Zhixiang Xu

Research progress on the reproductive and non-reproductive endocrine tumors by estrogen-related receptors.

Oncologists have traditionally considered that tumorigenesis are closely related to classical nuclear estrogen receptors (ERs), such as estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ), through the ligands binding and target gene transcription induction. Estrogen-related receptors (ERRs) have similar structures with ERs, which are also gradually thought to be relevant to reproductive endocrine tumor diseases, even non-reproductive endocrine tumors. In this review, different subtypes of ERRs and their structures firstly will be introduced, then the expression patterns in gynecological oncology (i.e., breast cancer, endometrial cancer, and ovarian cancer), male genitourinary system malignancy especially prostatic cancer along with other non-reproductive endocrine tumors (i.e., lung cancer, colorectal cancer, and liver cancer) will be described, and simultaneously the role of tumorigenesis related to ERRs will be discussed. Therefore, the review is benefit to explore the way of tumor prevention and treatment.

Nonmonotonic responses to low doses of xenoestrogens: A review

&NA; Xenoestrogens (XEs) mimic or block the synthesis, metabolism and transport of normal endogenous hormones, disturbing normal endocrine function. The available data on the nonmonotonic estrogenic effects of low doses of many XEs are reviewed, covering in vitro, in vivo and epidemiological studies. The observed nonmonotonic patterns of the dose‐response curves are discussed, along with possible underlying mechanisms. This review is intended to provide guidance for harm predication and to suggest prevention measures. HighlightsXenoestrogens are globally ubiquitous, and can directly or indirectly harm people and animals in different ways.The adverse effects of xenoestrogens show oscillating temporal patterns.The adverse effects of low‐dose xenoestrogens exposure may be underestimated.Different xenoestrogens, doses and exposure times may yield different or even opposite responses.The low‐dose and nonmonotonic responses to xenoestrogens are complex and time‐consuming to explore, even for a specific, single substance.

The microbial transformation of 17β‑estradiol in an anaerobic aqueous environment is mediated by changes in the biological properties of natural dissolved organic matter

Dissolved organic matter (DOM) is shown to act as an electron shuttle mediator which enhances the microbial degradation of steroid estrogens in natural water. Batch studies were conducted with 17β‑estradiol (E2), quinone-reducing bacteria, DOM, and Fe(III) as a terminal electron acceptor. The results show that anthraquinone‑2‑disulfonate (AQS) approximately doubles the microbial degradation of E2 by DOM alone. The effect decreases sharply at AQS concentrations above 1.0mmol·L-1. Over three oxidation-reduction cycles, the electron-shuttling ability of AQS and the E2 biodegradation rate decreased step by step. Changes in the biological properties of the dissolved organic matter increased its aromaticity, its quinone content, and its fulvic-like fluorescence while significantly improving the electron transfer between DOM and the microbes, which made the degradation more effective. This explains why steroid estrogens do not accumulate in natural aqueous environments. Moreover, the estrogenic activity of steroid estrogens is inhibited at low concentrations through the activity of DOM.

Electrochemically modified dissolved organic matter accelerates the combining photodegradation and biodegradation of 17α-ethinylestradiol in natural aquatic environment

The photochemical conversion and microbial transformation of pollutants mediated by dissolved organic matter (DOM), including 17α-ethinylestradiol (EE2), are often accompanied in natural water. However, there are few studies to explore the connection and mechanism between the two processes. This research aims to investigate the mechanism of DOM after electrochemically modification mediated EE2 combining photodegradation and biodegradation in the environment and it want to explain the natural phenomena of DOM after electrochemical advanced treatment entering the water environment mediated EE2 natural degradation. The results showed that combining photodegradation with biodegradation rates of EE2 mediated by DOM and electrochemically modified DOM (E-DOM) were promoted obviously. The efficiency of EE2 biodegradation was shown to be strongly correlated with electron accepting capacity (EAC) of DOM. Electrochemical modification can increase the EAC of DOM leading to EE2 biodegradation accelerated, and it also can form more triplet-state DOM moieties to promote the EE2 photodegradation in irradiation conditions, due to the increasing of quinone-type structures in DOM. Moreover, cell polymeric secretion (CPS) secreted from the microorganism could be stimulated to an excited state by irradiation, and that also accelerated EE2 degradation. Photolysis combined with biochemical degradation yielded less toxic degradation products. This study shows that the emission of DOM in wastewater after electrochemical treatment could accelerate estrogen degradation and play a positive role on the pollutant transformation in the environment.

The Functional Mechanisms and Application of Electron Shuttles in Extracellular Electron Transfer

Electron shuttles extensively exist in various environments. Some kinds of organic substances can be applied by microorganisms to produce electrons, and then the electrons can be transferred to other substances or microorganisms through electron shuttles, resulting in coexistence and interaction of diverse species of microbes. In this review, the functional mechanisms of extracellular electron transfer mediated by different electron shuttles are described. And different subtypes as well as the application of electron shuttles in microbial degradation of pollutants, microbial electricity, and the promotion of energy generation are also discussed. Summary results show that extracellular electron transfer is based on the electrogenesis microorganism with the structure of cytochromes or pili. Materials were usually used in long-distance electron transfer because of their widespread presence and abundance. Therefore, the review is beneficial to perceive the pathways of extracellular electron transfer mediated by electron shuttles and explore the contribution of different electron shuttles in extracellular electron transfer.

Combinatorial anti-proliferative effects of tamoxifen and naringenin: The role of four estrogen receptor subtypes

Breast cancer is the most diagnosed diseases and the second-leading cause of death in females, among which the estrogen receptor positive (ER+) patients are more common of all cases. In present study, we selected MCF-7 as an in vitro model and investigated the combinatorial anti-proliferative effects of tamoxifen and naringenin on ER+ breast cancer, and then explored the potential mechanisms involved in mitochondrial dysfunction and oxidative stress mediated by several estrogen receptor subtypes. Six assessment endpoints including cell viability, cell migration, cell cycle, cell apoptosis, mRNA, and protein expression were estimated. Tamoxifen and naringenin were shown to inhibit the cell growth of MCF-7 cells at higher concentrations, and co-exposure with them significantly inhibited cell proliferation in an additive manner. Results from a wound healing assay indicated that the combined treatment of tamoxifen and naringenin markedly suppressed cell migration compared with the single exposure by downregulating the expression of MMP-9 and MMP-2. Flow cytometry analysis revealed that the combined treatment of tamoxifen and naringenin blocked cell cycle in G2/M phase through suppressing the transcription of cell cycle regulation proteins. Simultaneously, co-treatment with them also induced cell apoptosis by regulating the expression of mitochondrial apoptotic proteins as well as by simulating the production of reactive oxygen species (ROS). Real-time quantitative polymerase chain reaction (RT-qPCR) and western blotting (WB) analysis results further demonstrated that the two nuclear estrogen receptors-ERα66 and ERβ, as well as the two membrane estrogen receptors-ERα36 and GPR30 were downregulated when cells were exposed to single tamoxifen, whereas naringenin treatment group not only downregulated the expression of ERα66 and GPR30 but also upregulated ERβ and ERα36. Interestingly, co-treatment group resulted in significant downregulation of ERα66, ERα36 and GPR30 but upregulation of ERβ. Taken together, co-treatment of tamoxifen and naringenin could inhibit cell proliferation more effectively in ER+ breast cancer cells, which was associated with a modulation of the expression levels of several estrogen receptors.

17β-Estradiol inhibits testosterone-induced cell proliferation in HepG2 by modulating the relative ratios of 3 estrogen receptor isoforms to the androgen receptor: XU et al.

Sex hormones, especially 17β‐estradiol (E2) and testosterone (TEST), play crucial roles in the oncogenesis and progression of liver cancer via hormone‐related receptors. As women have a lower rate of hepatocellular carcinoma (HCC) than men, estrogens might attenuate the occurrence and development of HCC. This study aimed to investigate the inhibitory effects and mechanisms of E2 on TEST‐induced HCC development; the HepG2 cell line was used as an in vitro model. Five endpoints, including cell viability, cell apoptosis, cell cycle, receptor protein expression, and messenger RNA transcription, were investigated. Different roles and the ratios of androgen receptor (AR) and 3 estrogen receptor (ER) subtypes were also estimated. Cell viability assay showed that co‐treatment of E2 and TEST resulted in a significant inhibition of E2‐induced or TEST‐induced cell proliferation. Flow cytometry analysis revealed that combined treatment of E2 and TEST blocked the cell cycle in the G0/G1 phase as well as induced cell early apoptosis, characterized by decreased cyclin‐dependent kinase transcription and the ratio of Bcl‐2/Bax. Real‐time quantitative polymerase chain reaction and Western blot analysis results further demonstrated that estrogen receptor estrogen receptor α66 (ERα66) and estrogen receptor β (ERβ) were upregulated, whereas AR and estrogen receptor α36 (ERα36) were downregulated, irrespective of whether E2 and TEST were considered separately or together, whereas the combined treatment of E2 and TEST resulted in a decrease in the ERα66/ERβ ratio, the ERα66/ERα36 ratio, and the ERβ/ERα36 ratio, but with an increase in the ERα66/AR ratio, the ERα36/AR ratio, and the ERβ/AR ratio. To sum up, E2 could inhibit TEST‐induced cell proliferation by modulating the ratio of different hormone‐related receptors.