform to achieve portable and visual detection of SO2. The test paper showed a strong luminescence stability, homogeneity and good anti-interference. The limit of detection for SO2 gas was found to be 1 ng L-1. This novel upconversion test paper was also demonstrated to directly monitor the concentration of SO2 gas in atmosphere.

Upconversional Nanoprobes with Highly Efficient Energy Transfer for Ultrasensitive Detection of Alkaline Phosphatase.

Sensitive detection of alkaline phosphatase (ALP) activity in human serum is important for diagnosis of various diseases. In this work, a novel sandwich-structured upconversion nanoparticle, NaYF4:Yb/Er@NaErF4@NaYF4, is fabricated to construct an upconversional nanoprobe for ultrasensitive detection of phosphate and ALP activity. The inner shell of NaErF4 bridges the emitters in the core with the external luminescence quenchers to greatly improve the energy transfer efficiency. The quencher, herein, is a coordination complex formed between sulfosalicylic acid and ferric ions. Owing to the higher affinity for phosphate, ferric ions dissociate from the complex and potently combine with phosphate ions, thus interrupting the energy transfer process and recovering the luminescence. This upconversional nanoprobe shows rapid and sensitive detection of phosphate with a limit of detection of 2.5 nM. Because ALP catalyzes the hydrolysis of p-nitrophenyl phosphate to form p-nitrophenol and inorganic phosphate ions, the nanoprobe is further utilized to achieve sensitive detection of ALP with a limit of detection of 0.5 µU/mL. This novel strategy offers a new opportunity for developing sensitive upconversional nanoprobes and many other energy transfer-based applications.

Real-Time Visualization of Cysteine Metabolism in Living Cells with Ratiometric Fluorescence Probes.

Sulfite from cysteine metabolism in living cells plays a crucial role in improving the water solubility of metabolic xenobiotics for their easier excretion in urine or bile. However, an imbalance of sulfite in vivo would lead to oxidative stress or age-related diseases, and an effective strategy for real-time imaging of cysteine metabolism in living cells is still lacking due to its low metabolite concentration and rapid reaction kinetics. Herein, a cyanine moiety based ratiometric fluorescence probe was developed for highly selective and sensitive detection of sulfite in aqueous solution and living cells. The free probe exhibited an orange emission color, and the fluorescence color would gradually change to blue once sulfite anions selectively reacted with the unsaturated carbon double bonds in the probe molecule. This ratiometric fluorescence manner endowed the probe excellent sensitivity with a detection limit of 0.78 nM, which was then explored to image the kinetic process of sulfite release in hepatic BRL cells after incubating with an excess amount of cysteine. This strategy opens new opportunities for revealing thiol-containing species metabolism and even quantitatively tracking their distributions in live cells or organelles.

2,4-Dimeth-oxy-6-[(E)-2-(4-meth-oxy-phenyl)ethen-yl]benzaldehyde.

There are two conformationally similar mol-ecules in the asymmetric unit of he title compound, C18H18O4, in which the dihedral angles between the benzene rings are 23.54 (12) and 31.11 (12)°. In the crystal, C-H⋯π inter-actions (minimum H⋯ring centroid distance = 2.66 Å) link the mol-ecules into a layered structure extending down a.

One-step fermentation of pretreated rice straw producing microbial oil by a novel strain of Mortierella elongata PFY.

A fungus strain producing microbial oils utilizing pretreated rice straw was isolated from soil. This strain was identified as Mortierella elongata PFY based on the morphology and internal transcribed spacer sequence. Using pretreated rice straw as substrate, the average yield of total lipids was 7.07% after 7 days fermentation. The GC-MS detection demonstrated that the lipids were composed of saturated fatty acids and polyunsaturated fatty acids. This work presents one new way to make the waste biomass (rice straw) valuable.

Structure and saccharification of rice straw pretreated with sulfur trioxide micro-thermal explosion collaborative dilutes alkali.

In this paper, a sulfur trioxide collaborative dilutes alkali method has been developed to pre-treat rice straw and it has been studied that the pre-treated rice straw structure affected the saccharification of the rice straw hydrolyzed by cellulose enzymatic hydrolysis. The results show that the reaction of the sulfur trioxide with rice straw resulted in the internal micro-thermal explosion, and the saccharification rate was 91% based on the pretreated rice straw with sulfur trioxide for 4h following 1% w/v NaOH treatment for 7h at 50°C.

Preparation of carboxymethylchitosan nanoparticles with Acid-sensitive bond based on solid dispersion of 10-hydroxycamptothecin.

Solid dispersions were prepared by a conventional solvent evaporation method from the water-insoluble model drug 10-hydroxycamptothecin (HCPT) and monomethoxypoly(ethylene glycol) 2000 (mPEG 2000). And then one type of novel biodegradable nanoparticles, the solid dispersion (HCPT/mPEG-CHO) grafted with carboxymethylchitosan (HCPT/mPEG-g-CMCTS) was synthesized. The increase in HCPT solubility of solid dispersion was up to 21-fold compared with the original drug. With the increasing of the amount of mPEG-CHO, solubility of HCPT was from 7.71 µg/mL to 25.82 µg/mL. Colloid systems based on solid dispersion were stable in aqueous medium at 5°C. After 5 months storage at 25°C, the solid dispersions do not change at all. HCPT/mPEG-g-CMCTS was synthesized by grafting reaction of carboxymethylchitosan with mPEG-CHO to form Schiff base which is sensitive to acid environment. The release rate of HCPT from this conjugate in pH 5.4 was much higher than that in the environment of pH 7.4 and p H 4.5. The cumulative release percentages are 45%, 25%, and 15%, respectively. The cumulative release percentage of HCPT in conjugate was only 15% within 85 h while the original drug was up to 70% in pH 7.4, showing a significant slow-release property. This drug model can be attractive candidates as delivery biosystems in tumor therapy.

Degradation of phenolic compounds with hydrogen peroxide catalyzed by enzyme from Serratia marcescens AB 90027.

In this paper, the degradation of phenolic compounds using hydrogen peroxide as oxidizer and the enzyme extract from Serratia marcescens AB 90027 as catalyst was reported. With such an enzyme/H2O2 combination treatment, a high chemical oxygen demand (COD) removal efficiency was achieved, e.g., degradation of hydroquinone exceeded 96%. From UV-visible and IR spectra, the degradation mechanisms were judged as a process of phenyl ring cleavage. HPLC analysis shows that in the degradation p-benzoquinone, maleic acid and oxalic acid were formed as intermediates and that they were ultimately converted to CO2 and H2O. With the enzyme/H2O2 treatment, vanillin, hydroquinone, catechol, o-aminophenol, p-aminophenol, phloroglucinol and p-hydroxybenzaldehyde were readily degraded, whereas the degradation of phenol, salicylic acid, resorcinol, p-cholorophenol and p-nitrophenol were limited. Their degradability was closely related to the properties and positions of their side chain groups. Electron-donating groups, such as -OH, -NH2 and -OCH3 enhanced the degradation, whereas electron-withdrawing groups, such as -NO2, -Cl and -COOH, had a negative effect on the degradation of these compounds in the presence of enzyme/H2O2. Compounds with -OH at ortho and para positions were more readily degraded than those with -OH at meta positions.