The Molecular Mechanism of Radix Paeoniae Rubra.-Cortex Moutan. Herb Pair in the Treatment of Atherosclerosis: A Work Based on Network Pharmacology and In Vitro Experiments.

Radix Paeoniae Rubra. (Chishao, RPR) and Cortex Moutan. (Mudanpi, CM) are a pair of traditional Chinese medicines that play an important role in the treatment of atherosclerosis (AS). The main objective of this study was to identify potential synergetic function and underlying mechanisms of RPR-CM in the treatment of AS. The main active ingredients, targets of RPR-CM and AS-related genes were obtained from public databases. A Venn diagram was utilized to screen the common targets of RPR-CM in treating AS. The protein-protein interaction network was established based on STRING database. Biological functions and pathways of potential targets were analyzed through Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. Cytoscape was used to construct the drug-compound-target-signal pathway network. Molecular docking was performed to verify the binding ability of the bioactive ingredients and the target proteins. The endothelial inflammation model was constructed with human umbilical vein endothelial cells stimulated with ox-LDL, and the function of RPR-CM in treating AS was verified by CCK-8 assay, enzyme-linked immunosorbent assay, and qPCR. In this study, 12 active components and 401 potential target genes of RPR-CM were identified, among which quercetin, kaempferol and baicalein were considered to be the main active components. A total of 1903 AS-related genes were identified through public databases and four GEO datasets (GSE57691, GSE72633, GSE6088 and GSE199819). There are 113 common target genes of RPR-CM in treating AS. PPI network analysis identified 17 genes in cluster 1 as the core targets. Bioinformatics analysis showed that RPR-CM in AS treatment was associated with multiple downstream biological processes and signal pathways. PTGS2, JUN, CASP3, TNF, IL1B, IL6, FOS, STAT1 were identified as the core targets of RPR-CM, and molecular docking showed that the main bioactive components of RPR-CM had good binding ability with the core targets. RPR-CM extract significantly inhibited the levels of inflammatory factors TNF-α, IL-6, IL-1ß, MCP-1, VCAM-1 and ICAM-1 in HUVECs, and inhibited endothelial inflammation. This study revealed the active ingredients of RPR-CM, and identified the key downstream targets and signaling pathways in the treatment of AS, providing theoretical basis for the application of RPR-CM in prevention and treatment of AS.

Imaging application of an MMP2-sensitive tumor-targeted prussian blue fluorescent nanoprobe.

In recent years, the application of nanoimaging technology on standardize tumor diagnosis has become a new research hotspot, especially nanoprobes. Our research group has synthesized a kind of nanocarrier, mPEG2000-GPLGIAGQ-DSPE, which has the characteristic of matrix metalloproteinase-2 (MMP2) sensitive ability in tumor microenvironment. Meanwhile, the encapsulation method is adopted to prepare MMP2-sensitive tumor-targeted prussian blue fluorescent nanoprobe with mPEG2000-GPLGIAGQ-DSPE as the carrier. On the one hand, this novel nanoprobe not only can effectively improve the solubility of prussian blue, but is non-toxic and safe for cells. On the other hand, octapeptide (GPLGIAGQ) in mPEG2000-GPLGIAGQ-DSPE nanocarrier can specifically respond to MMP2 in tumor cells to release prussian blue, and achieve targeted intelligent imaging of tumor cells.

Photoinduced Radical Sulfinylation of C(sp3)-H Bonds with Sulfinyl Sulfones.

A direct C(sp3)-H sulfinylation reaction of alkanes with sulfinyl sulfones via decatungstate photocatalysis is reported. The sulfinyl sulfones generated in situ from sulfinates in the presence of an acylating reagent were able to trap the alkyl radicals that were produced via the photoinduced direct hydrogen atom transfer of alkanes, leading to a range of sulfoxides. This radical sulfinylation process provides an efficient and concise method for the synthesis of sulfoxides from abundant alkanes under mild conditions. Using the same strategy, aldehydes can also be transferred to the corresponding sulfoxides via decarbonylative sulfinylation.

Nanomicelles for GLUT1-targeting hepatocellular carcinoma therapy based on NADPH depletion.

Hepatocellular carcinoma (HCC) is a malignant tumor leading cancer-associated high mortality worldwide. Unfortunately, the most commonly used drug therapeutics not only lack of target ability and efficiency, but also exhibit severe systemic toxicity to normal tissues. Thus, effective and targeted nanodrug of HCC therapy is emerging as a more important issue. Here, we design and develop the novel nanomicelles, namely Mannose-polyethylene glycol 600-Nitroimidazole (Man-NIT). This micelle compound with high purity comprise two parts, which can self-assemble into nanoscale micelle. The outer shell is selected mannose as hydrophilic moiety, while the inner core is nitroimidazole as hydrophobic moiety. In the cell experiment, Man-NIT was more cellular uptake by HCCLM3 cells due to the mannose modification. Mannose as a kind of glucose transporter 1 (GLUT1) substrate, can specifically recognize and bind to over-expressed GLUT1 on carcinoma cytomembrane. The nitroimidazole moiety of Man-NIT was reduced by the over-expressed nitroreductase with reduced nicotinamide adenine dinucleotide phosphate (NADPH) as the cofactor, resulting in transient deletion of NADPH and glutathione (GSH). The increase of reactive oxygen species (ROS) in HCCLM3 cells disturbed the balance of redox, and finally caused the death of tumor cells. Additional in vivo experiment was conducted using twenty-four male BALB/c nude mice to build the tumor model. The results showed that nanomicelles were accumulated in the liver of mice. The tumor size and pathological features were obviously improved after nanomicelles treatment. It indicates that namomicelles have a tumor inhibition effect, especially Man-NIT, which may be a potential nanodrug of chemotherapeutics for HCC therapy.

Design and evaluation of glutathione responsive glycosylated camptothecin nanosupramolecular prodrug.

A novel tumor-targeted glutathione responsive Glycosylated-Camptothecin nanosupramolecular prodrug (CPT-GL NSp) was designed and fabricated via a disulfide bond. The effects of glycoligand with different polarities on solubility, self-assembly, stability, cellular uptake, and glutathione responsive cleaving were explored, and an optimal glycosylated ligand was selected for nanosupramolecular prodrug. It has been found that CPT-GL NSp exhibited higher drug loading than traditional nanoparticles. Among of which maltose modified NSp had the strongest anti-tumor effects than that of glucose and maltotriose. CPT-SS-Maltose had a similar anti-tumor ability to Irinotecan (IR), but the superior performance in solubility, hemolysis, and uptake of HepG2 cells.

Kidney-targeted astaxanthin natural antioxidant nanosystem for diabetic nephropathy therapy.

Diabetic nephropathy (DN) is a frequent and severe microvascular complication associated with oxidative stress of diabetes mellitus. A novel astaxanthin-based natural antioxidant nanosystem, namely AST-GLU-LIP, with preferential renal uptake and bioavailability were prepared and applied for treatment of diabetic nephropathy in rats. Our results of kidney-targeted evaluation showed that glucose-PEG600-DSPE ligand modified AST liposomes could be specifically transported by overexpressed GLUT1 on the membrane of glomerular mesangial cells and achieved excellent kidney-targeted drug delivery. In addition, the results of pharmacodynamics and therapeutics in DN rats demonstrated that AST-GLU-LIP could improve the bioavailability and antioxidant capacity of AST to scavenge redundant ROS induced by oxidative stress. AST-GLU-LIP could also significantly improve the renal pathological morphology to protect the kidney as a therapeutic drug for diabetic nephropathy.

Advances in kidney-targeted drug delivery systems.

The management and treatment of kidney diseases currently have caused a huge global burden. Although the application of nanotechnology for the therapy of kidney diseases is still at an early stages, it has profound potential of development. More and more nano-based drug delivery systems provide novel solutions for the treatment of kidney diseases. This article summarizes the physiological and anatomical properties of the kidney and the biological and physicochemical characters of drug delivery systems, which affects the ability of drug to target the kidney, and highlights the prospects, opportunities, and challenges of nanotechnology in the therapy of kidney diseases.

Influences of different sugar ligands on targeted delivery of liposomes.

Ligands are an important part of targeted drug delivery systems. Optimised lignads not only improve the target efficiency, but also enhance therapeutical effect of drugs. In our research, five sugar molecules (Mannose, Galactose, Glucose, Malt disaccharide, and Maltotriose) conjugated PEG600-DSPE were synthesised, of which polysaccharides were first discovered by us as sugar ligands to modify liposomes, which interacts with over expressive GLUT on cancer cells. DiO was encapsulated as fluorescent probe to evaluate their cellular uptake abilities of targeting C6 glioma cells, and the distribution in different visceral organs of rats. The results demonstrated that Malt disaccharide and Glucose-PEG600-DSPE had the strong efficiency of cellular uptake by C6 glioma cells. The distribution and accumulation of liposomes showed that different sugars modified liposomes could target different visceral organs in rats. It has provided a novel idea for ligand selectivity and optimisation of nanocarriers for tumour targeted therapy.

Sonodynamic therapy in atherosclerosis by curcumin nanosuspensions: Preparation design, efficacy evaluation, and mechanisms analysis.

Previous studies have shown that curcumin (Cur) induced by ultrasound has protective effects on atherosclerosis even if low bioavailability of the Cur. The enhancement of bioavailability of the Cur further improved the curative effect of sonodynamic therapy (SDT) on atherosclerosis through nanotechnology. Nanosuspensions as a good drug delivery system had obvious advantages in increasing the solubility and improving the effectiveness of insoluble drugs. The aim of this study was to develop curcumin nanosuspensions (Cur-ns) which used polyvinylpyrrolidone (PVPK30) and sodium dodecyl sulfate (SDS) as stabilizers to improve poor water solubility and bioavailability of the Cur. And then the therapeutic effects of Cur-ns-SDT on atherosclerotic plaques and its possible mechanisms would be investigated and elucidated. Cur-ns with a small particle size has been successfully prepared and the data have confirmed that Cur-ns could be more easily engulfed into RAW264.7 cells than free Cur and accumulated more under the stimulation of the ultrasound. Reactive oxygen species (ROS) inside RAW264.7 cells after SDT led to the decrease of mitochondrial membrane potential (MMP) and the higher expression of cleaved caspase-9/3. The results of in vivo experiments showed that Cur-ns-SDT reduced the level of total cholesterol (TC) and low density lipoprotein (LDL) and promoted the transformation from M1 to M2 macrophages, relieved atherosclerosis syndrome. Therefore, Cur-ns-SDT was a potential treatment of anti-atherosclerosis by enhancing macrophages apoptosis through mitochondrial pathway and inhibiting the progression of plaques by interfering with macrophages polarization.

Targeting Regulation of Dually Modified Liposomes by Polyethylene Glycol Length of Vesicle Surface.

With aging of population, changing of living habits, and intake of high-fat diet, more and more people have been suffering from cardio-cerebral apoplexy. The synchronous treatment of cardio-cerebral conditions based on an integral strategy may bring benefit to the better clinical efficacy. The simultaneously-targeting delivery of active molecules by nanoscale carriers to heart and brain remains unmet problem. The physiological difference of targets between heart and brain makes it a huge challenge which one targeting ligand modification acquires the delivery of two organs and treatment, simultaneously. Traditionally, dually targeting strategies are introduced to enhance the selectivity for one aimed tissue and delivery efficiency of these particles. However, the interference between two targeting ligands on the surface of nanoscale carriers may influence the affinity of these ligands with their receptors or transporters, resulting to the change distribution of carriers. Herein, we observed that how anti-cardiac troponin I (cTnI) antibody (Ab) conjugated with the linker, polyethylene glycol (PEG), on the surface of liposomes influenced the affinity of mannose derivatives with transporter and regulated distribution of these vesicles in the heart and brain. The dually targeting liposomes can target to the heart and brain tissue simultaneously by the regulation length of PEG chain linking with p -pentanoic acid phenyl-α-D-acetylmannosamine (Ac4MAN). These results may bring benefit to design the multi-modification of nanocarriers and the treatment of cardio-cerebral diseases.

A Genetically Encoded Fluorescent Sensor for Rapid and Specific In Vivo Detection of Norepinephrine.

Norepinephrine (NE) is a key biogenic monoamine neurotransmitter involved in a wide range of physiological processes. However, its precise dynamics and regulation remain poorly characterized, in part due to limitations of available techniques for measuring NE in vivo. Here, we developed a family of GPCR activation-based NE (GRABNE) sensors with a 230% peak ΔF/F0 response to NE, good photostability, nanomolar-to-micromolar sensitivities, sub-second kinetics, and high specificity. Viral- or transgenic-mediated expression of GRABNE sensors was able to detect electrical-stimulation-evoked NE release in the locus coeruleus (LC) of mouse brain slices, looming-evoked NE release in the midbrain of live zebrafish, as well as optogenetically and behaviorally triggered NE release in the LC and hypothalamus of freely moving mice. Thus, GRABNE sensors are robust tools for rapid and specific monitoring of in vivo NE transmission in both physiological and pathological processes.

Effects of several acetylated chitooligosaccharides on antioxidation, antiglycation and NO generation in erythrocyte.

Three kinds of chitooligosaccharides (COS) with different degrees of deacetylation were prepared and named MD90, MD70 and MD50, respectively. Antioxidation, antiglycation and nitric oxide (NO) promotion in erythrocyte of these samples were investigated. The results showed that COS, especially MD90 had obviously inhibitory effects on oxidation and glycation. In addition, MD90 displayed stronger effect on increasing endogenous NO content than both MD70 and MD50, whose degrees of deacetylation were lower. The results indicated that amino group in COS has a certain effect on the activities of COS. As COS have a conformed activity to treat diabetes, the results of this study may be meaningful for further understanding the mechanism of the action.