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Isorhamnetin protects zearalenone-induced damage via the PI3K/Akt signaling pathway in porcine ovarian granulosa cells

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Animal Nutrition 2022年第4期11卷 381-390页

作者： Xiaoya Li Huali Chen Zelin Zhang Jiaxin Duan Rongmao Hua Xiaodi Li Li Yang Jianyong Cheng Qingwang Li College of Animal Science and Technology Northwest A&F UniversityYangling712100China School of Life Science and Engineering Southwest University of Science and TechnologyMianyang 621000China College of Basic Medicine Hebei University of Chinese MedicineShijiazhuang050000China

Zearalenone(ZEA)is widely derived from moldy cereal grain,which has adverse effects on animal reproduction.In particular,pigs are more sensitive to ZEA-induced toxicity than other animals.Isorhamnetin has extensive pharmacological activity.However,the role of isorhamnetin in ZEA-induced cytotoxicity remains unclear.This study was designed to investigate the therapeutic effect of isorhamnetin on ZEA-induced damage in porcine ovarian granulosa cells and elucidate its molecular mechanism.Two experiments were conducted,where a minimum of 3 biological replicates were used for each treatment.In Exp.1,ovarian granulosa cells were treated with different concentrations of isorhamnetin(1,5,10,20 and 30μmol/L)and ZEA(0,10,30,60,90 and 120μmol/L)for 24 h.Our results indicated that 60μmol/L ZEA(half-maximal inhibitory concentration value)and 20μmol/L isorhamnetin(the most effective concentration against ZEA-induced cytotoxicity)were optimum concentrations.In Exp.2,ovarian granulosa cells were treated with isorhamnetin(20μmol/L)for 2 h,before treatment with ZEA(60μmol/L)for 24 h.Apoptosis,endoplasmic reticulum stress,oxidative stress,proliferation and hormone secretion of ovarian granulosa cells were detected.Our findings showed that isorhamnetin suppressed(P<0.05)ZEA-induced apoptosis by altering mitochondrial membrane potential and apoptosis-related proteins(B-cell lymphoma-2[Bcl-2],Bcl2-associated x[Bax]and cleaved caspase-3[C-Casp3]).Changes in intracellular Ca2+levels and C/EBP homologous protein(CHOP),recombinant activating transcription factor 6(ATF6),glucose regulated protein78 k D(GRP78)indicated that isorhamnetin rescued(P<0.05)ZEA-induced endoplasmic reticulum stress.Furthermore,isorhamnetin prevented(P<0.05)ZEA-induced oxidative stress via the mitogen-activated protein kinase(P38)signaling pathway.Mechanistically,isorhamnetin stimulated(P<0.05)the expression of proliferating cell nuclear antigen(PCNA)and cyclin D,thereby increasing the ratio of S phase cells in response to ZEAinduced apoptosis via phosphatidylinosi

关键词： Zearalenone Isorhamnetin ovarian granulosa cell Apoptosis Endoplasmic reticulum stress Oxidative stress

Primary ovarian angiosarcoma:Two case reports and review of literature

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World Journal of Clinical Cases 2023年第21期11卷 5122-5128页

作者： Ying Zhou Yi-Wen Sun Xiao-Yang Liu Dan-Hua Shen Department of Pathology Peking University People’s HospitalBeijing 100044China

BACKGROUND Angiosarcoma(AS)is a rare and highly aggressive soft tissue disease that most commonly arises in deep soft tissues.There are only a few reported cases of AS involving the ovary and even fewer reports of the underlying molecular abnormalities.Here,we briefly review two cases of primary ovarian AS(oAS)with specific molecular events and immune checkpoints.The clinical features and prognosis of the disease,diagnosis,differential diagnosis,and new treatment approaches are discussed based on a literature review.CASE SUMMARY Case 1:A 51-year-old female patient was admitted with right lower limb pain for 5 mo,and lower abdominal pain with hematuria for 1 mo.Partial removal of rectus abdominis muscle and fascia,partial hysterectomy,bilateral salpingooophorectomy,and inguinal and pelvic lymphadenectomy were performed.Pathology revealed primary oAS.Fluorescence in situ hybridization revealed c-MYC gene amplification.MESNA+ADM+IFO+DTIC(MAID)regimen was administered,but stable disease was achieved.The patient died 1 mo later.Case 2:A 41-year-old female patient presented with fatigue,nausea,decreased appetite,and diffuse abdominal pain.On physical examination,the abdomen was distended and a complex cystic mass was palpable in the right pelvic cavity.Pathology revealed primary oAS.MAID chemotherapy was administered and programmed death ligand 1(PD-L1)staining was performed on the tumor samples.The patient benefited from anti-PD-1 immunotherapy and is alive without any evidence of disease 27 mo off therapy in follow-up.CONCLUSION Long-term survival benefit for primary oAS can be achieved by alternative therapeutic strategies using pathological indicators to inform treatment.

关键词： Primary angiosarcoma ovarian Therapy Diagnosis Prognosis Case report

Targeting slug-mediated non-canonical activation of c-Met to overcome chemo-resistance in metastatic ovarian cancer cells

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Acta Pharmaceutica Sinica B 2019年第3期9卷 484-495页

作者： Linlin Chang Yan Hu Yingying Fu Tianyi Zhou Jun You Jiamin Du Lin Zheng Ji Cao Meidan Ying Xiaoyang Dai Dan Su Qiaojun He Hong Zhu Bo Yang Zhejiang Province Key Laboratory of Anti-Cancer Drug Research College of Pharmaceutical SciencesZhejiang UniversityHangzhou310058China Zhejiang Cancer Hospital Hangzhou310022China

Metastasis-associated drug resistance accounts for high mortality in ovarian cancer and remains to be a major barrier for effective treatment. In this study, SKOV3/T4, a metastatic subpopulation of ovarian cancer SKOV3 cells, was enriched to explore potential interventions against metastaticassociated drug resistance. Quantitative genomic and functional analyses were performed and found that slug was significantly increased in the SKOV3/T4 subpopulation and contributed to the high resistance of SKOV3/T4. Further studies showed that slug activated c-Met in a ligand-independent manner due to elevated levels of fibronectin and provoked integrin α V function, which was confirmed by the significant correlation of slug and p-Met levels in 121 ovarian cancer patient samples. Intriguingly,c-Met inhibitor(s) exhibited greatly enhanced anti-cancer effects in slug-positive ovarian cancer models both in vitro and in vivo. Additionally, IHC analyses revealed that slug levels were highly correlated with reduced survival of ovarian cancer patients. Taken together, this study not only uncovers the critical roles of slug in drug resistance in ovarian cancer but also highlights a promising therapeutic strategy by targeting the noncanonical activation of c-Met in slug-positive ovarian cancer patients with poor prognosis.

关键词： Slug c-Met Drug resistance ovarian cancer XL184

Human epidermal growth factor receptor targeted inhibitors for the treatment of ovarian cancer

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Cancer Biology & Medicine 2018年第4期15卷 375-388页

作者： Maria Bonello ANDrew Harvey Sims Simon Peter Langdon Cancer Research UK Edinburgh Center and Division of Pathology Laboratory MRC Institute of Genetics and Molecular Medicine University of Edinburgh

ovarian cancer is the second most lethal gynecological cancer worldwide and while most patients respond to initial therapy, they often relapse with resistant disease. Human epidermal growth factor receptors(especially HER1/EGFR and HER2/ERBB2) are involved in disease progression; hence, strategies to inhibit their action could prove advantageous in ovarian cancer patients,especially in patients resistant to first line therapy. Monoclonal antibodies and tyrosine kinase inhibitors are two classes of drugs that act on these receptors. They have demonstrated valuable antitumor activity in multiple cancers and their possible use in ovarian cancer continues to be studied. In this review, we discuss the human epidermal growth factor receptor family; review emerging clinical studies on monoclonal antibodies and tyrosine kinase inhibitors targeting these receptors in ovarian cancer patients; and propose future research possibilities in this area.

关键词： Tyrosine kinase monoclonal antibodies ovarian cancer inhibitors HER receptors

Protective effects of human umbilical cord mesenchymal stem cell-derived conditioned medium on ovarian damage

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Journal of Molecular Cell Biology 2020年第5期12卷 372-385页

作者： Liming Hong Long Yan Zhimin Xin Jie Hao Wenjing Liu Shuyu Wang Shujie Liao Hongmei Wang Xiaokui Yang Department of Human Reproductive Medicine Beijing Obstetrics and Gynecology HospitalCapital Medical UniversityBeijing 100026China State Key Laboratory of Stem Cell and Reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China Department of Gynaecology and Obstetrics Reproductive Medical CenterTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China

Chemotherapeutic agents are extensively used to treat malignancies.However,chemotherapy-induced ovarian damage and reduced fertility are severe side effects.Recently,stem cell transplantation has been reported to be an effective strategy for premature ovarian insufficiency(POI)treatment,but safety can still be an issue in stem cell-based therapy.Here,we show the protective effects of human umbilical cord mesenchymal stem cell-derived conditioned medium(hUCMSC-CM)on a cisplatin(Cs)-induced ovarian injury model.hUCMSC-CM can relieve Cs-induced depletion of follicles and preserve fertility.In addition,hUCMSC-CM can decrease apoptosis of oocytes and granulosa cells induced by Cs.RNA sequencing analysis reveals the differentially expressed genes of ovaries after Cs and hUCMSC-CM treatments,including genes involved in cell apoptosis.Furthermore,we show that the granulocyte colony-stimulating factor(G-CSF)/phosphatidylinositol 3-kinase(PI3K)/protein kinase B(Akt)pathway plays an important role in protecting granulosa cells from Cs-induced apoptosis.Together,we confirm the protective effects of hUCMSC-CM on ovarian reserve and fertility in mice treated with Cs,highlighting the remarkable therapeutic effects of hUCMSC-CM.

关键词： stem cell ovarian damage RNA sequencing

Ability of human umbilical cord mesenchymal stem cells to repair chemotherapy-induced premature ovarian failure

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World Journal of Stem Cells 2020年第4期12卷 277-287页

作者： Jian Shen Dai Cao Jing-Li Sun Department of Obstetrics and Gynecology General Hospital of Northern Theater Command(Heping Campus)Shenyang 110000Liaoning ProvinceChina

BACKGROUND Premature ovarian insufficiency(POI)and premature ovarian failure(POF)have become one of the major problems threatening women of childbearing age.Studies have shown that stem cells transplanted from bone marrow,umbilical cord,peripheral blood and amniotic fluid can migrate and proliferate to the ovary,promote ovarian function repair,increase the number of follicles and granulosa cells at all levels of ovary,improve endocrine function,and can differentiate into oocytes in specific ovarian environment to restore fertility to some extent.AIM To study the ability of human umbilical cord mesenchymal stem cells(hUCMSCs)to repair ovarian injury after chemotherapy.METHODS A total of 110 female BALB/c mice(aged 7-8 wk old)with body masses of 16.0-20.0 g were selected.The mice were fed until 12 wk of age,and cyclophosphamide was administered by intraperitoneal injection for 14 consecutive days to induce premature ovarian failure in mice.Seventy-five mice with estrous cycle disorder were screened and randomly divided into 3 groups according to their body weight:model group,positive control group and hUCMSC group,and each group had 25 mice.Another 25 mice were used as negative controls.The mice in the hUCMSC group were injected with hUCMSCs in the tail vein,and the mice in the positive control group were given an oestradiol valerate solution and a medroxyprogesterone acetate solution in the tail vein.On the 1^st,15^th,30^th,45^th,and 60^th days after intravenous administration,vaginal smears were made to monitor the estrous cycles of the mice.The ovaries were weighed,and pathological sections were made to observe the morphology of the follicles;blood samples were collected to monitor the concentration of sex hormones(oestradiol and follicle-stimulating hormone).RESULTS The estrous cycles of the model group mice were disrupted throughout the experiment.Mice in the hUCMSC group and the positive control group resumed normal estrous cycles.The ovarian weight of the model group mice continued to decline.The ovarian wei

关键词： Umbilical cord mesenchymal stem cells Premature ovarian failure Chemotherapy Repair ovarian injury Endocrine function

Presence and role of stem cells in ovarian cancer

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World Journal of Stem Cells 2019年第7期11卷 383-397页

作者： Natasa Kenda Suster Irma Virant-Klun Department of Gynecology Division of Obstetrics and GynecologyUniversity Medical Centre LjubljanaLjubljana 1000Slovenia Department of Human Reproduction Division of Obstetrics and GynecologyUniversity Medical Centre LjubljanaLjubljana 1000Slovenia

ovarian cancer is the deadliest gynecological malignancy.It is typically diagnosed at advanced stages of the disease,with metastatic sites disseminated widely within the abdominal cavity.ovarian cancer treatment is challenging due to high disease recurrence and further complicated pursuant to acquired chemoresistance.Cancer stem cell(CSC)theory proposes that both tumor development and progression are driven by undifferentiated stem cells capable of self-renewal and tumor-initiation.The most recent evidence revealed that CSCs in terms of ovarian cancer are not only responsible for primary tumor growth,metastasis and relapse of disease,but also for the development of chemoresistance.As the elimination of this cell population is critical for increasing treatment success,a deeper understanding of ovarian CSCs pathobiology,including epithelial-mesenchymal transition,signaling pathways and tumor microenvironment,is needed.Finally,before introducing new therapeutic agents for ovarian cancer,targeting CSCs,accurate identification of different ovarian stem cell subpopulations,including the very small embryoniclike stem cells suggested as progenitors,is necessary.To these ends,reliable markers of ovarian CSCs should be identified.In this review,we present the current knowledge and a critical discussion concerning ovarian CSCs and their clinical role.

关键词： ovarian cancer Cancer stem cells Very small embryonic-like stem cells Epithelial-mesenchymal transition

Flexible GnRH Antagonist Protocol versus Progestin-primed ovarian Stimulation (PPOS) Protocol in Patients with Polycystic Ovary Syndrome: Comparison of Clinical Outcomes and ovarian Response

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Current Medical Science 2019年第3期39卷 431-436页

作者： Zhuo-ni XIAO Jia-li PENG Jing YANG Wang-ming XU Center for Reproductive Medicine Renmin Hospital of Wuhan University Wuhan 430060China

Polycystic ovary syndrome (PCOS) is one of the most common causes of infertility in women. Progestin-primed ovarian stimulation (PPOS) protocol, which used oral progestin to prevent premature luteinizing hormone (LH) surges in ovarian stimulation, has been proved to be effective and safe in patients with PCOS. The aim of the present study was to compare the efficacy of PPOS protocol with that of the traditional gonadotropin-releasing hormone (GnRH) antagonist protocol in patients with PCOS. A total of 157 patients undergoing in-vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) were recruited into this study. The patients were divided into two groups by the stimulation protocols: the GnRH antagonist protocol group and the PPOS protocol group. There was no significant difference in the clinical characteristics between the two groups. Dose and duration of gonadotropin were higher in the PPOS protocol group. Estradiol levels on the day of human chorionic gonadotropin (hCG) administration were significantly lower in the PPOS protocol group. Fertilization rates and the number of good quality embryos were similar between the two groups. Remarkably, we found 6 patients with moderate ovarian hyperstimulation syndrome (OHSS) in the GnRH antagonist protocol group but 0 in the PPOS protocol group. A total of 127 women completed their frozen embryo transfer (FET) cycles. There were no significant differences between the two groups in terms of clinical pregnancy rate per transfer, implantation rate, first-trimester miscarriage rate and on-going pregnancy rate per transfer. To conclude, PPOS protocol decreased the incidence of OHSS without adversely affecting clinical outcomes in patients with PCOS.

关键词： polycystic ovary syndrome ovarian hyperstimulation syndrome progestin-primed ovarian stimulation GnRH antagonist protocol controlled ovarian hyperstimulation

Evaluation of COC183B2 antibody targeting ovarian cancer by near-infrared fluorescence imaging

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Chinese Journal of Cancer Research 2019年第4期31卷 673-685页

作者： Chen Zhang Xinyu Ling Yanxiu Guo Cunzhong Yuan Hongyan Cheng Xue Ye Ruiqiong Ma Yinli Zhang Yi Li Xiaohong Chang Beihua Kong Tao Liu Heng Cui Department of Obstetrics and Gynecology Peking University People’s HospitalBeijing 100044China Center of Gynecologic Oncology Peking University People’s HospitalBeijing 100044China State Key Laboratory of Natural and Biomimetic Drugs School of Pharmaceutical SciencesPeking UniversityBeijing 100191China Department of Obstetrics and Gynecology Qilu Hospital of Shandong UniversityJinan 250012China Department of Pathology Peking University People’s HospitalBeijing 100044China

Objective: To evaluate the imaging potential of a novel near-infrared(NIR) probe conjugated to COC183 B2 monoclonal antibodies(MAb) in ovarian cancer(OC).Methods: The expression of OC183 B2 antigen in OC was determined by immunohistochemical(IHC) staining using tissue microarrays with the H-score system and immunofluorescence(IF) staining of tumor cell lines.Imaging probes with the NIR fluorescent dye cyanine 7(Cy7) conjugated to COC183 B2 Mab were chemically engineered. OC183 B2-positive human OC cells(SKOV3-Luc) were injected subcutaneously into BALB/c nude mice. Bioluminescent imaging(BLI) was performed to detect tumor location and growth. COC183 B2-Cy7 at 1.1,3.3, 10, or 30 μg were used for in vivo fluorescence imaging, and phosphate-buffered saline(PBS), free Cy7 dye and mouse isotype immunoglobulin G(IgG)-Cy7(delivered at the same doses as COC183 B2-Cy7) were used as controls.Results: The expression of OC183 B2 with a high H-score was more prevalent in OC tissue than fallopian tube(FT) tissue. Among 417 OC patients, the expression of OC183 B2 was significantly correlated with the histological subtype, histological grade, residual tumor size, relapse state and survival status. IF staining demonstrated that COC183 B2 specifically expressed in SKOV3 cells but not HeLa cells. In vivo NIR fluorescence imaging indicated that COC183 B2-Cy7 was mainly distributed in the xenograft and liver with optimal tumor-to-background(T/B)ratios in the xenograft at 30 μg dose. The highest fluorescent signals in the tumor were observed at 96 h postinjection(hpi). Ex vivo fluorescence imaging revealed the fluorescent signals mainly from the tumor and liver. IHC analysis confirmed that xenografts were OC183 B2 positive.Conclusions: COC183 B2 is a good candidate for NIR fluorescence imaging and imaging-guided surgery in OC.

关键词： COC183B2 antibody near-infrared fluorescence imaging ovarian cancer