Tripterygium wilfordii Hook.f induced kidney injury through mediating inflammation via PI3K-Akt/HIF-1/TNF signaling pathway: A study of network toxicology and molecular docking.

We intend to explore potential mechanisms of Tripterygium wilfordii Hook.f (TwHF) induced kidney injury (KI) using the methods of network toxicology and molecular docking. We determined TwHF potential compounds with its targets and KI targets, obtained the TwHF induced KI targets after intersecting targets of TwHF and KI. Then we conducted protein-protein interaction (PPI) network, gene expression analysis, gene ontology (GO) function and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis to explore the mechanism of TwHF-induced KI. Finally we conducted molecular docking to verify the core toxic compounds and the targets. We obtained 12 TwHF toxic compounds and 62 TwHF-induced KI targets. PPI network, gene expression analysis and GO function enrichment analysis unveiled the key biological process and suggested the mechanism of TwHF-induced KI might be associated with inflammation, immune response, hypoxia as well as oxidative stress. KEGG pathway enrichment analysis indicated PI3K-Akt signaling pathway, HIF-1 signaling pathway and TNF signaling pathway were key signaling pathways of TwHF induced KI. Molecular docking showed that the binding energy of core targets and toxic compounds was all less than -6.5 kcal/mol that verified the screening ability of network pharmacology and provided evidence for modifying TwHF toxic compounds structure. Through the study, we unveiled the mechanism of TwHF induce KI that TwHF might activate PI3K-Akt signaling pathway as well as TNF signaling pathway to progress renal inflammation, mediate hypoxia via HIF-1 signaling pathway to accelerate inflammatory processes, and also provided a theoretical basis for modifying TwHF toxic compounds structure as well as supported the follow-up research.

Controlled bacteriostasis of tea polyphenol loaded ultrahigh molecular weight polyethylene with high crosslink density and oxidation resistance for total joint replacement.

To avoid catastrophic bacterial infection in prosthesis failure, ultrahigh molecular weight polyethylene (UHMWPE), a common bearing material of artificial joints, has been formulated with antibiotics to eliminate bacteria locally at the implant site. However, the pressing issues regarding cytotoxic effects and evolution of drug resistant bacteria necessitates the development of bio-friendly bacteriostat with long bacteriostatic efficacy. Herein, tea polyphenol extracted from nature source was introduced in UHMWPE as a biogenic antimicrobial. Controlled antimicrobial activity was achieved by chemical crosslinking to regulate the release of the tea polyphenol. In addition, the crosslinking efficiency of UHMWPE blends with high loaded tea polyphenol was significantly improved in comparison to radiation crosslinking. The immobilized tea polyphenols also enhanced the oxidation stability of the UHMWPE, which is essential to prolong the service life in vivo and the storage time in vitro. The blends presented good biocompatibility, despite cell repellent on the highly crosslinked surface. Chemically crosslinked tea polyphenol/UHMWPE exhibited feasible properties for total joint implants, which is promising for clinical application.

Antibacterial and anti-inflammatory ultrahigh molecular weight polyethylene/tea polyphenol blends for artificial joint applications.

Periprosthetic joint infection (PJI) is one of the main causes for the failure of joint arthroplasty. In view of the limited clinical effect of oral/injectable antibiotics and the drug resistance problem, there is a pressing need to develop antibacterial implants with therapeutic antimicrobial properties. In this work, we prepared a highly antibacterial ultrahigh molecular weight polyethylene (UHMWPE) implant by incorporating tea polyphenols. The presence of tea polyphenols not only improved the oxidation stability of irradiated UHMWPE, but also gave it the desirable antibacterial property. The potent antibacterial activity was attributed to the tea polyphenols that produced excess intracellular reactive oxygen species and destroyed the bacterial membrane structure. The tea polyphenol-blended UHMWPE had no biological toxicity to human adipose-derived stem cells and effectively reduced bacteria-induced inflammation in vivo. These results indicate that tea polyphenol-blended UHMWPE is promising for joint replacement prostheses with multifunctionality to meet patient satisfaction.

High Oxidation Stability of Tea Polyphenol-stabilized Highly Crosslinked UHMWPE Under an in Vitro Aggressive Oxidative Condition.

BACKGROUND: Synovial fluid components, especially lipids, can trigger oxidation of ultrahigh-molecular-weight polyethylene (UHMWPE) artificial joint components in vivo. The use of antioxidants such as vitamin E effectively diminishes the oxidative cascade by capturing free radicals and reducing the oxidation potential of UHMWPE implants. Using a thermo-oxidative aging method, we recently found that tea polyphenols can enhance the oxidation resistance of irradiated UHMWPE in comparison with commercial vitamin E. However, it is yet unknown whether tea polyphenols can reduce lipid-induced oxidation. QUESTIONS/PURPOSES: We explored whether tea polyphenol-stabilized UHMWPE would exhibit (1) lower squalene absorption; (2) stronger oxidation resistance; and (3) lower content of free radicals than vitamin E-stabilized UHMWPE under a physiologically-motivated in vitro accelerated-aging model. METHODS: Tea polyphenol (lipid-soluble epigallocatechin gallate [lsEGCG]) and vitamin E were blended with UHMWPE powders followed by compression molding and electron beam irradiation at 100 and 150 kGy. Small cubes (n = 3, 60 mg, 4 × 4 × 4 mm) cut from the blocks were doped in squalene at 60°, 80°, 100°, and 120° C for 2 hours. Gravimetric change of the cubes after squalene immersion was measured to assess absorption. Thin films (n = 3, ∼60 µm) were also microtomed from the blocks and were doped at 120° C for 24 hours. Oxidation induction time (n = 3, 5 mg of material from the cubes) and incipient oxidation temperature (n = 3, thin films) were obtained to determine the oxidation stability. Signal intensity of the free radicals, obtained by electron spin resonance spectroscopy, was used to qualitatively rank the antioxidant ability of vitamin E and lsEGCG. RESULTS: Squalene absorption was comparable between lsEGCG/UHMWPE and vitamin E/UHMWPE at a given temperature and radiation dose. The oxidation induction time of 100 kGy-irradiated UHMWPE was increased with lsEGCG compared with vitamin E except at 120° C. For example, the oxidation induction time value of 100 kGy-irradiated lsEGCG/UHMWPE immersed at 60 C was 25.3 minutes (24.2-27.8 minutes), which was 8.3 minutes longer than that of 100 kGy-irradiated vitamin E/UHMWPE which was 17.0 minutes (15.0-17.1 minutes) (p = 0.040). After squalene immersion at 120° C, the incipient oxidation temperature of 100 and 150 kGy irradiated lsEGCG/UHMWPE was 234° C (227-240° C) and 227° C (225-229° C), which was higher than vitamin E-stabilized counterparts with value of 217° C (214-229° C; p = 0.095) and 216° C (207-218° C; p = 0.040), respectively. The electron spin resonance signal of 150 kGy irradiated lsEGCG/UHMWPE was qualitatively weaker than that of 150 kGy irradiated vitamin E/UHMWPE. CONCLUSIONS: lsEGCG-stabilized UHMWPE demonstrated higher oxidation resistance than vitamin E-stabilized UHMWPE after squalene immersion, likely because lsEGCG donates more protons to eliminate macroradicals than vitamin E. CLINICAL RELEVANCE: Our in vitro findings provide support that lsEGCG may be effective in protecting against oxidation that may be associated with synovial fluid-associated oxidation of highly crosslinked UHMWPE joint replacement components.

Enhanced oxidation stability of highly cross-linked ultrahigh molecular weight polyethylene by tea polyphenols for total joint implants.

Despite being currently state-of-the-art to prevent the oxidation of irradiated ultrahigh molecular weight polyethylene (UHMWPE) bearings, vitamin E (VE) poses concerns in the loss of cross-linking efficiency and is limited to be used at very low concentrations. It thus emphasizes the urgent demand for more efficient stabilizers. In this study, oxidation stability of highly cross-linked UHMWPE was demonstrated to be enhanced by tea polyphenols, such as lipid-soluble tea polyphenols (lsPPT), epigallocatechin gallate (EGCG), and lipid-soluble epigallocatechin gallate (lsEGCG). These antioxidants were blended with UHMWPE granules and consolidated by compression molding prior to E-beam irradiation. The presence of tea polyphenols substantially prolonged oxidation induction time of the irradiated UHMWPE before and after accelerated aging. Especially, lsEGCG was significantly superior to VE in terms of stabilizing capacity. Explained by the hydrogen donation mechanism, tea polyphenols with multiple phenolic hydroxyls could scavenge more radiation-induced free radicals than VE with only one phenolic hydroxyl, which was verified by the electron spin resonance spectra. Intriguingly, tea polyphenols showed less inhibitive effect on the cross-link density of irradiated UHMWPE than VE. Besides, there is no significant difference in crystallinity, mechanical performance as well as in vitro biocompatibility between the irradiated UHMWPE stabilized by tea polyphenols and VE. These findings highlight tea polyphenols, especially lsEGCG, are promising alternatives to extend the life span of UHMWPE implants.

L-tyrosine improves neuroendocrine function in a mouse model of chronic stress.

Adult BALB/c mice, individually housed, were stimulated with nine different stressors, arranged randomly, for 4 continuous weeks to generate an animal model of chronic stress. In chronically stressed mice, spontaneous locomotor activity was significantly decreased, escape latency in the Morris water maze test was prolonged, serum levels of total thyrotropin and total triiodothyronine were significantly decreased, and dopamine and norepinephrine content in the pallium, hippocampus and hypothalamus were significantly reduced. All of these changes were suppressed, to varying degrees, by L-tyrosine supplementation. These findings indicate that the neuroendocrine network plays an important role in chronic stress, and that L-tyrosine supplementation has therapeutic effects.

Regulation of copper homeostasis by Cuf1 associates with its subcellular localization in the pathogenic yeast Cryptococcus neoformans H99.

Here, we present further characterization of cryptococcal CUF1 in copper homeostasis. We demonstrated that CUF1 was involved both in copper acquisition and in copper detoxification in response to copper variation. This was verified by direct measurement of the quantity of intracellular copper with flame atomic absorption spectrometry (FAAS) and molecular evidence. In copper-limited growth, the mutant cuf1Δ exhibited copper deficiency, growth defect on glycerol and sensitivity to hydrogen peroxide and methionine. A novel function of cryptococcal CUF1 is revealed in copper detoxification when copper is in excess. The mutant cuf1Δ showed severe hypersensitivity to exogenous copper, while a high level of copper was accumulated shown by FAAS, suggesting that CUF1 may be required in copper export events. On cloning of cDNA, it was found that Cuf1 distinguishably harbors functional elements that are found in Ace1 and Mac1 of Saccharomyces cerevisiae. The regulation of copper homeostasis by Cuf1 is realized by its subcellular localization. Epifluorescence microscopy observed that, upon copper depletion, Cuf1 was localized exclusively to the nucleus as an activator for CTR4 transcription, while it was located to the cell periphery in the presence of exogenous copper. This work reveals a unique copper regulator and may provide insights into the copper metabolism in fungi.