Icariin alleviates cisplatin-induced premature ovarian failure by inhibiting ferroptosis through activation of the Nrf2/ARE pathway.

Cisplatin is a widely used chemotherapeutic drug that can induce ovarian damage. Icariin (ICA), a natural antioxidant derived from Epimedium brevicornum Maxim., has been found to protect against organ injury. The aim of the present study was to investigate whether ICA can exert an ovarian-protective effect on cisplatin induced premature ovarian failure (POF) and the underlying mechanism involved. The preventive effect of ICA was evaluated using body weight, the oestrous cycle, ovarian histological analysis, and follicle counting. ICA treatment increased body weight, ovarian weight, and the number of follicles and improved the oestrous cycle in POF mice. ICA reduced cisplatin-induced oxidative damage and upregulated the protein expression levels of Nrf2, GPX4 and HO-1. Moreover, ICA reduced the expression levels of Bax and γH2AX and inhibited ovarian apoptosis. In addition, ICA activated the Nrf2 pathway in vitro and reversed changes in the viability of cisplatin-induced KGN cells, reactive oxygen species (ROS) levels, lipid peroxidation, and apoptosis, and these effects were abrogated when Nrf2 was knocked down or inhibited. Molecular docking confirmed that ICA promotes the release of Nrf2 by competing with Nrf2 for binding to Keap1. The inhibitory effects of ICA on cisplatin-induced oxidative stress, ferroptosis, and apoptosis may be mediated by its modulatory effects on the Nrf2 pathway, providing a novel perspective on the potential mechanisms by which ICA prevents POF.

Indole-3-carbinol ameliorates ovarian damage in female old mice through Nrf2/HO-1 pathway activation.

Ovarian aging leads to infertility and birth defects. We aimed to clarify the role of Indole-3-carbinol (I3C) in resistance to oxidative stress, apoptosis, and fibrosis in ovarian aging. I3C was administered via intraperitoneal injection for 3 weeks in young or old mice. Immunohistochemistry; Masson, Sirius red, and TUNEL staining; follicle counting; estrous cycle analysis; and Western blotting were used for validating the protective effect of I3C against ovarian senescence. Human granulosa-like tumor cell line and primary granulosa cells were used for in vitro assay. The results indicated that I3C inhibited ovarian fibrosis and apoptosis while increasing the number of primordial follicles. Mechanistic studies have shown that I3C promoted the nuclear translocation of nuclear factor-erythroid 2-related factor (Nrf2) and upregulated the expression of heme oxygenase 1 (HO-1). Additionally, I3C increased cell viability and decreased lactate dehydrogenase, malondialdehyde, reactive oxygen species and JC-1 levels. Furthermore, the antioxidant effect of I3C was found to be dependent on the activation of Nrf2 and HO-1, as demonstrated by the disappearance of the effect upon inhibition of Nrf2 expression. In conclusion, I3C can alleviate the ovarian damage caused by aging and may be a protective agent to delay ovarian aging.

Practice guideline on ovarian tissue cryopreservation and transplantation in the prevention and treatment of iatrogenic premature ovarian insufficiency.

Premature ovarian insufficiency (POI) refers to the decline of ovarian function before the age of 40. POI causes a reduction in or loss of female fertility, accompanied by different degrees of menopausal symptoms, which increases the risk of chronic diseases related to early menopause and seriously affects patients' quality of life and health. It is conservatively estimated that at least one million prepubertal girls and women of reproductive age in China are at risk of iatrogenic POI caused by radiotherapy and chemotherapy every year. With the development of medical technology and the breakthrough of scientific and technological advances, preventing and treating iatrogenic POI have become possible. International and national guidelines consider cryopreserved ovarian tissue transplantation to be the most promising method of preserving the ovarian function and fertility of prepubertal girls and women of reproductive age who cannot delay radiotherapy and chemotherapy. In order to guide the clinical application of ovarian tissue cryopreservation and transplantation technology in China, the Guideline Working Group finally included 14 scientific questions and 18 recommendations through a questionnaire survey, field investigation, and consultation of a large number of Chinese and English literature databases in order to provide a reference for colleagues in clinical practice.

Pyruvate dehydrogenase kinase 1 regulates the function of human decidual natural killer cells.

PROBLEM: Pyruvate dehydrogenase kinase 1 (PDK1) is an important enzyme for immune cell development. However, PDK1's role in human decidual natural killer (dNK) cells remains largely unknown. METHODS OF STUDY: PDK1 expression in dNK cells from patients with recurrent spontaneous abortions (RSA) and age-matched healthy controls was analyzed by qRT-PCR, western bolt and flow cytometry. Moreover, dNK cells were treated with PDK1 inhibitor or the PDK1 siRNA followed by functional assays. RESULTS: The dNK cells from patients who underwent RSAs had higher mRNA expression and increased protein of PDK1, perforin (PRF1), Granzyme B (GZMB), IFN-γ (IFNG), and CD107a expression compared to dNK cells from age-matched healthy controls. Perforin, Granzyme B, IFN-γ and CD107a expression levels in dNK cells were down-regulated when dNK cells were treated with a PDK1 inhibitor. As measured by the 51 Cr release assay, the killing activity of dNK cells was found to be decreased. We also demonstrated that PDK1 blockade could up-regulate the migration and adhesion of dNK cells. Furthermore, PDK1 inhibition reduced the glycolysis of dNK cells. CONCLUSION: This study suggested that PDK1 plays an important role in regulating dNK cell functions and human RSA.

Pesticide residues in common fruits and vegetables in Henan Province, China.

In this study 3307 samples of 24 vegetables and fruits from 18 regions of Henan Province, China, were collected in 2021 with the aim of assessing the levels of pesticide residues and analysing the differences between different sources in Henan Province. Thirteen kinds of pesticides were analysed by gas chromatography-mass spectrometry (GC-MS) and detection rates were compared by the chi-square test. In all samples, except ginger, pimento, edible fungi and yam, pesticide residues were detected. The detection rates of difenoconazole, acetamiprid, carbendazim, procymidone, emamectin benzoate, lambda-cyhalothrin, cypermethrin and dimethomorph in supermarkets and traditional farmers' markets were different. The difenoconazole group and the dimethomorph group were both statistically different (P < 0.05). This study showed common vegetables and fruits to contain pesticide residues in Henan Province and provided a scientific basis for their evaluation. Different sources take different regulatory measures to control pesticide residues to ensure food safety.

The Efficacy and Safety of Continuous Intravenous Endostar Treatment Combined With Concurrent Chemoradiotherapy in Patients With Locally Advanced Cervical Squamous Cell Carcinoma: A Randomized Controlled Trial.

OBJECTIVE: To investigate the short-term efficacy and safety of Endostar combined with concurrent chemoradiotherapy in the treatment of locally advanced cervical squamous cell carcinoma (LACSC). METHODS: A total of 91 patients with LACSC admitted to the First Affiliated Hospital of Anhui Medical University from June 2019 to December 2020 were randomly assigned to either the experimental group (n = 48) or control group (n = 43). The control group received radiotherapy for cervical cancer and paclitaxel combined with platinum chemotherapy (CCRT), and the experimental group received Endostar continuous intravenous infusion of anti-angiogenic therapy plus CCRT. The short-term efficacy, common clinical indicators, tumor indicators, changes in serum vascular endothelial growth factor-A (VEGF-A), and the occurrence of adverse events (AEs) were explored after treatment. RESULTS: Compared with the control group, the complete response (CR) rate in the experimental group was significantly increased (83.33% vs 65.12%, P < 0.05). Both routine indicators and tumor indicators in the two groups were significantly decreased compared to before treatment. Compared with the control group, patients in the experimental group had higher incidences of neutropenia, hypertension, and infection, but lower incidence of nausea. After treatment, the serological expression of VEGF-A was significantly decreased in both groups. CONCLUSION: Endostar combined with CCRT in the treatment of LACSC can further improve the efficacy of CR rate and significantly reduce serum tumor indicators and VEGF-A levels, with mild and controllable AEs. Endostar combined with CCRT is expected to be a new treatment regimen for LACSC.

[Association between recurrent miscarriages and insulin resistance: a meta analysis].

OBJECTIVE: To evaluate the association between recurrent miscarriages and insulin resistance. METHODS: The case-control studies on the association between recurrent spontaneous abortion and insulin resistance from June 1996 to April 2012 were collected from Medline, Elsevier, Chinese Journal Full-text Database, Chinese Biological Medicine Database, data base of Wanfang, Springer link and EMBASE. RevMan 5.1 software was used for Meta analysis. RESULTS: According to the included criteria, 7 clinical trials were finally selected. Total 467 cases with recurrent pregnancy loss were enrolled in study group, while 413 women with no history of abnormal pregnancies were enrolled in control group. No significant difference was found in average age and body mass index between the two groups (P > 0.05). Meta analysis results showed that the level of fasting glucose was no statistical difference between study group and control group (WMD = 2.27, 95%CI: -1.11 to 5.65, P > 0.05); fasting insulin level was higher 2.05 mU/L in study group than that of in control group, the difference was statistically significant (WMD = 2.05, 95%CI: 1.03 to 3.08, P < 0.01). Case number of study group on Homa-insulin resistance > 4.5 was more than that of control group (OR = 3.36, 95%CI: 1.72 to 6.57, P < 0.01). Case number of study group on glucose/insulin ratio < 4.5 was more than that of the control group, statistical difference was found (OR = 3.37, 95%CI: 1.90 to 5.99, P < 0.01). CONCLUSION: Insulin resistance is associated with the susceptibility to recurrent miscarriages, and it may contribute to the occurrence of recurrent miscarriages.

[Study on the correlation of transforming growth factor beta1 and its receptors with spontaneous abortion after in vitro fertilization and embryo transfer].

OBJECTIVE: To understand the expressions of transforming growth factor beta1 (TGF-beta1) and its receptors (TbetaR) in villi and decidua during early pregnancy and their effects on early embryo development, and explore the mechanism of spontaneous abortion. METHODS: By immunohistochemical technique, expressions of TGF-beta1 and its receptors were determined in villi and decidua from 10 cases of spontaneous abortion women after in vitro fertilization and embryo transfer (IVF-ET group), 20 cases of spontaneous abortion women (spontaneous abortion group), and 20 cases of normal early pregnancy women (control group). RESULTS: TGF-beta1 and its receptors had high expressions in decidua cells, villus glands and interstitial cytoplasm in all three groups. The average light density of the expressions of TGF-beta1 in the villi and decidua of IVF-ET, spontaneous abortion and control groups were 0.167 and 0.199, 0.198 and 0.201, 0.277 and 0.274, respectively. The intensity of TbetaR-I in the villi and decidua of IVF-ET, spontaneous abortion and control groups were 0.144 and 0.150, 0.202 and 0.201, 0.238 and 0.281, respectively. And the expressions of TbetaR-II in the villi and decidua of IVF-ET, spontaneous abortion and control groups were 0.199 and 0.145, 0.153 and 0.156, 0.300 and 0.301, respectively. The differences between the control group and both abortion groups were all significant (P < 0.01). CONCLUSIONS: The expressions of TGF-beta1 and its receptors in the early pregnancy tissues of aborted women declined. It demonstrates that the abnormal expressions of TGF-beta1 and its receptors play an important role in spontaneous abortion, they are one of the causes of spontaneous abortion.