Therapeutic Role of Mesenchymal Stem Cell-Derived Extracellular Vesicles in Female Reproductive Diseases

Reproductive disorders, including intrauterine adhesion (IUA), premature ovarian insufficiency (POI), and polycystic ovary syndrome (PCOS), are great threats to female reproduction. Recently, mesenchymal stem cells derived–extracellular vesicles (MSC-EVs) have presented their potentials to cure these diseases, not only for the propensity ability they stemmed from the parent cells, but also for the higher biology stability and lower immunogenicity, compared to MSCs. EVs are lipid bilayer complexes, functional as mediators by transferring multiple molecules to recipient cells, such as proteins, microRNAs, lipids, and cytokines. EVs appeared to have a therapeutic effect on the female reproductive disorder, such as repairing injured endometrium, suppressing fibrosis of endometrium, regulating immunity and anti-inflammatory, and repressing apoptosis of granulosa cells (GCs) in ovaries. Although the underlying mechanisms of MSC-EVs have reached a consensus, several theories have been proposed, including promoting angiogenesis, regulating immunity, and reducing oxidate stress levels. In the current study, we summarized the current knowledge of functions of MSC-EVs on IUA, POI, and PCOS. Given the great potentials of MSC-EVs on reproductive health, the critical issues discussed will guide new insights in this rapidly expanding field.

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Elucidating the Role of Extracellular Vesicles in Pancreatic Cancer

Cancers ◽

10.3390/cancers13225669 ◽

2021 ◽

Vol 13 (22) ◽

pp. 5669

Author(s):

Akbar Lulu Marzan ◽

Sarah Elizabeth Stewart

Keyword(s):

Drug Delivery ◽

Pancreatic Cancer ◽

Survival Rate ◽

Extracellular Vesicles ◽

Cancer Progression ◽

Current Knowledge ◽

Treatment Options ◽

Metabolic Dysfunction ◽

Underlying Mechanisms

Pancreatic cancer is one of the deadliest cancers worldwide, with a 5-year survival rate of less than 10%. This dismal survival rate can be attributed to several factors including insufficient diagnostics, rapid metastasis and chemoresistance. To identify new treatment options for improved patient outcomes, it is crucial to investigate the underlying mechanisms that contribute to pancreatic cancer progression. Accumulating evidence suggests that extracellular vesicles, including exosomes and microvesicles, are critical players in pancreatic cancer progression and chemoresistance. In addition, extracellular vesicles also have the potential to serve as promising biomarkers, therapeutic targets and drug delivery tools for the treatment of pancreatic cancer. In this review, we aim to summarise the current knowledge on the role of extracellular vesicles in pancreatic cancer progression, metastasis, immunity, metabolic dysfunction and chemoresistance, and discuss their potential roles as biomarkers for early diagnosis and drug delivery vehicles for treatment of pancreatic cancer.

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Involvement of Novel Adipokines, Chemerin, Visfatin, Resistin and Apelin in Reproductive Functions in Normal and Pathological Conditions in Humans and Animal Models

International Journal of Molecular Sciences ◽

10.3390/ijms20184431 ◽

2019 ◽

Vol 20 (18) ◽

pp. 4431 ◽

Cited By ~ 17

Author(s):

Anthony Estienne ◽

Alice Bongrani ◽

Maxime Reverchon ◽

Christelle Ramé ◽

Pierre-Henri Ducluzeau ◽

...

Keyword(s):

Animal Models ◽

Polycystic Ovary ◽

Female Reproduction ◽

Reproductive Disorders ◽

Ovary Syndrome ◽

Reproductive Axis ◽

Uterine Growth ◽

Endocrine Factors ◽

Intra Uterine Growth Retardation

It is well known that adipokines are endocrine factors that are mainly secreted by white adipose tissue. Their central role in energy metabolism is currently accepted. More recently, their involvement in fertility regulation and the development of some reproductive disorders has been suggested. Data concerning the role of leptin and adiponectin, the two most studied adipokines, in the control of the reproductive axis are consistent. In recent years, interest has grown about some novel adipokines, chemerin, visfatin, resistin and apelin, which have been found to be strongly associated with obesity and insulin-resistance. Here, we will review their expression and role in male and female reproduction in humans and animal models. According to accumulating evidence, they could regulate the secretion of GnRH (Gonadotropin-Releasing Hormone), gonadotropins and steroids. Furthermore, their expression and that of their receptors (if known), has been demonstrated in the human and animal hypothalamo-pituitary-gonadal axis. Like leptin and adiponectin, these novel adipokines could thus represent metabolic sensors that are able to regulate reproductive functions according to energy balance changes. Therefore, after investigating their role in normal fertility, we will also discuss their possible involvement in some reproductive troubles known to be associated with features of metabolic syndrome, such as polycystic ovary syndrome, gestational diabetes mellitus, preeclampsia and intra-uterine growth retardation in women, and sperm abnormalities and testicular pathologies in men.

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Abstract P040: Role of 20-HETE in Elevated Blood Pressure in Hyperandrogenemic Female Rats, a Model of Polycystic Ovarian Syndrome

Hypertension ◽

10.1161/hyp.66.suppl_1.p040 ◽

2015 ◽

Vol 66 (suppl_1) ◽

Author(s):

Chetan N Patil ◽

Carolina Dalmasso ◽

Rodrigo O Maranon ◽

Huimin Zhang ◽

Richard J Roman ◽

...

Keyword(s):

Blood Pressure ◽

Polycystic Ovary ◽

Premenopausal Women ◽

Female Rats ◽

Elevated Blood Pressure ◽

Female Rat ◽

Elevated Blood ◽

Reproductive Disorder ◽

Consomic Strain

Polycystic ovary syndrome (PCOS) is the most common reproductive disorder in premenopausal women, is characterized by hyperandrogenemia, metabolic syndrome and inflammation. They also exhibit elevated blood pressure (BP) but may not be treated since they do not meet the criteria for hypertension (BP>130/90 mm Hg). We have characterized a female rat model of hyperandrogenemia (HAF) using dihydrotestosterone (DHT) that mimics many characteristics of women with PCOS. In the present study we tested the hypothesis that androgen-induced upregulation of the cytochrome P450 4A2 isoform (CYP4A2) and the formation of 20-hydroxyeicosatetraenoic acid (20-HETE) in renal microvasculature contributes to the elevated BP in HAF rats. Female rats of SS.5BN consomic strain (wild type) rats and CYP4A2-/- rats on this same background were implanted with DHT (7.5mg/90d) or placebo pellets (n=5-8/grp) beginning at 6 wks of age; pellets were changed every 85 d. At 14 wks of age, rats were implanted with radiotelemetry transmitters, and mean arterial pressure (MAP) was measured for 10 days. Endogenous 20-HETE levels were measured using LC-MS in renal microvessels isolated using an Evans Blue sieving technique. DHT-treated HAF-SS.5BN rats had significantly higher MAP compared to placebo-SS.5BN (128±6 vs. 104±1 mmHg, p<0.004). In contrast, HAF-CYP4A2-/- rats had no change in MAP compared to placebo-CYP4A2-/- controls (120±4 vs 118±3 mmHg, p=NS). Endogenous 20-HETE levels in renal microvessels of HAF-SS.5BN rats were significantly increased compared to Placebo-SS.5BN (2.27±0.91 vs. 0.32±0.037 pmol/mg, p<0.01). The 20-HETE levels were lower in CYP4A2-/- than SS.5BN but DHT in HAF-CYP4A2-/- had no effect on 20-HETE levels compared to Placebo- CYP4A2-/-. These results suggest that androgen-mediated upregulation of the expression of CYP4A2 and the production of 20-HETE in renal microvessels contribute to elevated BP in HAF rats. These data also suggest that methods to attenuate 20-HETE may provide a novel therapeutic to reduce BP in women with PCOS. Work supported by NIH RO1HL66072 and PO1HL51971.

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The relationship between workplace ostracism and information exchange: the mediating role of self-serving behavior

Management Decision ◽

10.1108/md-09-2015-0421 ◽

2016 ◽

Vol 54 (3) ◽

Cited By ~ 15

Author(s):

Panagiotis Gkorezis ◽

Victoria Bellou

Keyword(s):

Information Exchange ◽

Design Methodology ◽

Current Knowledge ◽

Organizational Outcomes ◽

Cross Sectional ◽

Mediating Role ◽

Workplace Ostracism ◽

Negative Effect ◽

Underlying Mechanisms

Purpose The detrimental effect of workplace ostracism on core employee and organizational outcomes has received increasing attention. However, very little is known about its impact on group related outcomes. Given that workplace relationships play a salient role in enhancing employee willingness to share information and knowledge, the present paper examines the link between workplace ostracism and information exchange. In doing so, we also highlight the mediating role of a novel construct, namely self-serving behavior. Design/methodology/approach To test our hypotheses, we conducted two studies using both a scenario paradigm (54 students) and a field study (172 working adults). Findings Results indicated that self-serving behavior fully mediates the effect of workplace ostracism on employee information exchange. Research limitations/implications Both studies have limitations that need to be considered. The scenario paradigm lacks realism whereas the cross-sectional nature of our survey cannot infer causality. As regards the latter, data were collected using a single source and thus common method variance may exist. Originality/value The present study provides novel insights into the outcomes of workplace ostracism and the underlying mechanisms that account for its negative effect. Moreover, it adds to limited current knowledge on self-serving behavior.

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Impact of nutrition on canine behaviour: current status and possible mechanisms

Nutrition Research Reviews ◽

10.1017/s095442240781331x ◽

2007 ◽

Vol 20 (2) ◽

pp. 180-194 ◽

Cited By ~ 25

Author(s):

G. Bosch ◽

B. Beerda ◽

W. H. Hendriks ◽

A. F. B. van der Poel ◽

M. W. A. Verstegen

Keyword(s):

Stress Resistance ◽

Current Knowledge ◽

Current Status ◽

Contributing Factors ◽

Problem Behaviour ◽

Animal Shelters ◽

Self Mutilation ◽

Feeding Motivation ◽

Underlying Mechanisms

Each year, millions of dogs worldwide are abandoned by their owners, relinquished to animal shelters, and euthanised because of behaviour problems. Nutrition is rarely considered as one of the possible contributing factors of problem behaviour. This contribution presents an overview of current knowledge on the influence of nutrition on canine behaviour and explores the underlying mechanisms by which diet may affect behaviour in animals. Behaviour is regulated by neurotransmitters and hormones, and changes in the availability of their precursors may influence behaviour. Tryptophan, the precursor of serotonin, may affect the incidence of aggression, self-mutilation and stress resistance. The latter may also be influenced by dietary tyrosine, a precursor to catecholamines. As diet composition, nutrient availability and nutrient interactions affect the availability of these precursors in the brain, behaviour or stress resistance may be affected. PUFA, especially DHA, have an important role as structural constituents in brain development, and dietary supply ofn-3 andn-6 PUFA could modify aspects of the dopaminergic and serotonergic system and, consequently, cognitive performance and behaviour. Finally, persistent feeding motivation between meals can increase stereotyped behaviour and aggression and decrease resting time. This feeding motivation may be altered by dietary fibre content and source. At present, few studies have been conducted to evaluate the role of nutrition in canine (problem) behaviour through the above mentioned mechanisms. Studies that explore this relationship may help to improve the welfare of dogs and their owners.

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Applications of Melatonin in Female Reproduction in the Context of Oxidative Stress

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/6668365 ◽

2021 ◽

Vol 2021 ◽

pp. 1-11

Author(s):

Yonghui Jiang ◽

Huangcong Shi ◽

Yue Liu ◽

Shigang Zhao ◽

Han Zhao

Keyword(s):

Oxidative Stress ◽

Polycystic Ovary ◽

Oocyte Quality ◽

Early Embryo ◽

Female Reproduction ◽

Adverse Conditions ◽

Wide Range

Oxidative stress has been recognized as one of the causal mediators of female infertility by affecting the oocyte quality and early embryo development. Improving oxidative stress is essential for reproductive health. Melatonin, a self-secreted antioxidant, has a wide range of effects by improving mitochondrial function and reducing the damage of reactive oxygen species (ROS). This minireview illustrates the applications of melatonin in reproduction from four aspects: physiological ovarian aging, vitrification freezing, in vitro maturation (IVM), and oxidative stress homeostasis imbalance associated with polycystic ovary syndrome (PCOS), emphasising the role of melatonin in improving the quality of oocytes in assisted reproduction and other adverse conditions.

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The Complicated Effects of Extracellular Vesicles and Their Cargos on Embryo Implantation

Frontiers in Endocrinology ◽

10.3389/fendo.2021.681266 ◽

2021 ◽

Vol 12 ◽

Author(s):

Nan-Xing Jiang ◽

Xue-Lian Li

Keyword(s):

Extracellular Vesicles ◽

Intercellular Communication ◽

Current Knowledge ◽

Polycystic Ovary ◽

Embryo Implantation ◽

Implantation Failure ◽

Rate Limiting Step ◽

Non Coding Rna ◽

Long Non Coding Rna

As a rate-limiting step in pregnancy, embryo implantation is highly dependent on intercellular communication. Extracellular vesicles (EVs) are newly identified to be important in the course of intercellular communication. EVs have been isolated from a wide variety of biofluids and tissues, including plasma, liver, uterine, semen, embryo, etc. The present and future use of EVs not only as biomarkers, but also as targeting drug delivery system, is promisingly pave the way for advanced comprehension of implantation failure in reproductive diseases. However, as the precise mechanisms of EVs in embryo implantation has not been elucidated yet. Herein, we summarize the current knowledge on the diverse effects of EVs from various sources and their cargos such as microRNA, long non-coding RNA, protein, etc. on embryo implantation, and the potential mechanisms of EVs in reproductive diseases such as recurrent implantation failure, polycystic ovary syndrome and endometriosis. It is essential to note that many of the biologically plausible functions of EVs in embryo implantation discussed in present literatures still need further research in vivo.

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Multiple Roles of Prostaglandin E2 Receptors in Female Reproduction

Endocrines ◽

10.3390/endocrines1010003 ◽

2020 ◽

Vol 1 (1) ◽

pp. 22-34

Author(s):

Yao Ye ◽

Peng Lin ◽

Junyan Zhu ◽

Udo Jeschke ◽

Viktoria von Schönfeldt

Keyword(s):

Prostaglandin E2 ◽

Multiple Roles ◽

Receptor Subtypes ◽

Peroxisome Proliferator ◽

Female Reproduction ◽

Reproductive Disorders ◽

Broad Perspective ◽

Ep Receptors ◽

Peroxisome Proliferator Activated Receptors

Among prostaglandins, Prostaglandin E2 (PGE2) (PGE2) is considered especially important for decidualization, ovulation, implantation and pregnancy. Four major PGE2 receptor subtypes, EP1, EP2, EP3, EP4, as well as peroxisome proliferator-activated receptors (PPARs), mediate various PGE2 effects via their coupling to distinct signaling pathways. This review summarizes up-to-date literatures on the role of prostaglandin E2 receptors in female reproduction, which could provide a broad perspective to guide further research in this field. PGE2 plays an indispensable role in decidualization, ovulation, implantation and pregnancy. However, the precise mechanism of Prostaglandin E2 (EP) receptors in the female reproductive system is still limited. More investigations should be performed on the mechanism of EP receptors in the pathological states, and the possibility of EP agonists or antagonists clinically used in improving reproductive disorders.

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Extracellular Vesicles in Viral Spread and Antiviral Response

Viruses ◽

10.3390/v12060623 ◽

2020 ◽

Vol 12 (6) ◽

pp. 623 ◽

Cited By ~ 5

Author(s):

Raquel Bello-Morales ◽

Inés Ripa ◽

José Antonio López-Guerrero

Keyword(s):

Immune Response ◽

Extracellular Vesicles ◽

Current Knowledge ◽

Host Immune Response ◽

Host Cells ◽

Viral Spread ◽

Viral Responses ◽

Hsv 1

Viral spread by both enveloped and non-enveloped viruses may be mediated by extracellular vesicles (EVs), including microvesicles (MVs) and exosomes. These secreted vesicles have been demonstrated to be an efficient mechanism that viruses can use to enter host cells, enhance spread or evade the host immune response. However, the complex interplay between viruses and EVs gives rise to antagonistic biological tasks—to benefit the viruses, enhancing infection and interfering with the immune system or to benefit the host, by mediating anti-viral responses. Exosomes from cells infected with herpes simplex type 1 (HSV-1) may transport viral and host transcripts, proteins and innate immune components. This virus may also use MVs to expand its tropism and evade the host immune response. This review aims to describe the current knowledge about EVs and their participation in viral infection, with a specific focus on the role of exosomes and MVs in herpesvirus infections, particularly that of HSV-1.

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Physiological and Pathological Androgen Actions in the Ovary

Endocrinology ◽

10.1210/en.2019-00101 ◽

2019 ◽

Vol 160 (5) ◽

pp. 1166-1174 ◽

Cited By ~ 11

Author(s):

Olga Astapova ◽

Briaunna M N Minor ◽

Stephen R Hammes

Keyword(s):

Granulosa Cells ◽

Polycystic Ovary ◽

Follicular Development ◽

Follicle Development ◽

Female Reproduction ◽

Negative Effects ◽

Androgen Excess ◽

Male Sex ◽

Androgen Effects

Abstract Androgens, although traditionally thought to be male sex steroids, play important roles in female reproduction, both in healthy and pathological states. This mini-review focuses on recent advances in our knowledge of the role of androgens in the ovary. Androgen receptor (AR) is expressed in oocytes, granulosa cells, and theca cells, and is temporally regulated during follicular development. Mouse knockout studies have shown that AR expression in granulosa cells is critical for normal follicular development and subsequent ovulation. In addition, androgens are involved in regulating dynamic changes in ovarian steroidogenesis that are critical for normal cycling. Androgen effects on follicle development have been incorporated into clinical practice in women with diminished ovarian reserve, albeit with limited success in available literature. At the other extreme, androgen excess leads to disordered follicle development and anovulatory infertility known as polycystic ovary syndrome (PCOS), with studies suggesting that theca cell AR may mediate many of these negative effects. Finally, both prenatal and postnatal animal models of androgen excess have been developed and are being used to study the pathophysiology of PCOS both within the ovary and with regard to overall metabolic health. Taken together, current scientific consensus is that a careful balance of androgen activity in the ovary is necessary for reproductive health in women.

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