The mechanisms of minocycline in alleviating ischemic stroke damage and cerebral ischemia-reperfusion injury.

Stroke is a group of diseases resulting from cerebral vascular rupture or obstruction and subsequent brain blood circulation disorder, leading to rapid neurological deficits. Ischemic stroke accounts for the majority of all stroke cases. The current treatments for ischemic stroke mainly include t-PA thrombolytic therapy and surgical thrombectomy. However, these interventions aimed at recanalizing cerebral vessels can paradoxically lead to ischemia-reperfusion injury, which exacerbates the severity of brain damage. Minocycline, a semi-synthetic tetracycline antibiotic, has been shown to possess a wide range of neuroprotective effects independent of its antibacterial activity. Here we summarize the mechanisms underlying the protective effects of minocycline against cerebral ischemia-reperfusion injury based on the pathogenesis of cerebral ischemia-reperfusion injury, including its modulation of oxidative stress, inflammatory response, excitotoxicity, programmed cell death and blood-brain barrier injury, and also introduce the role of minocycline in alleviating stroke-related complications, in order to provide a theoretical basis for the clinical application of minocycline in cerebral ischemia-reperfusion injury.

NDC80 status pinpoints mitotic kinase inhibitors as emerging therapeutic options in clear cell renal cell carcinoma.

∼30% of clear cell renal cell carcinoma (ccRCC) patients present with metastatic disease at the time of diagnosis, causing a dire 5-year survival rate of 13%. Although anti-PD-1 immunotherapy has improved survival, a strong need remains for new therapeutic options. Using integrated network analysis, we identified the mitotic regulator NDC80 as a predictor of ccRCC progression. Overexpression of NDC80 fosters the malignant phenotype by promoting cell cycle progression through S phase as well as boosting glycolysis and mitochondrial respiration. Despite high levels of immune infiltration, particularly derived from tumor resident CD8+T cells with an exhausted phenotype, NDC80 defines a class of ccRCCs that poorly respond to immune checkpoint blockade. Instead, bioinformatics identified NDC80-high ccRCCs as sensitive to inhibitors of mitotic kinases, PLK1 and AURK, therapeutic approaches we validated in cell lines and mouse xenograft studies. Thus, NDC80 status pinpoints mitotic kinase inhibitors as promising therapeutic options in difficult-to-treat ccRCCs.

Property of arylsulfatase and ß-glucuronidase extracted from digestive tracts of Cipangopaludina chinensis and their cleavage performance on conjugated natural estrogens.

Arylsulfatase and ß-glucuronidase are the two substantial enzymes having a significant role in the cleavage of conjugated natural estrogens (C-NEs). The present study reports that arylsulfatase and ß-glucuronidase have been abundantly found in the digestive tracts of Cipangopaludina chinensis; in which, their corresponding activities were 60 and 5 U/g wet waste, respectively. The arylsulfatase from Cipangopaludina chinensis could show high activity at low temperatures. Hence, its activity still remained at 53.2% of maximal activity even at an extremely low temperature of 4 ℃; while the corresponding activities of arylsulfatase from Helix pomatia or activated sludge were less than 20% and 10%, respectively. The arylsulfatase and ß-glucuronidase from Cipangopaludina chinensis could efficiently cleave C-NEs suggesting that they could be alternative enzymes derived from Helix pomatia that are used for cleavage of conjugated compounds in environmental or biological sample analysis. Meanwhile, they might also be used to enhance the cleavage of C-NEs in municipal wastewater.

Activity measurement of arylsulfatase and ß-glucuronidase in activated sludge: HPLC-based versus classical spectrophotometric method.

Arylsulfatase and ß-glucuronidase are two important enzymes in wastewater and surface water, which play important roles on cleavage of sulfate/glucuronide estrogens. In this work, a high-performance liquid chromatography (HPLC)-based new method was firstly established for arylsulfatase/ß-glucuronidase with determination of p-nitrophenyl sulfate (pNPS)/p-nitrophenyl-ß-D-glucuronide (pNPG). The limits of detections (LODs) of the developed method for pNPS and pNPG were 0.164 and 0.098 µM, respectively. Intraday and interday reproducibility expressed as relative standard deviation (RSD) values of retention times and peak areas was 0.39%-3.68% and 0.23%-4.74%, respectively. The respective recovery efficiencies of this HPLC-based method spiking at three different concentrations for p-nitrophenol (pNP), pNPS, and pNPG in activated sludge were 76.5%-88.1%, 79.2%-93.1%, and 84.2%-96.1%, with RSD below 3.9%. The HPLC-based method was finally applied to estimate the enzyme activity of arylsulfatase/ß-glucuronidase in one activated sludge system and along which the classical spectrophotometric method was also evaluated. Compared with the classic spectrophotometric analytical method, the HPLC-based new method could simultaneously measure arylsulfatase/ß-glucuronidase one time, which was convenient and time-saving. Moreover, the developed method could effectively avoid possible underestimation that the spectrophotometric method might encounter. PRACTITIONER POINTS: A new HPLC-based method for activity estimation of arylsulfatase and ß-glucuronidase was developed. The HPLC-based method can simultaneously estimate enzyme activity of both arylsulfatase and ß-glucuronidase. The HPLC-based method can avoid possible underestimation that spectrophotometric method may encounter.

Sulfite may disrupt estrogen homeostasis in human via inhibition of steroid arylsulfatase.

Steroid arylsulfatase is an important enzyme in human, which plays an important role in dynamic equilibrium of natural estrogens. On the other hand, sulfite can be endogenously produced as a consequence of human body's metabolism of sulfur-containing amino acids, while its main sources to human are mainly derived from food as it is a widely used additive. Sulfite-sensitivity is a well-known phenomenon to a small proportion of populations. However, its potential adverse effects on healthy individuals have been hardly reported. It was for the first time reported in this study that sulfite could effectively inhibit arylsulfatase, and its IC50 values for the snail- and human urine-derived arylsulfatase were determined to be 71.9 and 142.8 µM, which were lower than the concentration of sulfite in some healthy population. Consequently, it appears that sulfite might disrupt estrogen homeostasis in human, and this deserves further investigation.