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1.
A. Carlson K. S. Alderete M. K. O. Grant D. M. Seelig L. C. Sharkey B. N. M. Zordoky 《Veterinary and comparative oncology》2018,16(2):253-261
Hemangiosarcoma (HSA) is a highly malignant tumour with aggressive biological behaviour. HSAs are more common in dogs than other domestic animals. The median survival time of dogs with HSA remains short, even with chemotherapy and surgery. Therefore, there is a critical need to improve the adjuvant chemotherapeutic regimens to improve clinical outcomes in dogs with HSA. Resveratrol has been shown to possess strong anti‐proliferative and/or pro‐apoptotic properties in human cancer cell lines. Nevertheless, the potential anticancer effects of resveratrol have not been reported in canine HSAs. The objective of this study is to determine the growth inhibitory effects of resveratrol in HSA cells when used alone or in combination with doxorubicin, a commonly used chemotherapeutic agent. Frog and DD‐1 canine HSA cell lines were treated with varying concentrations of resveratrol with and without doxorubicin. Cell viability was measured by the MTT assay. The expression of apoptotic proteins, activation of p38 mitogen‐activated protein kinase (MAPK), AMP‐activated protein kinase (AMPK) and extracellular signal‐regulated kinase 1/2 (ERK1/2) were assessed by western blotting. Similar to human cancer cell lines, resveratrol markedly inhibited the growth and induced apoptosis in both HSA cell lines. Mechanistically, resveratrol activated p38 MAPK, but did not affect the AMPK or the ERK1/2 pathways. Additional experiments showed that resveratrol augmented the growth‐inhibitory and apoptotic effects of doxorubicin in both HSA cell lines. These findings suggest that resveratrol has pro‐apoptotic effects in canine HSA cells; therefore, its use as a potential adjunct therapy in canine HSA patients warrants further investigation. 相似文献
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N Manabe F Matsuda-Minehata Y Goto A Maeda Y Cheng S Nakagawa N Inoue K Wongpanit H Jin H Gonda J Li 《Reproduction in domestic animals》2008,43(S2):268-272
Several hundred thousand primordial follicles are present in the mammalian ovary, however, only a limited number develop to the pre-ovulatory stage, and then finally ovulate. The others, more than 99%, will be eliminated through a degenerative process called 'atresia'. The endocrinological regulatory mechanisms involved in follicular development and atresia have been characterized to a large extent, but the precise temporal and molecular mechanisms involved in the regulation of these events have remained unknown. From many recent studies, it is suggested that the apoptosis in ovarian granulosa cells plays a crucial role in follicular atresia. Notably, death ligand–receptor interaction and subsequent intracellular signalling have been demonstrated to be the key mechanisms regulating granulosa cell apoptosis. In this review, we provide an overview of granulosa cell apoptosis regulated by death ligand–receptor signalling. The roles of death ligands and receptors [Fas ligand (FasL)–Fas, tumour necrosis factor (TNF)α–TNF receptor (TNFR), and TNFα-related apoptosis-inducing ligand (TRAIL)–TRAIL receptor (TRAILR)] and intracellular death-signal mediators [Fas-associated death domain protein (FADD), TNF receptor 1-associated death domain protein (TRADD), caspases, apoptotic protease-activating factor 1 (Apaf1), TNFR-associated factor 2 (TRAF2), and cellular FLICE-like inhibitory protein (cFLIP), etc.] in granulosa cells will be discussed. 相似文献
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Expression of Mitochondria‐Associated Genes (PPARGC1A,NRF‐1, BCL‐2 and BAX) in Follicular Development and Atresia of Goat Ovaries 
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下载免费PDF全文 G Zhang Y Wan Y Zhang S Lan R Jia Z Wang Y Fan F Wang 《Reproduction in domestic animals》2015,50(3):465-473
Most follicles undergo atresia during the developmental process. Follicular atresia is predominantly regulated by apoptosis of granulosa cells, but the mechanism underlying apoptosis via the mitochondria‐dependent apoptotic pathway is unclear. We aimed to investigate whether the mitochondria‐associated genes peroxisome proliferator‐activated receptor‐gamma, coactivator1‐alpha (PPARGC1A), nuclear respiratory factor‐1 (NRF‐1), B‐cell CLL/lymphoma 2 (BCL‐2) and BCL2‐associated X protein (BAX) played a role in follicular atresia through this pathway. The four mitochondria‐associated proteins (PGC‐1α, which are encoded by the PPARGC1A gene, NRF‐1, BCL‐2 and BAX) mainly expressed in granulosa cells. The mRNA and protein levels of PPARGC1A/PGC‐1α and NRF‐1 in granulosa cells increased with the follicular development. These results showed that these genes may play a role in the regulation of the follicular development. In addition, compared with healthy follicles, the granulosa cell in atretic follicles had a reduced expression of NRF‐1, increased BAX expression and increased ratio of BAX to BCL‐2 expression. These results suggested that changes of the mitochondria‐associated gene expression patterns in granulosa cells may lead to follicular atresia during goat follicle development. 相似文献
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Fuko MATSUDA-MINEHATA Akihisa MAEDA Yuan CHENG Takafumi SAI Hiroshi GONDA Yasufumi GOTO Noboru MANABE 《Animal Science Journal》2008,79(1):1-10
Several hundred thousand primordial follicles are present in the mammalian ovary, however, only 1% develop to the preovulatory stage and finally ovulate. The remainder will be eliminated via a degenerative process called ‘atresia’. The endocrinological regulatory mechanisms involved in follicular development and atresia have largely been characterized but the precise temporal and molecular mechanisms involved in the regulation of these events remain unknown. Many recent studies suggest that apoptosis in ovarian granulosa cells plays a crucial role in follicular atresia. Notably, death ligand‐receptor interaction and subsequent intracellular signaling have been demonstrated to be the key mechanisms regulating granulosa cell apoptosis. In this review we provide an overview of granulosa cell apoptosis regulated by death ligand‐receptor signaling. The roles of death ligands and receptors [Fas ligand (FasL)]‐Fas, tumor necrosis factor α (TNFα)‐TNF receptor and TNFα‐related apoptosis‐inducing ligand (TRAIL)‐TRAIL receptor (TRAILR)] and intracellular death‐signal mediating molecules (Fas‐associated death domain protein), TNF receptor 1‐associated death domain protein, caspases, apoptotic protease‐activating factor 1, TNFR‐associated factor 2 and cellular FLICE‐like inhibitory protein in granulosa cells are discussed. 相似文献
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RC Bohrer PRA Rosa R Ferreira V Bordignon JFC Oliveira PBD Gonçalves 《Reproduction in domestic animals》2013,48(3):396-401
The growth factor receptor‐bound protein 14 (Grb14) is a cellular adapter protein belonging to the Grb7 family of proteins. Studies with human and rodent cells have demonstrated that Grb14 acts as a negative regulator of tyrosine kinase receptor signalling through the MAPK and PI3K pathways. In cattle, tyrosine kinase receptors are activated during follicular development but the role of Grb14 in this process has not yet been investigated. Therefore, the aim of the present study was to characterize Grb14 mRNA expression in ovarian somatic cells during follicular growth and deviation in cattle. We found Grb14 mRNA expressed in both granulosa and theca cells derived from follicles at different stages of development (3–5 , 6–8, >8 mm in diameter). The abundance of mRNA for Grb14 was higher in granulosa cells of subordinate compared with those from dominant follicles at days 3 and 4 of the follicular wave (p < 0.05). Further, there was a negative correlation between the abundance of mRNA for Grb14 and P450Arom in granulosa cells (R2 = 0.367; p < 0.05) and between the abundance of mRNA for Grb14 in granulosa cells and concentration of oestradiol in follicular fluid (R2 = 0.545; p < 0.05). In theca cells, the expression of Grb14 mRNA did not differ between dominant and subordinate follicles (p > 0.05). These findings suggest that Grb14 may play a regulatory role in granulosa cells during follicular deviation in cattle. 相似文献
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The ovarian follicle components must provide an ideal environment to ensure the success of reproductive processes, and communication between follicular cells is crucial to support proper oocyte growth. Recently, it has been demonstrated that the presence of extracellular vesicles (EVs) carrying microRNAs (miRNAs) in follicular fluid represents an important autocrine and paracrine communication mechanism inside the ovarian follicle. In this study, we tested the hypothesis that the miRNA content of EVs isolated from ovarian follicular (granulosa and cumulus–oocyte complexes) cell‐conditioned culture media is dependent upon cell type. We initially screened bovine granulosa cells (GCs) and cumulus–oocyte complexes (COCs), as well as their derived EVs for 348 miRNAs using real‐time PCR, and detected 326 miRNAs in GCs and COCs cells and 62 miRNAs in GCs and COCs EVs. A bioinformatics analysis of the identified cell‐specific and differentially expressed miRNAs predicted that they likely modulate important cellular processes, including signalling pathways such as the PI3K‐Akt, MAPK and Wnt pathways. By investigating the origins of miRNAs within the follicular fluid, the results of this study provide novel insights into follicular miRNA content and intercellular communication that may be of invaluable use in the context of reproductive technologies, diagnostic of ovarian‐related diseases and/or the identification of biomarkers for oocyte and embryo quality. 相似文献
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The mammalian ovary is an extremely dynamic organ in which a large majority of follicles are effectively eliminated throughout their reproductive life. Due to the numerous efforts of researchers, mechanisms regulating follicular growth and atresia in mammalian ovaries have been clarified, not only their systemic regulation by hormones (gonadotropins) but also their intraovarian regulation by gonadal steroids, growth factors, cytokines and intracellular proteins. Granulosa cells in particular have been demonstrated to play a major role in deciding the fate of follicles, serving molecules that are essential for follicular growth and maintenance as well as killing themselves by an apoptotic process that results in follicular atresia. In this review, we discuss the factors that govern follicular growth and atresia, with a special focus on their regulation by granulosa cells. First, ovarian folliculogenesis in adult life is outlined. Then, we explain about the regulation of follicular growth and atresia by granulosa cells, in which hormones, growth factors and cytokines, death ligand-receptor system and B cell lymphoma/leukemia 2 (BCL2) family members (mitochondria-mediated apoptosis) are further discussed. 相似文献
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卵巢是家禽的重要繁殖器官,会产生大量卵泡,而卵泡在生长发育的各个阶段中都可能因为不同因素的调控而发生闭锁,最终导致繁殖性能衰退。颗粒细胞对卵泡的生长发育有重要调控作用,其凋亡会诱导卵泡发生闭锁。诱导颗粒细胞发生凋亡的因素较多,包括激素、细胞因子、氧化应激、线粒体及其他体外因素。颗粒细胞凋亡主要由线粒体途径导致,其涉及到半胱天冬酶（Caspase）家族参与,当线粒体裂解时会释放细胞色素C （Cyt-C）,随后形成凋亡小体激活Caspase-3和Caspase-8,最终激活Caspase-9导致颗粒细胞凋亡;当颗粒细胞发生凋亡,家禽体内卵泡丧失生物功能并且卵泡细胞之间的调控失衡,促使卵泡内卵母细胞和膜细胞凋亡,最终导致卵泡发生闭锁;颗粒细胞在存活状态下所分泌的生长因子、性腺类固醇、细胞因子能减少卵母细胞氧化损伤,防止细胞内活性氧（ROS）水平过高导致的线粒体DNA损伤,从而避免线粒体功能障碍而造成的颗粒细胞凋亡。作者从颗粒细胞凋亡及其影响因素、颗粒细胞凋亡和卵泡闭锁的关系、颗粒细胞凋亡对卵泡闭锁的影响3个方面进行阐述,以期为减少卵泡闭锁、提高家禽繁殖性能提供理论依据。 相似文献
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Oxytocin (OT) and protein kinase A (PKA), a possible intracellular mediator of hormone action in the ovary, can be potent activators of ovarian functions and fertility. Nevertheless, action of OT on ovarian follicle atresia has not been studied yet. Only single administration of PKA activators [3‐isobutyl‐1‐methyl‐xanthine (IBMX) and dibutyryl cyclic adenosine monophosphate (dbcAMP)] on ovarian follicle atresia was studied previously. The aim of this study was to examine the effect of OT (single treatment per one reproductive cycle, multiple treatments for three cycles), IBMX and dbcAMP (multiple treatments) on folliculogenesis and follicular atresia in rabbit. The ovarian cycle in control females was induced only by gonadotropins. Experimental females received co‐administration of gonadotropins with OT, IBMX or dbcAMP (at 50 μg/female). All females were artificially inseminated. Single‐treated females were euthanized after 18–19 h. Multiple‐treated females were euthanized after the third reproductive cycle. Histological sections of the ovaries were prepared and evaluated by a light microscopy. The follicles were divided into four classes according to the structure of granulosa and theca cells as follows: none or small atresia, cystic atresia, obliterative atresia and atresia associated with luteinization. The ovaries from the control and experimental females, treated during one reproductive cycle or three cycles, were compared. Single OT co‐administration increased proportion of follicles with atresia associated with luteinization, but not other types of atresia. No influence of multiple OT co‐administration on follicular atresia was recorded. Multiple IBMX and dbcAMP co‐administration decreased the proportion of atretic follicles and increased the proportion of healthy follicles without atresia. 相似文献
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生殖激素控制卵泡细胞凋亡的研究进展 总被引：8，自引：0，他引：8
研究表明颗粒细胞凋亡是导致卵泡闭锁的重要原因，而颗粒细胞凋亡涉及许多因素，其中生殖激素，如GnRH、FSH、LH、P4、E、A、GH、Mel、inhibin、activin、follistatin等间接地和直接地对卵巢卵泡细胞凋亡发挥重要的综合控制作用，因此正确理解激素对体内、外卵泡及颗粒细胞发育和衰亡的调节网络具有很重要的理论和实践意义。 相似文献
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Matsuda-Minehata F Inoue N Goto Y Manabe N 《The Journal of reproduction and development》2006,52(6):695-705
In the mammalian ovary, follicular development and atresia are closely regulated by cell death and survival-promoting factors, including hormones (gonadotropins) and intraovarian regulators (gonadal steroids, cytokines, and intracellular proteins). Several hundred thousand primordial follicles are present in the mammalian ovary; however, only a limited number of primordial follicles develop to the preovulatory stage and ovulate. The others, more than 99% of follicles, will be eliminated via a degenerative process known as "atresia". The endocrinological regulatory mechanisms involved in follicular development and atresia have been characterized to a large extent, but the precise temporal and molecular mechanisms involved in the regulation of these events have remained largely unknown. Recent studies suggest that the apoptosis of ovarian granulosa cells plays a major role in follicular atresia. In this review, we provide an overview of development and atresia of follicles, and apoptosis of granulosa cells in mammals. 相似文献
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Role of intracellular kinases in the regulation of equine eosinophil migration and actin polymerization 总被引：2，自引：0，他引：2
Weston MC Collins ME Cunningham FM 《Journal of veterinary pharmacology and therapeutics》2008,31(1):31-38
Inappropriately activated eosinophils can contribute to disease pathogenesis and intracellular signalling pathways that regulate functional responses may represent a therapeutic target. Little is known about intracellular signalling in equine eosinophils and this study examined the role of phospholipase C (PLC) and a range of protein kinases on responses to histamine and CCL11. Histamine (10(-4) M) or CCL11 (5.6 x 10(-9) M)-induced actin polymerization, migration and superoxide production by eosinophils from healthy horses were compared in the presence and absence of selective kinase inhibitors. Inhibition of phosphatidylinositol-3 kinase (PI3K) significantly reduced the response in each assay. In contrast, whilst inhibition of PLC decreased actin polymerization and superoxide production, an increase in migration was observed; the latter effect was also seen when protein kinase C (PKC) was inhibited. With the exception of histamine-induced migration, which was significantly reduced by blocking extracellular regulated kinase (ERK)1/2, activation of ERK1/2, p38 MAPK and tyrosine kinase did not appear to play an important role in the responses studied. These results suggest that equine eosinophil activation by histamine and CCL11 is mediated through PI3K. Whilst PLC activation is required for actin polymerization and superoxide production, migration may be negatively regulated by PLC and PKC. These kinases represent potential targets for modulating eosinophil activation by multiple stimuli. 相似文献
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Monget P Fabre S Mulsant P Lecerf F Elsen JM Mazerbourg S Pisselet C Monniaux D 《Domestic animal endocrinology》2002,23(1-2):139-154
Involvement of insulin-like growth factors (IGFs) and IGF binding proteins (IGFBPs) in ovarian folliculogenesis has been extensively studied during the last decade. In all mammalian species, IGF-I stimulates granulosa cell proliferation and steroidogenesis. The concentrations of IGF-I and -II do not vary during terminal follicular growth and atresia. In contrast, the levels of IGFBP-2 and -4, as well as IGFBP-5 in ruminants, dramatically decrease and increase during terminal follicular growth and atresia, respectively. These changes are responsible for an increase and a decrease in IGF bioavailability during follicular growth and atresia, respectively. They are partly explained by changes in ovarian expression. In particular, expression of IGFBP-2 mRNA decreases during follicular growth in ovine, bovine and porcine ovaries, and expression of IGFBP-5 mRNA dramatically increases in granulosa cells of bovine and ovine atretic follicles. Changes in IGFBP-2 and -4 levels are also due to changes in intrafollicular levels of specific proteases. Recently, we have shown that the pregnancy-associated plasma protein-A (PAPP-A) is responsible for the degradation of IGFBP-4 in preovulatory follicles of domestic animals. Expression of PAPP-A mRNA is restricted to the granulosa cell compartment, and is positively correlated to expression of aromatase and LH receptor. From recent evidence, the bone morphogenetic protein (BMP) family would also play a key role in ovarian physiology of domestic animals. In particular, we and others have recently shown that a non-conservative substitution (Q249R) in the bone morphogenetic protein-receptor type IB (BMPR-IB) coding sequence is fully associated with the hyperprolific phenotype of FecB(B)/FecB(B) Booroola ewes. BMP-4 and GDF-5, natural ligands of BMPR-IB, strongly inhibit secretion of progesterone by ovine granulosa cells in vitro, but granulosa cells from FecB(B)/FecB(B) ewes are less responsive than those from FecB(+)/FecB(+) to the action of these peptides. It is suggested that in FecB(B)/FecB(B) ewes, Q249R substitution would impair the function of BMPR-IB, leading to a precocious differentiation of granulosa cells and of follicular maturation. Interestingly, recent findings have described mutations in BMP-15 gene associated with hyperprolific phenotypes in Inverdale and Hanna ewes, suggesting that the BMP pathway plays a crucial role in the control of ovulation rate. 相似文献
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Cystic ovarian disease (COD) is one of the main causes of infertility in dairy cattle. It has been shown that intra‐ovarian factors may contribute to follicular persistence. Transforming growth factor‐beta (TGFB) isoforms are important paracrine and autocrine signalling molecules that regulate ovarian follicle growth and physiology. Considering the importance of these factors in the ovarian physiology, in this study, we examined the expression of TGFB isoforms (TGFB1, TGFB2 and TGFB3) in the ovary of healthy cows and animals with spontaneous and adrenocorticotrophic hormone (ACTH)‐induced COD. In the oestrous‐synchronized control group, the expression of TGFB1 in granulosa and theca cells was higher in spontaneous cysts than in atretic or tertiary follicles. When we compared TGFB2 expression in granulosa cells from atretic or tertiary follicles from the oestrous‐synchronized control group with that in ACTH‐induced or spontaneous follicular cysts, we found a higher expression in the latter. The expression of the TGFB isoforms studied was also altered during folliculogenesis in both the spontaneous and ACTH‐induced COD groups. As it has been previously shown that TGFB influences steroidogenesis, ovarian follicular proliferation and apoptosis, an alteration in its expression may contribute to the pathogenesis of this disease. 相似文献
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Weihua Zhu Min Yang Jinnan Shang Yiliang Xu Yuanlang Wang Qiangqiang Tao Liang Zhang Yueyun Ding Yige Chen Dongdong Zhao Chonglong Wang Mingxing Chu Zongjun Yin Xiaodong Zhang 《Animal Science Journal》2019,90(6):719-727
Apoptosis of granulosa cells affects follicular atresia and reproduction and is regulated by miRNAs and the expression of certain genes. For the present study, we investigated the regulatory relationship between microRNA‐222 (miR‐222) and THBS1 in porcine follicular granulosa cells (pGCs) and its effects on apoptosis to provide empirical data for developing methods to improve pig fecundity. Results revealed that miR‐222 promotes the proliferation of pGCs. MiRNA mimics and luciferase reporter assays revealed that miR‐222 functions as an anti‐apoptotic factor in pGCs. MiR‐222 mimics in pGCs result in the upregulation of the anti‐apoptotic BCL‐2 gene, down‐regulation of the proapoptotic caspase‐3 gene, and inhibition of apoptosis. MiR‐222 inhibitors reduced BCL‐2 and had no significant effect on caspase‐3. MiR‐222 mimics promoted estrogen levels. Inhibition of THBS1 inhibited pGC apoptosis. Transfection of THBS1‐siRNA reduced the proapoptotic BAX gene. MiR‐222 can directly target the 3′‐untranslated region of the THBS1 gene. MiR‐222 mimics suppressed THBS1 mRNA and proteins, but these were upregulated by the miR‐222 inhibitor. Transfection of THBS1‐siRNA resulted in the inhibition of the miR‐222 inhibitor, which suggests that miR‐222 inhibits pGC apoptosis by targeting THBS1. These findings suggest that miR‐222 and THBS1 play important roles in follicular atresia, ovarian development, and female reproduction. 相似文献