Exploring the possible mechanism(s) underlying the nephroprotective effect of Zhenwu Decoction in diabetic kidney disease: An integrated analysis.

BACKGROUND: Diabetic kidney disease (DKD) is one of the major chronic microvascular complications of diabetes and the main cause of end-stage renal failure. Zhenwu Decoction (ZWD), an ancient classic herbal formula in Chinese medicine, has been clinically used for the treatment of kidney disease in China for many years. However, there is currently limited research investigating the application of ZWD in the treatment of DKD and the underlying chemical and biochemical mechanisms involved. Therefore, in the present study, we aimed to identify active components in ZWD and unravel the possible mechanism(s) of action for ZWD in treating DKD. METHODS: The protective effect of ZWD against DKD was evaluated utilizing an in vitro model of diabetic renal proximal tubulopathy. The major chemical components from ZWD were identified by LC-MS/MS. Drug targets were predicted by submitting the SMILES (Simplified Molecular Input Line Entry System) of the compounds to SEA (Similarity Ensemble Approach) search server and SwissTargetPrediction. The differentially expressed genes (DEGs) of the disease were collected and integrated from GeneCards. The constructions of "Compounds-potential targets interaction" (CTI) network and Protein-Protein Interaction (PPI) network, as well as topology analysis were conducted by Cytoscape. Gene Ontology (GO) enrichment and Metacore pathway enrichment analysis were also performed. Lastly, molecular docking and experimental studies were adopted to validate the core target and identify an active component(s) of ZWD. RESULTS: We demonstrated that the ZWD extract could significantly rescue the palmitic acid (PA) and high glucose-induced apoptotic cell death in HK-2 cells, and the cytoprotection was accompanied by decreases in the extent of reactive oxygen species (ROS) production, mitochondrial membrane depolarization and ATP depletion. Fifty-seven compounds in the aqueous extract of ZWD were identified by LC-MS. The results of PPI analysis showed that top hub genes involved epidermal growth factor receptor (EGFR), Signal Transducer and Activator of Transcription 3 (STAT3), Serine/Threonine Kinase 1 (AKT1), Vascular Endothelial Growth Factor A (VEGFA) and Fibroblast Growth Factor 2 (FGF2). Pathway enrichment analysis revealed the involvement of S1P1 receptor signaling and EGFR pathways. The results of molecular docking analysis showed that albiflorin has a high binding affinity to EGFR. Albiflorin could also exert protective effects in an HK-2 cell model of DKD, which may be related to the inhibition of the high glucose/high lipid-induced EGFR and Akt phosphorylation. CONCLUSION: ZWD has been shown to be effective in ameliorating cell death in an experimental model of DKD. The beneficial effect of ZWD against DKD was associated with the interactions between the active ingredients and the hub genes, such as EGFR, STAT3, AKT1, and VEGF-A. Albiflorin may be one of the active components responsible for the nephroprotective effect in ZWD.

Self-Assembled Nanoparticles of a Prodrug Conjugate Based on Pyrimethanil for Efficient Plant Disease Management.

Self-assembled nanotechnology is a promising strategy for improving the effective utilization of pesticides due to its distinct advantages. Herein, an amide-bonded prodrug conjugate based on pyrimethanil (PYR) and butyric acid (BA) was successfully synthesized by the nucleophilic substitution reaction and subsequently self-assembled into spherical nanoparticles (PB NPs) with an average size of 85 nm through the solvent exchange method without using any toxic adjuvant. The results showed that PB NPs based on PYR and BA had a synergistic antimicrobial activity against S. sclerotiorum on plant leaves due to good photostability, low volatilization, good surface activity, and improved retention. Additionally, PB NPs could be used by plant cells as nutrients to promote the growth of plants and thus reduced the toxicity of PYR to plant. Therefore, this prodrug conjugate self-assembly nanotechnology would provide a promising strategy for improving the effective utilization rates of pesticides and reducing their toxicities to plants.

Formation of protein-anthocyanin complex induced by grape skin extracts interacting with wheat gliadins: Multi-spectroscopy and molecular docking analysis.

In order to broaden the application of grape skin anthocyanin extract (GSAE) in flour products, the interaction of gliadin (Gli) and GSAE were investigated. Seven anthocyanin components from GSAE were identified by HPLC-MS2, which could form complexes with Gli having different binding rates based on UV, FTIR and HPLC analysis. The fluorescence quenching experiment showed that GSAE was capable of efficiently quenching the intrinsic fluorescence of Gli through hydrophobic interactions, and the binding parameters were near to one unit at the given temperatures. Additionally, GSAE binding changed the conformational properties of Gli, increasing α-helix and ß-turn content, but decreasing ß-sheet and irregular coil content. The molecular docking suggested that Gli possessed various binding sites bound with different anthocyanin monomers, mainly depending on hydrogen bonds and hydrophobic interactions. These findings further proved the formation of Gli-GSAE complex, indicating the potential of anthocyanins as natural colorant.

An Integrative Proteome-Based Pharmacologic Characterization and Therapeutic Strategy Exploration of SAHA in Solid Malignancies.

Targeting histone epigenetic modification is an important strategy for anticancer therapy. Histone deacetylase inhibitors (HDACis) have been clinically approved in the treatment of diverse hematological cancers, but mechanisms of drug resistance and poor therapeutic efficacy in solid malignancies remain largely unknown. In this study, we applied a mass spectrometry-based quantitative proteomic strategy to investigate the molecular differences in HDACi vorinostat (SAHA) sensitive and resistant cell lines. The proteomic results revealed that the glycolysis pathway was highly enriched after vorinostat treatment in the resistant cell line, leading to the prediction of a new drug combination, SAHA and hexokinase inhibitor (2-deoxyglucose). The efficacy of this combination was further verified in several solid tumor cell lines. Quantitative proteomics revealed that alterations in the transcription process and protein homeostasis could play roles in the synergetic utilization of these two compounds. Our study showed the application of proteomics in elucidating the drug mechanism and predicting drug combination and the potential of expanding the utilization of HDACi.

The Use of Chinese Yang/Qi-Invigorating Tonic Botanical Drugs/Herbal Formulations in Ameliorating Chronic Kidney Disease by Enhancing Mitochondrial Function.

Background: Chronic kidney disease (CKD) is a leading cause of morbidity and mortality. Mitochondrial dysfunction has been implicated as a key factor in the development of CKD. According to traditional Chinese medicine (TCM) theory, many Chinese Yang/Qi-invigorating botanical drugs/herbal formulations have been shown to produce promising outcomes in the clinical management of CKD. Experimental studies have indicated that the health-promoting action of Yang/Qi invigoration in TCM is related to the up-regulation of mitochondrial energy generation and antioxidant status. Objective: In this review, we aim to test whether Chinese Yang/Qi-invigorating tonic botanical drugs/herbal formulations can provide medical benefits in CKD and its complications. And we also explore the possible involvement of mitochondrial-associated signaling pathway underlying the beneficial effects of Yang/Qi invigoration in TCM. Methods: A systematic search of "PubMed", "China National Knowledge Infrastructure (CNKI)" and "Google Scholar" was carried out to collect all the available articles in English or Chinese related to Chinese Yang/Qi-invigorating tonic botanical drugs/herbal formulations and their effects on mitochondrial function and chronic kidney disease. Result and Discussion: The relationship between the progression of CKD and mitochondrial function is discussed. The effects of Chinese Yang/Qi-invigorating tonic botanical drugs/herbal formulations and their active ingredients, including phytosterols/triterpenes, flavonoids, and dibenzocyclooctadiene lignans, on CKD and related alterations in mitochondrial signaling pathways are also presented in this review. In the future, exploration of the possible beneficial effects and clinical studies of more Yang- and Qi-invigorating botanical drugs/herbal formulations in the prevention and/or/treatment of CKD and the molecular mechanisms relating to the enhancement of mitochondrial functions warrants further investigation. Conclusion: Given the critical role of mitochondrial function in safeguarding renal functional integrity, the enhancement of mitochondrial energy metabolism and antioxidant status in kidney tissue is likely involved in renal protection. Future studies on the biochemical and chemical basis underlying the effects of Chinese Yang/Qi-invigorating tonic botanical drugs/herbal formulations from a mitochondrial perspective will hopefully provide novel insights into the rational development of new drugs for the prevention and/or treatment of CKD.

Transport of Flavanolic Monomers and Procyanidin Dimer A2 across Human Adenocarcinoma Stomach Cells (MKN-28).

It has been proven that A-type procyanidins, containing an additional ether bond, compared to B-type procyanidins are also bioavailable in vitro and in vivo. However, their bioavailability and absorption in the gastrointestinal tract remain uncertain. In this study, a model of the human adenocarcinoma stomach cell line (MKN-28) was established to explore the cellular transport of flavanolic monomers and procyanidin dimer A2, which were isolated from the litchi pericarp extract. After the integrity and permeability of the cell monolayer were ensured by measurement of the transepithelial electrical resistance and the apparent permeability coefficient for Lucifer yellow, the transportation of procyanidins A2 and B2, (-)-epicatechin (EC), and (+)-catechin (CC) was studied at pH 3.0, 5.0, or 7.0 in the apical side, with compound concentrations of 0.05 and 0.1 mg/mL based on the cytotoxicity test. High-performance liquid chromatography and liquid chromatography-mass spectrometry analyses indicated that EC, CC, and A2 were transported in the MKN-28 cell line from 30 to 180 min, while B2 showed no transport. The maximal transport efficiencies of EC, CC, and A2 were 23 ± 0.81, 13.16 ± 1.53, and 16.41 ± 1.36%, respectively, existing at 120, 180, and 120 min of transportation. Laser scanning confocal microscopy analysis presented the dynamic transmission of EC, in accordance with the result of concentration determination, suggesting that the A-type procyanidins are possibly absorbed through the stomach barrier, which is pH- and time-dependent.

The formation and bioactivities of green substances in Chrysanthemum morifolium tea.

One interesting phenomenon of Chrysanthemum morifolium tea is its formation of green or dark green color after hours of brewing. We investigated the greening reaction and its bioactivities, including an analysis of the green compounds. Results showed that the green color was due to a decrease in the L* (lightness), b* (yellowness/blueness), chroma values and an increase in hue angle. The green substances were found to be substances with similar polarities and unstable in acidic conditions. There was no significant difference (p < 0.01) in antioxidant activity between non-green and green samples. The green substances did not lead to cytotoxicity in PC12 cells at low concentrations, but at high concentrations, they caused a significant (p < 0.01) decrease in cell viability. The saccharide percentage and FT-IR results showed that the greening reaction was affected by the glycosides or groups attached to the saccharides, which might suggest a new mechanism for color-forming reactions.

Extraction, Purification, and Hydrolysis Behavior of Apigenin-7-O-Glucoside from Chrysanthemum Morifolium Tea.

Apigenin-7-O-glucoside is an active phenolic compound in Asteraceae flowers and possesses remarkable therapeutic applications. However, its high price and low abundance in plants limit its use, meanwhile it would hydrolyze in the purification process. In this study, apigenin-7-O-glucoside extracted with ultrasound and purified with preparative HPLC from Chrysanthemum morifolium 'Huangju' was investigated, as well as its hydrolysis behavior and bioactivities. The optimized extraction conditions were: solid/liquid ratio: 1:20, extraction time: 35 min, temperature: 50 °C, and ultrasound power: 350 W. The content of apigenin-7-O-glucoside was up to 16.04 mg/g. Apigenin-7-O-glucoside was then purified with preparative HPLC from the extract, and confirmed by Q-TOF/MS. Apigenin-7-O-glucoside was partially hydrolyzed in acidic condition, and the hydrolysis rate depended on the pH value and temperature. The antioxidant activity increased as a result of the hydrolysis process. This study provided a green and effective way to obtain apigenin-7-O-glucoside and would be beneficial for further investigations into nutritional and functional aspects apigenin-7-O-glucoside and other glycosides.