Brusatol sensitizes endometrial hyperplasia and cancer to progestin by suppressing NRF2-TET1-AKR1C1-mediated progestin metabolism.

Progestin resistance is the main obstacle for the conservative therapy to maintain fertility in women with endometrial cancer. Brusatol was identified as an inhibitor of the NRF2 pathway; however, its impact on progestin resistance and the underlying mechanism remains unclear. Here, we found that brusatol sensitized endometrial cancer to progestin by suppressing NRF2-TET1-AKR1C1-mediated progestin metabolism. Brusatol transcriptionally suppressed AKR1C1 via modifying the hydroxymethylation status in its promoter region through TET1 inhibition. Suppression of AKR1C1 by brusatol resulted in decreased progesterone catabolism and maintained potent progesterone to inhibit endometrial cancer growth. This inhibition pattern has also been found in the established xenograft mouse and organoid models. Aberrant overexpression of AKR1C1 was found in paired endometrial hyperplasia and cancer samples from the same individuals with progestin resistance, whereas attenuated or loss of AKR1C1 was observed in post-treatment samples with well progestin response as compared with paired pre-treatment tissues. Our findings suggest that AKR1C1 expression pattern may serve as an important biomarker of progestin resistance in endometrial cancer.

Spatiotemporal distribution and controlling factors on ammonium in waters in the central Yangtze River Basin, China.

High levels of ammonium in water can compromise the ecological environment and be harmful to human beings. It is of great significance to understand the source and controlling factors of ammonium in waters. However, the distribution and controlling factors on ammonium in the central Yangtze River Basin have been rarely reported. The results showed that 6.58% of the surface water (SW) exceeded the China national guideline of category III for NH4+-N (i.e., 1.0 mg/L) and 30.19% of the groundwater (GW) exceeded the China national guideline of category III for NH4+-N (i.e., 0.5 mg/L). Notably, the ammonium concentrations of the plain area in the middle were much higher, which reached to the highest value at the junction of the Yangtze River and Dongting Lake. Nitrogen in SW may originate from manure but more nitrogen sources in GW. The net anthropogenic nitrogen input (NANI) can provide enough organic nitrogen for the mineralization. NH4+-N in SW was more affected by fertilizer nitrogen and feed nitrogen input but more affected by agricultural nitrogen fixation in GW. Agricultural and industrial activities controlled NH4+-N in SW and GW by increasing nitrogen input and changing hydrological conditions. In general, this research exposed the controlling of different types of factors on ammonium in waters, providing a guidance for the water pollution prevention in study area.

Spatial and temporal distribution and affecting factors of iron and manganese in the groundwater in the middle area of the Yangtze River Basin, China.

Iron (Fe) and manganese (Mn) are heavy metals ubiquitous in groundwater. High levels of Fe and Mn in groundwater can compromise water quality and pose a risk to human health if the groundwater is used for drinking or irrigation. In the middle region of the Yangtze River Basin, groundwater has been extensively used for domestic and agricultural purposes. However, little is known about the distribution of Fe and Mn in the groundwater in this area. It was found that the 74.4% and 48.9% of the groundwater exceed the China national guideline for Fe (i.e., 0.3 mg/L) and Mn (i.e., 0.1 mg/L), respectively. And 6.38% and 2.13% of the wells had Fe and Mn health risks, respectively. Spatial heterogeneity of Fe and Mn was observed. Notably, the concentrations of Fe and Mn in a plain region located between two major rivers (i.e., the Yangtze River and the Han River) were significantly higher than those in other regions. Modeling using PHREEQC revealed that the Fe-bearing minerals in the plain region were more saturated compared to those in the other regions. Besides, temporal change of Fe and Mn was observed in the plain region, significantly affected by rainfalls and groundwater levels. In addition, the distribution of Fe and Mn was significantly affected by various physicochemical factors. Particularly, Fe was more sensitive to redox potential compared to Mn. Under a reducing condition, organic matter concentration and water residence time also affect the release of Fe from Fe-bearing minerals. Overall, a comprehensive understanding of distribution characteristics of Fe and Mn and affecting factors in the middle area of the Yangtze River Basin can provide guidance for the distribution of industrial water, agricultural water, and drinking water in different regions of the study area. Especially in the plain area between the Yangtze River and the Han River, direct drinking of groundwater shall be reduced since the higher health risk value of Fe and Mn.

LASS2 mediates Nrf2-driven progestin resistance in endometrial cancer.

Progestin administration serves as the optimal conservative treatment method for women with endometrial cancer or precancer lesions who want to preserve fertility. However, there are still at least 30% of patients in which progestin resistance occurs. LASS2 (Ceramide Synthase 2) has been reported to be involved in chemotherapy resistance, whether it also plays a role in progestin resistance is not clear. Here, we explored the detailed mechanism by which Nrf2/LASS2 contributes to progestin resistance and disease progression. METHODS: IHC assays were performed to estimate the expression pattern of Nrf2 and LASS2. Moreover, it bears three antioxidant response elements (ARE) in the promoter region of LASS2 gene, therefore, Luciferase assays were performed to determine if Nrf2 regulates LASS2 by binding with these ARE sequence. Western Blot assays were used to determine the expression of Nrf2 and LASS2 protein among various endometrial cell lines. Relative mRNA expression levels were detected by RT-PCR. Cellular growth was monitored with CCK-8 tests. Apoptosis was determined with Annexin V-PI staining and flow cytometry analysis. siRNA knockdown was performed to investigate the effects of Nrf2 on cell proliferation. RESULT: Nrf2/LASS2 is highly expressed in endometrial cancer tissue, as compared to expression levels in normal endometrial tissue. Proliferation assays demonstrated that overexpression of Nrf2/LASS2 resulted in progestin resistance. Conversely, knockdown of LASS2 increased apoptosis and decreased cell viability. In addition, metformin overcame progestin resistance by down-regulating Nrf2/LASS2 expression. CONCLUSION: Our findings provide new insight into the mechanism of progestin resistance in type I endometrial cancer. Nrf2/LASS2 may not only be a possible marker for predicting the prognosis of endometrial cancer but also serve as a potential therapeutic target.

Roles of follicle stimulating hormone and its receptor in human metabolic diseases and cancer.

Follicle stimulating hormone (FSH) and its receptor (FSHR) play an important role in human metabolic diseases and cancer. Evidence showed that FSHR is not only distributed in ovary and testis but also in other cells or organs such as osteoclast, adipocytes, liver, pituitary cancer and so forth. Moreover, FSH is associated with lipogenesis, inflammation, insulin sensitivity, thermogenesis, skeletal metabolism, osteogenesis and ovarian cancer, all of which have been confirmed closely related to metabolic diseases or metabolic-related cancer. Therefore, FSH and FSHR may be potential therapeutic targets for metabolic diseases and metabolic-related cancer. Epidemiological researches revealed close relationship between FSH/FSHR and metabolic diseases or cancer. Experimental studies elucidated the underlying mechanism both in vivo and in vitro. We reviewed the recent researches and present an integrated framework of FSH/FSHR and metabolic diseases and cancer, which provides potential targets for the treatments of metabolic diseases and cancer.