Mogroside-rich extract from Siraitia grosvenorii fruits protects against the depletion of ovarian reserves in aging mice by ameliorating inflammatory stress.

Mogroside-rich extract (MGE), the main bioactive component of dried Siraitia grosvenorii fruit, has long been used as a natural sweetener and traditional Chinese medicine. This extract possesses various types of pharmacological activities, such as anti-inflammatory, antioxidative, hypoglycemic and hypolipemic activities. Moreover, we recently revealed that MGE has beneficial effects on female reproduction. Increasing maternal age leads to a rapid reduction in female fertility; in particular, it dramatically decreases ovarian function. Nevertheless, whether MGE can alleviate ovarian aging and the underlying mechanisms have not yet been explored. In this study, mice were treated with MGE by supplementation in drinking water from 10 to 44 weeks of age. Then, ovarian function and molecular changes were determined. Our findings showed that MGE treatment protected aged mice from estrous cycle disorder. Moreover, MGE treatment significantly increased the ovarian reserves of aged mice. RNA-seq data showed that MGE upregulated the expression of genes related to gonad development, follicular development, and hormone secretion in ovarian tissue. Additionally, inflammatory stress was induced, as indicated by upregulation of inflammation-related gene expression and elevated TNF-α levels in the ovarian tissues of aged mice; however, MGE treatment attenuated inflammatory stress. In summary, our findings demonstrate that MGE can ameliorate age-related estrous cycle disorder and ovarian reserve decline in mice, possibly by alleviating ovarian inflammatory stress.

Anthropogenic impacts on nutrient variability in the lower Yellow River.

Excessive nutrient discharges and changes in nutrient ratios caused by global change and anthropogenic activities have been reported in global rivers; however, the actual alterations occurring in the Yellow River environment is too fast to catch up with. From 2001 to 2018, dissolved inorganic nitrogen (DIN), dissolved inorganic phosphorus (DIP) and dissolved silicon (DSi) concentrations showed decreasing trends in the lower Yellow River throughout the study period. Dissolved organic phosphorus (DOP) concentrations increased since 2009, reaching up to 95% of the total dissolved phosphorus. Annual minimum dissolved organic nitrogen concentrations increased with time. We observed extremely low nutrient concentration events since 2014 in response to the retention effect of large reservoirs; this significantly reduced the downstream water discharge and sediment load and increased phytoplankton uptake. To further analyze the variability of nutrient fluxes, we quantified the fluxes to the Yellow River from natural (runoff, precipitation deposition, and sediment load from the Loess Plateau), anthropogenic (recharged water, fertilizer application, and vegetation coverage), social and industrial (population urbanization, GDP, and sewage effluents) sources. The highest contributions of total nutrient fluxes emptied into the Yellow River was fertilizer losing (44-48%) for DIN, sewage effluents (85-88%) for DIP, and runoff (35-65%) for DSi, respectively. Strictly controlling the amount of fertilizer and improving the application methods, improving sewage treatment technology, and vigorously promoting "green travel" might reduce nutrients emptied into the Yellow River based on the main sources of nutrients. Our study may help policy makers formulate strategies and it is possible to own a better water quality in the Yellow River.

A phase I clinical pharmacologic study of pralatrexate in combination with probenecid in adults with advanced solid tumors.

PURPOSE: The antifolate pralatrexate (10-propargyl-10-deazaaminopterin, PDX) demonstrates greater in vitro and in vivo antitumor efficacy than methotrexate. Preclinical models indicated that the efficacy of pralatrexate may be enhanced by coadministration with probenecid. The aim of this phase I study was to determine the maximum-tolerated dose of pralatrexate when combined with probenecid given every 2 weeks in humans. METHODS: The starting dose was pralatrexate 40 mg/m(2) intravenously and probenecid 70 mg/m(2) intravenously administered every 14 days, where one cycle of treatment was every 28 days. The pralatrexate dose was initially fixed while probenecid dose escalation was explored. The pralatrexate area under the curve (AUC), terminal-half life (t1/2), and maximum plasma concentration (Cmax) were determined in cycle 1. RESULTS: Seventeen patients with advanced solid tumors were treated with a median of two prior chemotherapy regimens. Stomatitis was dose-limiting with pralatrexate 40 mg/m(2) and probenecid 233 mg/m(2). Mean pralatrexate AUC and half life (t1/2) increased with increasing doses of probenecid. No objective responses were seen. CONCLUSION: For patients with advanced solid tumors, the maximum-tolerated dose of this drug combination was pralatrexate 40 mg/m(2) and probenecid 140 mg/m(2). Vitamin B(12) and folate supplementation may allow for further dose escalation of pralatrexate and probenecid. This is a suitable question for a future study.