S-methyl-L-cysteine Protects against Antimycin A-induced Mitochondrial Dysfunction in Neural Cells via Mimicking Endogenous Methionine-centered Redox Cycle.

Mitochondrial superoxide overproduction is believed to be responsible for the neurotoxicity associated with neurodegeneration. Mitochondria-targeted antioxidants, such as MitoQ, have emerged as potentially effective antioxidant therapies. Methionine sulfoxide reductase A (MsrA) is a key mitochondrial-localized endogenous antioxidative enzyme and it can scavenge oxidizing species by catalyzing the methionine (Met)-centered redox cycle (MCRC). In this study, we observed that the natural L-Met acted as a good scavenger for antimycin A-induced mitochondrial superoxide overproduction in PC12 cells. This antioxidation was largely dependent on the Met oxidase activity of MsrA. S-methyl-L-cysteine (SMLC), a natural analogue of Met that is abundantly found in garlic and cabbage, could activate the Met oxidase activity of MsrA to scavenge free radicals. Furthermore, SMLC protected against antimycin A-induced mitochondrial membrane depolarization and alleviated 1-methyl-4-phenylpyridinium (MPP+)-induced neurotoxicity. Thus, our data highlighted the possibility for SMLC supplement in the detoxication of mitochondrial damage by activating the Met oxidase activity of MsrA.

Risk factors and clinical characteristics of tacrolimus-induced acute nephrotoxicity in children with nephrotic syndrome: a retrospective case-control study.

PURPOSE: Acute nephrotoxicity is a common adverse reaction of tacrolimus therapy; however, its risk factors in pediatric nephrotic syndrome (NS) remain to be evaluated. The objective of this study was to investigate the risk factors and characteristics of tacrolimus-induced acute nephrotoxicity in children with NS. METHODS: Past records of children with NS admitted to our hospital from 2014 to 2018 were reviewed. The incidence and characteristics of nephrotoxicity were analyzed. Multivariate logistic regression analysis was used to identify the risk factors of nephrotoxicity. A clinically applicable risk score was developed and validated. RESULTS: Tacrolimus-induced nephrotoxicity occurred in 25 of 129 patients, 13 patients were grade 1, and the renal function was recovered in 22 patients. Multivariate regression analysis showed that the maximum trough concentrations (C12h) of tacrolimus (OR, 1.48; 95% CI, 1.16 to 1.88; P < 0.001), huaiqihuang granules (OR, 0.095; 95% CI, 0.014 to 0.66; P = 0.017), and diarrhea (OR, 22.00; 95% CI, 1.58 to 306.92; P = 0.022) were independently associated with tacrolimus-induced nephrotoxicity. The maximum C12h were significantly higher in patients with nephrotoxicity (median 9.0 ng/ml) and the cut-off value for acute nephrotoxicity was 6.5 ng/ml. The area under the receiver operating characteristic curve was 0.821 for the proposed model based on the observations used to create the model and 0.817 obtained from k-fold cross-validation. CONCLUSIONS: High trough concentration of tacrolimus and diarrhea can potentiate the risk of tacrolimus-induced acute nephrotoxicity in children with NS, while huaiqihuang granules can protect this condition.

Dimethyl sulfide protects against oxidative stress and extends lifespan via a methionine sulfoxide reductase A-dependent catalytic mechanism.

Methionine (Met) sulfoxide reductase A (MsrA) is a key endogenous antioxidative enzyme with longevity benefits in animals. Only very few approaches have been reported to enhance MsrA function. Recent reports have indicated that the antioxidant capability of MsrA may involve a Met oxidase activity that facilities the reaction of Met with reactive oxygen species (ROS). Herein, we used a homology modeling approach to search the substrates for the oxidase activity of MsrA. We found that dimethyl sulfide (DMS), a main metabolite that produced by marine algae, emerged as a good substrate for MsrA-catalytic antioxidation. MsrA bounds to DMS and promoted its antioxidant capacity via facilitating the reaction of DMS with ROS through a sulfonium intermediate at residues Cys72, Tyr103, and Glu115, followed by the release of dimethyl sulfoxide (DMSO). DMS reduced the antimycin A-induced ROS generation in cultured PC12 cells and alleviated oxidative stress. Supplement of DMS exhibited cytoprotection and extended longevity in both Caenorhabditis elegans and Drosophila. MsrA knockdown abolished the cytoprotective effect and the longevity benefits of DMS. Furthermore, we found that the level of physiologic DMS was at the low micromolar range in different tissues of mammals and its level decreased after aging. This study opened a new window to elucidate the biological role of DMS and other low-molecular sulfides in the cytoprotection and aging.

A specific and rapid colorimetric method to monitor the activity of methionine sulfoxide reductase A.

Considerable evidence indicates that methionine sulfoxide (MetO) reductase A (MsrA) plays an important role in cytoprotection against oxidative stress and serves as a potential drug target. To screen for MsrA regulators, a rapid and specific assay to monitor MsrA activity is required. Most of current assays for MsrA activity are based on the reduction of radioactive substrates such as [3H]-N-acetyl-MetO or fluorescent derivatives such as dimethylaminoazo-benzenesulfonyl-MetO. However, these assays require extraction procedures and special instruments. Here, we developed a specific colorimetric microplate assay for testing MsrA activity quickly, which was based on the fact that MsrA can catalyze the reduction of methyl sulfoxides and simultaneously oxidize dithiothreitol (DTT), whose color can be produced by reacting with Ellman's reagent (dithio-bis-nitrobenzoic acid, DTNB). The corresponding absorbance change at 412nm was recorded with a microplate reader as the reaction proceeded. This method to monitor MsrA activity is easy to handle. Our findings may serve as a rapid method for the characterization of recombinant enzyme and for the screening of enzyme inhibitors, pharmacological activators, gene expression regulators and novel substrates.

The inhibitory effect of Binens bipinnata L. extract on U14 tumour in mice.

The objective of this paper was to study the in vitro and in vivo inhibitory effect of Bidens bipinnata L. extract on growth of cervical carcinoma U14 cells. MTT method was used to determine the inhibitory effect of Bidens bipinnata L. extract on U14 tumour cells, and the effects of Bidens bipinnata L. extract on inhibition rate of solid tumour and life prolongation rate of ascites tumour were observed through the establishment of two animal models of mouse cervical carcinoma U14 solid tumour and ascites tumour. In the in vitro MTT assay, the inhibition rate gradually increased with the increase of dose of Bidens bipinnata L. and the extension of time. Its inhibition rate was 70.44% at a concentration of 80µg/L. Solid tumour inhibition rates in the high- and low-dose groups and cisplatin group were 49.13%, 2.26% and 75.72% respectively; life prolongation rates in each ascites tumour group were 63.63%, 34.86% and 87.34% respectively. The Bidens bipinnata L. extract has a certain inhibitory effect on growth of mouse cervical carcinoma U14.