a-modified-technique-for-inducing-polycystic-ovary-syndrome-in-mice

A Modified Technique for Inducing Polycystic Ovary Syndrome in Mice

Polycystic ovary syndrome (PCOS) is one of the leading causes of infertility in women. Animal models are widely used to study the etiologic mechanisms of ...

Fudan University

Two major challenges encountered during radiotherapy for colorectal cancer (CRC) are radioresistance of tumor cells and damage to normal cells. An understanding of the mechanisms of radioresistance in CRC may lead to new strategies for overcoming obstacles to affective clinical therapy. In this study, the miR-29a expression was compared among four cell lines: the normal human intestinal epithelial crypt cell line, HIEC and three CRC cell lines, HT29, DLD-1 and HCT116. The roles of miR-29a in regulating cellular radiosensitivity were then investigated. The findings from this study showed that miR-29a mimic enhanced radioresistance in HIEC, HT29 and DLD-1 cells with low levels of intrinsic miR-29a. On the other hand, a miR-29a inhibitor significantly sensitized HCT116 cells with high levels of miR-29a after irradiation. Further studies indicated that PTEN was the direct functional target of miR-29a and was involved in radiosensitivity. MiR-29a could activate the PI3K/Akt signaling pathway through negatively regulated PTEN expression. In conclusion, miR-29a may regulate the radiosensitivity of intestinal cell lines by targeting the PTEN gene, which indicates miR-29a might serve as a novel approach to enhance radiosensitivity in CRC.

MiR-29a Regulates Radiosensitivity in Human Intestinal Cells by Targeting PTEN Gene.

China has repeatedly been the subject of genetic studies to elucidate its prehistoric and historic demography. While some studies reported a genetic distinction between Northern and Southern Han Chinese, others showed a more clinal picture of small differences within China. Here, we investigated the distribution of Y chromosome variation along administrative as well as ethnic divisions in the mainland territory of the People's Republic of China, including 28 administrative regions and 19 recognized Chinese nationalities, to assess the impact of recent demographic processes. To this end, we analyzed 37,994 Y chromosomal 17-marker haplotype profiles from the YRHD database with respect to forensic diversity measures and genetic distance between groups defined by administrative boundaries and ethnic origin. We observed high diversity throughout all Chinese provinces and ethnicities. Some ethnicities, including most prominently Kazakhs and Tibetans, showed significant genetic differentiation from the Han and other groups. However, differences between provinces were, except for those located on the Tibetan plateau, less pronounced. This discrepancy is explicable by the sizeable presence of Han speakers, who showed high genetic homogeneity all across China, in nearly all studied provinces. Furthermore, we observed a continuous genetic North-South gradient in the Han, confirming previous reports of a clinal distribution of Y chromosome variation and being in notable concordance with the previously observed spatial distribution of autosomal variation. Our findings shed light on the demographic changes in China accrued by a fast-growing and increasingly mobile population.

Revisiting the male genetic landscape of China: a multi-center study of almost 38,000 Y-STR haplotypes.

Tumor resistance towards radiation has been a big obstacle in the poor prognosis of lung cancer. It has been reported that hypoxia and autophagy partly contribute to this resistance. However, there is controversy over whether autophagy plays a positive role in cancer therapy or not. We aim to find out the specific mechanism of radiation resistance.

Autophagy enhanced the radioresistance of non-small cell lung cancer by regulating ROS level under hypoxia condition.

Radiation effects are dependent of linear energy transfer (LET), but it is still obscure whether the daughter cells (DCs) derived from irradiated population are radioresistance and much less the underlying mechanism. With the measurements of survival, proliferation and γH2AX foci, this study shows that the DCs from γ-ray irradiated cells (DCs-γ) became more radioresistant than its parent control without irradiation, but the radiosensitivity of DCs from α-particle irradiated cells (DCs-α) was not altered. After irradiation with equivalent doses of γ-rays and α-particles, the foci number of histone H3 lysine 9 dimethylation (H3K9me3) and the activity of histone deacetylase (HDAC) in DCs-γ was extensively higher than these in DCs-α and its parent control, indicating that a higher level of heterochromatin was formed in DCs-γ but not in DCs-α. Treatment of cells with SAHA (an inhibitor of HDAC) decreased the level of heterochromatin domains by inhibiting the expressions of H3K9m3 and HP-1a proteins and triggering the expression of acetylated core histone H3 (Ac-H3). When cells were treated with SAHA, the radioresistance phenotype of DCs-γ was eliminated so that the radiosensitivities of DCs-γ, DCs-α and their parent cells approached to same levels. Our current results reveal that γ-rays but not α-particles could induce chromatin remodeling and heterochromatinization which results in the occurrence of radioresistance of DCs, indicating that the combination treatment of irradiation and HDAC inhibitor could serve as a potential cancer therapy strategy, especially for the fraction radiotherapy of low-LET irradiation.

Chromatin remodeling modulates radiosensitivity of the daughter cells derived from cell population exposed to low- and high-LET irradiation.

Recently, a growing number of ADP ribosylation factor (ARF) family members has been suggested to be critical in tumorigenesis. However, the effects of most ARF members on lung adenocarcinoma pathogenesis are still not well disclosed yet. In this study,  was screened as an important prognostic factor of lung adenocarcinoma from The Cancer Genome Atlas (TCGA) database and validated by our  experiments. It was found that silencing of  gene inhibited cell proliferation and the abilities of cell migration and invasion, and it also attenuated radiation damage of lung adenocarcinoma cells but had no effect on the proliferation of normal lung cells. Notably,  siRNA blocked the extracellular signal-regulated kinase (ERK)/p38 signaling pathway and induced cell cycle arrest in G0 phase, ultimately leading to cell dormancy. Moreover,  siRNA enhanced the expression of  () that had opposite roles in cell proliferation and migration to . Collectively, our results suggest that  has an important role in the pathogenesis of lung adenocarcinoma through CIDEC/ERK/p38 signaling pathway, and thus it could be applied as a new candidate of prognosis indicator and/or therapeutic target of lung adenocarcinoma.

Silencing of  Gene Induces Lung Adenocarcinoma Cells to a Dormant State.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder worldwide. We aimed to examine the associations of two mitochondrial DNA (mtDNA) biomarkers in the peripheral blood, mtDNA copy number (CN), and mtDNA deletion rate (DR), with PCOS in a clinical setting.

Mitochondrial DNA 4977 bp Deletion in Peripheral Blood Is Associated With Polycystic Ovary Syndrome.

Retraction Note to: Revisiting the male genetic landscape of China: a multi-center study of almost 38,000 Y-STR haplotypes.

Anovulation is the most prominent cause of infertility in polycystic ovary syndrome (PCOS) patients. Although ovulation can be corrected pharmacologically, the number of pregnancies remains low. Even if excellent embryos are transferred by IVF, it does not change the high miscarriage rate of PCOS patients. These facts collectively indicate that there is a disorder of endometrial development and receptivity to the embryo in PCOS patients, including the decrease of receptive ability, inhibition of embryo adhesion, undersupply of energy, poor blood perfusion, and pro-inflammatory status in the endometrium. However, it has never received the same attention as ovulatory dysfunction. Here we list some alternations of endometrial receptivity in women with PCOS, discuss the underlying intricate mechanisms, and try to find out the possible therapeutic targets, which may bring new perspectives to those who are able to provide high-quality embryos.

Altered Molecular Pathways and Biomarkers of Endometrial Receptivity in Infertile Women with Polycystic Ovary Syndrome.

To exhibit the lipid profiles in PCOS women with different characteristics and to access correlations between alternation of key lipid parameters and characteristics of PCOS.

The Lipid Profiles in Different Characteristics of Women with PCOS and the Interaction Between Dyslipidemia and Metabolic Disorder States: A Retrospective Study in Chinese Population.

Gliomatosis peritonei (GP) refers to the implantation of glial tissue on the visceral and parietal peritoneal surface, often associated with immature teratoma. It is a rare condition and the pathogenesis is not fully understood. In addition, the indistinguishable radiological appearance of immature and mature teratomas, and limited pathology samples make an accurate diagnosis difficult in most cases. More importantly, patients are also at risk of recurrence after surgery. This report aims to describe the process of diagnosis and treatment of GP with immature teratoma.

Human chorionic gonadotropin elevation in gliomatosis peritonei complicated with immature teratoma: A case report and review of the literature.

The increased hypothalamic neurokinin B (NKB) level may contribute to the hyperactive LH pulse secretion in Polycystic ovary syndrome (PCOS). However, the expression and role of the neurokinin B-neurokinin 3 receptor (NKB-NK3R) system in the local ovarian tissue of PCOS have not been clarified. We constructed in vivo and in vitro models to elucidate the mechanism of the NKB-NK3R pathway in reproductive endocrine disorders of PCOS.

The overexpression of neurokinin B-neurokinin 3 receptor system exerts direct effects on the ovary under PCOS-like conditions to interfere with mitochondrial function.

Shc SH2 domain-binding protein (SHCBP1) is involved in regulating tumour progression in a variety of tumour types. The aim of this study was to analyze the prognostic landscape of SHCBP1 in pan-cancer and investigate the relationship between SHCBP1 expression and tumour immune microenvironment.

SHCBP1 Is a Prognostic Biomarker Related to the Tumour Immune Microenvironment in Pan-Cancer.

Hyperandrogenism is an endocrine disorder affecting a large population of reproductive-aged women, thus proportionally high number of fetuses are subjected to prenatal androgenic exposure (PNA). The short-term stimulations at critical ontogenetic stages can wield lasting influences on the health. The most commonly diagnosed conditions in reproductive age women is polycystic ovary syndrome (PCOS). PNA may affect the growth and development of many systems in the whole body and disrupts the normal metabolic trajectory in the offspring of PCOS, contributing to the prevalence of cardiovascular and metabolic diseases (CVMD), including myocardial hypertrophy, hypertension, hyperinsulinemia, insulin resistance, hyperglycemia, obesity, and dyslipidemia, which are the leading causes of hospitalizations in young PCOS offspring. In this review, we focus on the effects of prenatal androgenic exposure on the cardiovascular and metabolic diseases in offspring, discuss the possible pathogenesis respectively, and summarize potential management strategies to improve metabolic health of PCOS offspring. It is expected that the incidence of CVMD and the medical burden will be reduced in the future.

The Influences of Perinatal Androgenic Exposure on Cardiovascular and Metabolic Disease of Offspring of PCOS.

Diabetic patients receiving the antidiabetic drug metformin have been observed to exhibit a lower prevalence of anxiety disorders, yet the precise mechanism behind this phenomenon is unclear. In our study, we found that anxiety induces a region-specific reduction in AMPK activity in the medial prefrontal cortex (mPFC). Concurrently, transgenic mice with brain-specific AMPK knockout displayed abnormal anxiety-like behaviors. Treatment with metformin or the overexpression of AMPK restored normal AMPK activity in the mPFC and mitigated social stress-induced anxiety-like behaviors. Furthermore, the specific genetic deletion of AMPK in the mPFC not only instigated anxiety in mice but also nullified the anxiolytic effects of metformin. Brain slice recordings revealed that GABAergic excitation and the resulting inhibitory inputs to mPFC pyramidal neurons were selectively diminished in stressed mice. This reduction led to an excitation-inhibition imbalance, which was effectively reversed by metformin treatment or AMPK overexpression. Moreover, the genetic deletion of AMPK in the mPFC resulted in a similar defect in GABAergic inhibitory transmission and a consequent hypo-inhibition of mPFC pyramidal neurons. We also generated a mouse model with AMPK knockout specific to GABAergic neurons. The anxiety-like behaviors in this transgenic mouse demonstrated the unique role of AMPK in the GABAergic system in relation to anxiety. Therefore, our findings suggest that the activation of AMPK in mPFC inhibitory neurons underlies the anxiolytic effects of metformin, highlighting the potential of this primary antidiabetic drug as a therapeutic option for treating anxiety disorders.

Anxiolytic effect of antidiabetic metformin is mediated by AMPK activation in mPFC inhibitory neurons.

Reducing cardiovascular disease burden among women remains challenging. Epidemiologic studies have indicated that polycystic ovary syndrome (PCOS), the most common endocrine disease in women of reproductive age, is associated with an increased prevalence and extent of coronary artery disease. However, the mechanism through which PCOS affects cardiac health in women remains unclear.

Polycystic Ovary Syndrome Fuels Cardiovascular Inflammation and Aggravates Ischemic Cardiac Injury.

Enteroendocrine cells (EECs) and vagal afferent neurons constitute functional sensory units of the gut, which have been implicated in bottom-up modulation of brain functions. Sodium oligomannate (GV-971) has been shown to improve cognitive functions in murine models of Alzheimer's disease (AD) and recently approved for the treatment of AD patients in China. In this study, we explored whether activation of the EECs-vagal afferent pathways was involved in the therapeutic effects of GV-971. We found that an enteroendocrine cell line RIN-14B displayed spontaneous calcium oscillations due to TRPA1-mediated calcium entry; perfusion of GV-971 (50, 100 mg/L) concentration-dependently enhanced the calcium oscillations in EECs. In ex vivo murine jejunum preparation, intraluminal infusion of GV-971 (500 mg/L) significantly increased the spontaneous and distension-induced discharge rate of the vagal afferent nerves. In wild-type mice, administration of GV-971 (100 mg· kg ·d, i.g. for 7 days) significantly elevated serum serotonin and CCK levels and increased jejunal afferent nerve activity. In 7-month-old APP/PS1 mice, administration of GV-971 for 12 weeks significantly increased jejunal afferent nerve activity and improved the cognitive deficits in behavioral tests. Sweet taste receptor inhibitor Lactisole (0.5 mM) and the TRPA1 channel blocker HC-030031 (10 µM) negated the effects of GV-971 on calcium oscillations in RIN-14B cells as well as on jejunal afferent nerve activity. In APP/PS1 mice, co-administration of Lactisole (30 mg ·kg ·d, i.g. for 12 weeks) attenuated the effects of GV-971 on serum serotonin and CCK levels, vagal afferent firing, and cognitive behaviors. We conclude that GV-971 activates sweet taste receptors and TRPA1, either directly or indirectly, to enhance calcium entry in enteroendocrine cells, resulting in increased CCK and 5-HT release and consequent increase of vagal afferent activity. GV-971 might activate the EECs-vagal afferent pathways to modulate cognitive functions.

Article	Year
MiR-29a Regulates Radiosensitivity in Human Intestinal Cells by Targeting PTEN Gene. Radiation research\| PubMed ID: 27548517	2016
Revisiting the male genetic landscape of China: a multi-center study of almost 38,000 Y-STR haplotypes. Human genetics\| PubMed ID: 28138773	2017
Autophagy enhanced the radioresistance of non-small cell lung cancer by regulating ROS level under hypoxia condition. International journal of radiation biology\| PubMed ID: 28463025	2017
Chromatin remodeling modulates radiosensitivity of the daughter cells derived from cell population exposed to low- and high-LET irradiation. Oncotarget\| PubMed ID: 28881774	2017
Silencing of Gene Induces Lung Adenocarcinoma Cells to a Dormant State. Frontiers in cell and developmental biology\| PubMed ID: 31750299	2019
Mitochondrial DNA 4977 bp Deletion in Peripheral Blood Is Associated With Polycystic Ovary Syndrome. Frontiers in endocrinology\| PubMed ID: 34305813	2021
Retraction Note to: Revisiting the male genetic landscape of China: a multi-center study of almost 38,000 Y-STR haplotypes. Human genetics\| PubMed ID: 34894272	2022
Altered Molecular Pathways and Biomarkers of Endometrial Receptivity in Infertile Women with Polycystic Ovary Syndrome. Reproductive sciences (Thousand Oaks, Calif.)\| PubMed ID: 35006579	2022
The Lipid Profiles in Different Characteristics of Women with PCOS and the Interaction Between Dyslipidemia and Metabolic Disorder States: A Retrospective Study in Chinese Population. Frontiers in endocrinology\| PubMed ID: 35860700	2022
Human chorionic gonadotropin elevation in gliomatosis peritonei complicated with immature teratoma: A case report and review of the literature. Medicine\| PubMed ID: 36316907	2022
The overexpression of neurokinin B-neurokinin 3 receptor system exerts direct effects on the ovary under PCOS-like conditions to interfere with mitochondrial function. American journal of reproductive immunology (New York, N.Y. : 1989)\| PubMed ID: 36453600	2023
SHCBP1 Is a Prognostic Biomarker Related to the Tumour Immune Microenvironment in Pan-Cancer. Annals of clinical and laboratory science\| PubMed ID: 36564070	2022
The Influences of Perinatal Androgenic Exposure on Cardiovascular and Metabolic Disease of Offspring of PCOS. Reproductive sciences (Thousand Oaks, Calif.)\| PubMed ID: 37380913	2023
Anxiolytic effect of antidiabetic metformin is mediated by AMPK activation in mPFC inhibitory neurons. Molecular psychiatry\| PubMed ID: 37798418	2023
Polycystic Ovary Syndrome Fuels Cardiovascular Inflammation and Aggravates Ischemic Cardiac Injury. Circulation\| PubMed ID: 37937441	2023
Sodium oligomannate activates the enteroendocrine-vagal afferent pathways in APP/PS1 mice. Acta pharmacologica Sinica\| PubMed ID: 38702501	2024

Fei Guo

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