17??-Estradiol protects isolated human pancreatic islets against proinflammatory cytokine-induced cell death: molecular mechanisms and islet functionality1

Contreras, Juan L.; Smyth, Cheryl A.; Bilbao, Guadalupe; Young, Carlton J.; Thompson, John A.; Eckhoff, Devin E.

doi:10.1097/00007890-200211150-00010

Cited by 110 publications

(67 citation statements)

References 29 publications

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“…This finding is important as apoptosis is known to play an important role in growth plate homeostasis . Although estrogen is well known to have antiapoptotic actions in other tissues (Contreras et al 2002, Rau et al 2003, it is not clear how estrogen affects chondrocyte cell death. Here, we demonstrate that the withdrawal of estrogen induces apoptosis in a caspasedependent manner.…”

Section: Discussionmentioning

confidence: 99%

Locally produced estrogen promotes fetal rat metatarsal bone growth; an effect mediated through increased chondrocyte proliferation and decreased apoptosis

Chagin¹,

Chrysis²,

Takigawa³

et al. 2006

Journal of Endocrinology

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The importance of estrogens for the regulation of longitudinal bone growth is unequivocal. However, any local effect of estrogens in growth plate cartilage has been debated. Recently, several enzymes essential for estrogen synthesis were shown to be expressed in rat growth plate chondrocytes. Local production of 17 -estradiol (E2) has also been demonstrated in rat costal chondrocytes. We aimed to determine the functional role of locally produced estrogen in growth plate cartilage. The human chondrocyte-like cell line HCS-2/8 was used to study estrogen effects on cell proliferation ( 3 H-labeled thymidine uptake) and apoptosis (cell death detection ELISA kit). Chondrocyte production of E2 was measured by RIA and organ cultures of fetal rat metatarsal bones were used to study the effects of estrogen on longitudinal growth rate. We found that significant amounts of E2 were produced by HCS-2/8 chondrocytes (64·1 5·3 fmol/3 days/10 6 cells). The aromatase inhibitor letrozole (1 µM) and the pure estrogen receptor antagonist ICI 182,780 (10 µM) inhibited proliferation of HCS-2/8 chondrocytes by 20% (P<0·01) and almost 50% (P<0·001), respectively. Treatment with ICI 182,780 (10 µM) increased apoptosis by 228% (P<0·05). Cotreatment with either caspase-3 or pan-caspase inhibitors completely blocked ICI 182,780-induced apoptosis (P<0·001 vs ICI 182,780 only). Moreover, both ICI 182,780 (10 µM) and letrozole (1 µM) decreased longitudinal growth of fetal rat metatarsal bones after 7 days of culture (P<0·01). In conclusion, our data clearly show that chondrocytes endogenously produce E2 and that locally produced estrogen stimulates chondrocyte proliferation and protects from spontaneous apoptosis. In addition, longitudinal growth is promoted by estrogens locally produced within the epiphyseal growth plate.

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Section: Discussionmentioning

confidence: 99%

Locally produced estrogen promotes fetal rat metatarsal bone growth; an effect mediated through increased chondrocyte proliferation and decreased apoptosis

Chagin¹,

Chrysis²,

Takigawa³

et al. 2006

Journal of Endocrinology

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“…Estradiol also has a protective role for isolated human islets. It acts against pro-inflammatory cytokine-induced cell death by lowering NF-kappaB nuclear translocation, cytochrome release, and caspase-9 activation (Contreras et al, 2002a). Similarly, Giannoukakis et al (2000a) found that Fas-triggered apoptosis of human islets with IkappaB was inhibited following IkappaB alpha gene transfer.…”

Section: Increasing the Expression Of Apoptotic Inhibitors-flipmentioning

confidence: 96%

Role of caspases in the regulation of apoptotic pancreatic islet beta‐cells death

Hui

Dotta

Mario

et al. 2004

Journal Cellular Physiology

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The homeostatic control of beta-cell mass in normal and pathological conditions is based on the balance of proliferation, differentiation, and death of the insulinsecreting cells. A considerable body of evidence, accumulated during the last decade, has emphasized the significance of the disregulation of the mechnanisms regulating the apoptosis of beta-cells in the sequence of events that lead to the development of diabetes. The identification of agents capable of interfering with this process needs to be based on a better understanding of the beta-cell specific pathways that are activated during apoptosis. The aim of this article is fivefold: (1) a review of the evidence for beta-cell apoptosis in Type I diabetes, Type II diabetes, and islet transplantation, (2) to review the common stimuli and their mechanisms in pancreatic beta-cell apoptosis, (3) to review the role of caspases and their activation pathway in beta-cell apoptosis, (4) to review the caspase cascade and morphological cellular changes in apoptotic beta-cells, and (5) to highlight the putative strategies for preventing pancreatic beta-cells from apoptosis.

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“…Studies examining the role of cytokines in the pancreatic ␤-cell indicated, by means of mitochondrial depolarization and cytochrome c release, that MPT is a common effector of both apoptosis and necrosis (14,15). Thus, MPT is implicated in ␤-cell death, which is a key factor in the etiology of type 1 diabetes and a potentially important contributor to some forms of type 2 diabetes (16).…”

mentioning

confidence: 99%

The Characterization of Mitochondrial Permeability Transition in Clonal Pancreatic β-Cells

Koshkin

Bikopoulos

Chan

et al. 2004

Journal of Biological Chemistry

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Mitochondrial permeability transition (MPT), which contributes substantially to the regulation of normal mitochondrial metabolism, also plays a crucial role in the initiation of cell death. It is known that MPT is regulated in a tissue-specific manner. The importance of MPT in the pancreatic ␤-cell is heightened by the fact that mitochondrial bioenergetics serve as the main glucose-sensing regulator and energy source for insulin secretion. In the present study, using MIN6 and INS-1 ␤-cells, we revealed that both Ca 2؉ -phosphate-and oxidant-induced MPT is remarkably different from other tissues. Ca 2؉ -phosphate-induced transition is accompanied by a decline in mitochondrial reactive oxygen species production related to a significant potential dependence of reactive oxygen species formation in ␤-cell mitochondria. Hydroperoxides, which are indirect MPT co-inducers active in liver and heart mitochondria, are inefficient in ␤-cell mitochondria, due to the low mitochondrial ability to metabolize them. Direct cross-linking of mitochondrial thiols in pancreatic ␤-cells induces the opening of a low conductance ion permeability of the mitochondrial membrane instead of the full scale MPT opening typical for liver mitochondria. Low conductance MPT is independent of both endogenous and exogenous Ca 2؉ , suggesting a novel type of nonclassical MPT in ␤-cells. It results in the conversion of electrical transmembrane potential into ⌬pH instead of a decrease in total protonmotive force, thus mitochondrial respiration remains in a controlled state. Both Ca 2؉ -and oxidant-induced MPTs are phosphate-dependent and, through the "phosphate flush" (associated with stimulation of insulin secretion), are expected to participate in the regulation in ␤-cell glucose-sensing and secretory activity.Mitochondrial permeability transition (MPT) 1 is a permeability increase of the inner mitochondrial membrane to solutes of molecular mass up to ϳ1500 Da, which is caused by an opening of specific nonselective proteinaceous pores in the inner mitochondrial membrane (1, 2). Increased permeability of the inner membrane is initiated by an increased level of intramitochondrial Ca 2ϩ and is regulated by multiple effectors, including inorganic phosphate, the redox state of pyridine nucleotides and thiols (oxidative stress), membrane potential, cyclosporin A, and other factors (3). MPT pores are thought to have at least two open conformations and a variable degree of reversibility. Most importantly, MPT in its different forms contributes to both normal cell physiology (regulation of oxidative phosphorylation and Ca 2ϩ metabolism) and to regulatory processes leading to apoptosis (2-4). Specific features of MPT show significant tissue-specific variability (5-8). The most significant and well documented deviation from classical MPT described in liver mitochondria was observed in brain tissue (9). Brain mitochondria demonstrate high resistance to MPT opening (10), low sensitivity to cyclosporin A (5), different responses to MPT modifiers, and a distinctive...

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17??-Estradiol protects isolated human pancreatic islets against proinflammatory cytokine-induced cell death: molecular mechanisms and islet functionality1

Cited by 110 publications

References 29 publications

Locally produced estrogen promotes fetal rat metatarsal bone growth; an effect mediated through increased chondrocyte proliferation and decreased apoptosis

Locally produced estrogen promotes fetal rat metatarsal bone growth; an effect mediated through increased chondrocyte proliferation and decreased apoptosis

Role of caspases in the regulation of apoptotic pancreatic islet beta‐cells death

The Characterization of Mitochondrial Permeability Transition in Clonal Pancreatic β-Cells

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