FoxM1-mediated RFC5 expression promotes temozolomide resistance.

Although methylguanine-DNA-methyltransferase (MGMT) plays an important role in resistance to temozolomide (TMZ) in glioma, 40% of gliomas with MGMT inactivation are still resistant to TMZ. The underlying mechanism is not clear. Here, we report that forkhead box M1 (FoxM1) transcriptionally activates the expression of DNA repair gene replication factor C5 (RFC5) to promote TMZ resistance in glioma cells independent of MGMT activation. We showed that RFC5 expression is positively correlated with FoxM1 expression in human glioma cells and FoxM1 is able to transcriptionally activate RFC expression by interaction with the RFC5 promoter. Furthermore, knockdown of FoxM1 or RFC5 partially re-sensitizes glioma cells to TMZ. Consistently, thiostrepton, a FoxM1 inhibitor, in combination with TMZ significantly inhibits proliferation and promotes apoptosis in glioma cells. Taken together, these findings suggest that the FoxM1-RFC5 axis may mediate TMZ resistance and thiostrepton may serve as a potential therapeutic agent against TMZ resistance in glioma cells.

Egr-1 promotes hypoxia-induced autophagy to enhance chemo-resistance of hepatocellular carcinoma cells.

Previous studies suggest that early growth response gene-1 (Egr-1) plays an important role in hypoxia-induced drug-resistance. However, the mechanism still remains to be clarified. Herein, we investigated the role of Egr-1 in hypoxia-induced autophagy and its resulted hypoxia-driven chemo-resistance in Hepatocellular Carcinoma (HCC) cells. Our data demonstrated that Egr-1 was overexpressed in HCC tissues and cells and conferred them drug resistance under hypoxia. Mechanistically, Egr-1 transcriptionally regulated hypoxia-induced autophagy by binding to LC3 promoter in HCC cells, which resulted in resistance of HCC cells to chemotherapeutic agents; while dominant negative Egr-1 could inhibit autophagy level, and thus enhanced the sensitivity of HCC cells to chemotherapeutic agents, indicating that hypoxia-induced Egr-1 expression enhanced drug resistance of HCC cells likely through autophagy. Accordingly, it is suggested that a mechanism of hypoxia/Egr-1/autophagy axis might be involved in drug resistance in HCC.

Aging alters histone H3 lysine 4 methylation in mouse germinal vesicle stage oocytes.

Decreasing oocyte competence with maternal aging is a major factor in mammalian infertility. One of the factors contributing to this infertility is changes to chromatin modifications, such as histone acetylation in old MII stage oocytes. Recent studies indicate that changes in histone acetylation at MII arise at the germinal vesicle (GV) stage. We hypothesised that histone methylation could also change in old GV oocytes. To test this hypothesis, we examined mono-, di- and trimethylation of histone H3 lysine 4 (H3K4 me1, me2 and me3, respectively) in young and older oocytes from 6-8- and 42-44-week-old mice, respectively. We found that H3K4 me2 and me3 decreased in older compared with young GV oocytes (100% vs. 81% and 100% vs. 87%, respectively; P<0.05). H3K4 me2 later increased in older MII oocytes (21% vs. 56%; P<0.05). We also examined the expression of genes encoding the H3K4 demethylases lysine (K)-specific demethylase 1A (Kdm1a) and retinol binding protein 2 (Rbp2). Expression of Kdm1a increased at both the mRNA and protein levels in older GV oocytes, but decreased in older MII oocytes (P<0.05), and was negatively correlated with H3K4 me2 levels. Conversely, expression of Rbp2 mRNA and protein decreased in older GV oocytes (P<0.05), and this was not correlated with H3K4 me3 levels. Finally, we showed that inhibition of Kdm1a of older oocytes at the GV stage restored levels of H3K4 me2 at the MII stage to those seen in 'young' oocytes (41% vs. 38%; P>0.05). These results suggest that changes in expression of H3K4 me2 and Kdm1a in older GV oocytes may represent a molecular mechanism underlying human infertility caused by aging.

[Spatiotemporal Coupling Analysis of Urbanization and Ecosystem Services in Southeastern Fujian].

Revealing the spatiotemporal coupling relationship between urbanization and ecosystem services can help to clarify regional development differences, optimize the implementation path of urbanization, and improve the quality of ecosystem services. Taking southeastern Fujian, a region with a good ecological foundation and strong urbanization potential, as a case study, the levels of multidimensional urbanization systems and typical ecosystem services of this region in the years 2000, 2010, and 2020 were quantified using the index comprehensive evaluation method and the InVEST model. The Pearson correlation coefficient and the coupling coordination degree model were used to analyze the spatiotemporal coupling relationship between urbanization and ecosystem services, and suggestions for improving regional coordinated development were proposed. The results showed that： ① The comprehensive urbanization level in southeastern Fujian increased continuously, with an average annual growth rate of 7.3%, of which social urbanization was the fastest, followed by economic urbanization and population urbanization, and spatial urbanization was relatively backward. Ecosystem services tended to decline, especially food and water provision services, which decreased by 61.9% and 46.9%, respectively. The spatial distribution showed a mismatch pattern of "high urbanization level and weak ecosystem services" in the southeast coastal area and "low urbanization level and strong ecosystem services" in the northwest inland area. ② The correlation between urbanization and ecosystem services was mainly negative. The negative effect of economic and social urbanization on ecosystem services was weaker than that of population and spatial urbanization, with a clear weakening tendency. As population and spatial urbanization slowed down sharply and economic and social urbanization accelerated, the driving force of urbanization development gradually shifted from "quantitative increase" to "qualitative improvement." Thus, the decline of ecosystem services was alleviated. ③ Comprehensive urbanization and various ecosystem services experienced three stages of "imbalance-transition-reconciliation," with an average increase of 60.5% to 120.6% in the coupling coordination degree. However, highly coordinated regions remained scarce, indicating that there is still significant room for improvement. The relative relationship between urbanization and ecosystem services evolved from urbanization lag to ecosystem services lag. The fluctuation problem of backward coupling coordination level caused by excessive urbanization had initially appeared in the southeastern coastal area. Therefore, in future construction, southeastern Fujian should improve economic quality and social benefits； strengthen the overall management, protection, and restoration of ecological space； and enhance the order and stability of the coordinated development of urbanization and ecosystem services.

FOS protein expression and role of the vagus nerve in the rat medullary visceral zone in multiple organ dysfunction syndrome caused by subarachnoid hemorrhage.

This study was designed to observe the role of FOS protein expression in the rat medullary visceral zone (MVZ) in multiple organ dysfunction syndrome (MODS) caused by subarachnoid hemorrhage (SAH), with and without severing the vagus nerve. We also investigated the regulatory and control mechanisms of the MVZ and the vagus nerve in MODS following SAH. A model of MODS following SAH was established by injecting arterial blood into the Willis' circle. The vagus nerve was cut off and blocked. The FOS protein expression in the MVZ was detected by immunohistochemistry. The positive expression levels of FOS in the MVZ in the SAH and SAH + severed-down vagus nerve (SDV) groups were higher than those in the normal control, sham surgery and SDV groups (P<0.01). However, expression in the SAH+SDV group was lower than that in the SAH group (P<0.01). Inflammatory damage was observed in each visceral organ at every time-phased point in the SAH group and the SAH+SDV group. The most apparent damage was at 24-36 h, consistent with the peak of FOS protein expression; the SAH+SDV group presented a greater level of damage. The inflammatory changes in surrounding visceral organs following SAH correlated with FOS protein expression in the MVZ, which indicates that the MVZ participates in the functional control of surrounding visceral organs following SAH. Severing the subphrenic vagus nerve increases the incidence of MODS following SAH and enhances SAH-induced inflammatory damage to the surrounding visceral organs, which indicates that the vagus nerve plays a role in the protection of the surrounding visceral organs in MODS following SAH.