Caspase-3-mediated cleavage of Akt: involvement of non-consensus sites and influence of phosphorylation.

Here, we show for the first time that Akt1 is cleaved in vitro at the caspase-3 consensus site DQDD(456) downward arrow SM. Our data suggest QEEE(116) downward arrow E(117) downward arrow MD, EEMD(119) downward arrow, TPPD(453) downward arrow QD and DAKE(398) downward arrow IM as novel non-consensus caspase-3 cleavage sites. More importantly, we demonstrate that phosphorylation of Akt1 modulates its cleavage in a site-specific manner: Resistance to cleavage at site DAKE(398) (within the kinase domain) in response to phosphorylation suggests a possible mechanism by which the anti-apoptotic role of Akt1 is regulated.

Upregulation of myocellular DGAT1 augments triglyceride synthesis in skeletal muscle and protects against fat-induced insulin resistance.

Increased fat deposition in skeletal muscle is associated with insulin resistance. However, exercise increases both intramyocellular fat stores and insulin sensitivity, a phenomenon referred to as "the athlete's paradox". In this study, we provide evidence that augmenting triglyceride synthesis in skeletal muscle is intrinsically connected with increased insulin sensitivity.

Gonadotropin and intra-ovarian signals regulating follicle development and atresia: the delicate balance between life and death.

Regulation of mammalian follicular development is tightly regulated by both cell death and survival signals, including endocrine (e.g. gonadotropin) and intra-ovarian regulators (e.

Sperm surface arylsulfatase A can disperse the cumulus matrix of cumulus oocyte complexes.

Cumulus cell layers of expanded cumulus oocyte complexes (COCs) are interlinked with networks of hyaluronic acid, chondroitin sulfate B proteoglycans and link proteins, and they can be dispersed by sperm surface hyaluronidases. In this report, we showed that arylsulfatase A (AS-A), existing on the sperm head surface, also had this dispersion action. Purified AS-A free of protease, hyaluronidase and chondroitinase activities could disperse the cumulus matrix of expanded COCs.

Fatty acid transport protein 1 is required for nonshivering thermogenesis in brown adipose tissue.

Nonshivering thermogenesis in brown adipose tissue (BAT) generates heat through the uncoupling of mitochondrial beta-oxidation from ATP production. The principal energy source for this process is fatty acids that are either synthesized de novo in BAT or are imported from circulation. How uptake of fatty acids is mediated and regulated has remained unclear.

Protracted myelin clearance hinders central primary afferent regeneration following dorsal rhizotomy and delayed neurotrophin-3 treatment.

Regeneration within or into the CNS is thwarted by glial inhibition at the site of a spinal cord injury and at the dorsal root entry zone (DREZ), respectively. At the DREZ, injured axons and their distal targets are separated by degenerating myelin and an astrocytic glia limitans. The different glial barriers to regeneration following dorsal rhizotomy are temporally and spatially distinct.

Granulosa cells promote differentiation of cortical stromal cells into theca cells in the bovine ovary.

Formation of a theca cell (TC) layer is an important physiologic event that occurs during early follicular development. Nevertheless, little is known concerning the nature and regulation of the formation of the TC layer during follicular growth. Using an established coculture system in this study, we examined the hypothesis that stromal cells differentiate into TCs during early follicular development and that this process involves interaction with granulosa cells (GCs).

Growth differentiation factor 9 is antiapoptotic during follicular development from preantral to early antral stage.

Ovarian follicular atresia represents a selection process that ensures the release of only healthy and viable oocytes during ovulation. The transition from preantral to early antral stage is the penultimate stage of development in terms of gonadotropin dependence and follicle destiny (survival/growth vs. atresia).

Role and regulation of nodal/activin receptor-like kinase 7 signaling pathway in the control of ovarian follicular atresia.

Although the role of the TGF beta superfamily members in the regulation of ovarian folliculogenesis has been extensively studied, their involvement in follicular atresia is not well understood. In the present study, we have demonstrated for the first time that Nodal, a member of the TGF beta superfamily, is involved in promoting follicular atresia as evidenced by the following: 1) colocalization of Nodal and its type I receptor Activin receptor-like kinase 7 (ALK7) proteins in the granulosa cells was only observed in atretic antral follicles, whereas they were present in theca cells and granulosa cells of healthy follicles, respectively; 2) addition of recombinant Nodal or overexpression of Nodal by adenoviral infection induced apoptosis of otherwise healthy granulosa cells; 3) constitutively active ALK7 (ALK7-ca) overexpression mimicked the function of Nodal in the induction of granulosa cell apoptosis. Furthermore, overexpression of Nodal or ALK7-ca increased phosphorylation and nuclear translocation of Smad2, decreased X-linked inhibitor of apoptotic proteins (Xiap) expression at both mRNA and protein level and phospho-Akt content, as well as triggered mitochondrial release of death proteins Smac/DIABLO, Omi/HtrA2, and cytochrome c in the granulosa cells.

Targeted deletion of FATP5 reveals multiple functions in liver metabolism: alterations in hepatic lipid homeostasis.

Background & Aims: Fatty acid transport protein 5 (FATP5/Slc27a5) has been shown to be a multifunctional protein that in vitro increases both uptake of fluorescently labeled long-chain fatty acid (LCFA) analogues and bile acid/coenzyme A ligase activity on overexpression. The aim of this study was to further investigate the diverse roles of FATP5 in vivo.

Methods: We studied FATP5 expression and localization in liver of C57BL/6 mice in detail.

FATP1 is an insulin-sensitive fatty acid transporter involved in diet-induced obesity.

Fatty acid transport protein 1 (FATP1), a member of the FATP/Slc27 protein family, enhances the cellular uptake of long-chain fatty acids (LCFAs) and is expressed in several insulin-sensitive tissues. In adipocytes and skeletal muscle, FATP1 translocates from an intracellular compartment to the plasma membrane in response to insulin. Here we show that insulin-stimulated fatty acid uptake is completely abolished in FATP1-null adipocytes and greatly reduced in skeletal muscle of FATP1-knockout animals while basal LCFA uptake by both tissues was unaffected.

Over-expression of PTEN sensitizes human ovarian cancer cells to cisplatin-induced apoptosis in a p53-dependent manner.

Objective: Resistance to cisplatin-centered chemotherapy is a major cause of treatment failure in human ovarian cancer. Whereas PTEN, a tumor suppressor gene product, is believed to promote apoptosis primarily via inactivation of the PI3K/Akt cell survival pathway, recent evidence suggests that PTEN may function independently of this pathway. Activation of p53 is a key determinant of sensitivity to cisplatin-induced apoptosis.

Akt-mediated cisplatin resistance in ovarian cancer: modulation of p53 action on caspase-dependent mitochondrial death pathway.

Akt is a determinant of cisplatin [cis-diammine-dichloroplatinum (CDDP)] resistance in ovarian cancer cells, and this may be related to the regulation of p53. Precisely how Akt facilitates CDDP resistance and interacts with p53 is unclear. Apoptotic stimuli induce second mitochondria-derived activator of caspase (Smac) release from mitochondria into the cytosol, where it attenuates inhibitor of apoptosis protein-mediated caspase inhibition.

Transmission dynamics of Taenia solium and potential for pig-to-pig transmission.

Taenia solium taeniasis/cysticercosis is one of few potentially eradicable infectious diseases and is the target of control programs in several countries. The larval stage of this zoonotic cestode invades the human brain and is responsible for most cases of adult-onset epilepsy in the world. Our current understanding of the life cycle implicates humans as the only definitive host and tapeworm carrier, and thus the sole source of infective eggs that are responsible for cysticercosis in both human and pigs through oral-faecal transmission.

Regulation of p53 and suppression of apoptosis by the soluble guanylyl cyclase/cGMP pathway in human ovarian cancer cells.

Dysregulated apoptosis plays a critical role in the development of a number of aberrant cellular processes, including tumorigenesis and chemoresistance. However, the mechanisms that govern the normal apoptotic program are not completely understood. Soluble guanylyl cyclase (sGC) and cyclic guanosine monophosphate (cGMP) promote mammalian cell viability via an unknown mechanism and p53 status is a key determinant of cell fate in human ovarian cancer cells.

Proteasome subunit LMP2 is required for matrix metalloproteinase-2 and -9 expression and activities in human invasive extravillous trophoblast cell line.

The ubiquitin-proteasome pathway (UPP) is involved in the degradation of the extracellular matrix (ECM) and trophoblastic invasion during early pregnancy. Our previous studies demonstrated that inhibition of UPP suppresses expression of matrix metalloproteinase (MMP)-2 and -9. LMP2 is an important proteasome subunit that is critical for proteasome activity.

Short report: secondary transmission in porcine cysticercosis: description and their potential implications for control sustainability.

Taenia solium taeniasis/cysticercosis is one of few potentially eradicable infectious diseases and is the target of control programs in several countries. The larval stage of this zoonotic cestode invades the human brain and is responsible for most cases of adult-onset epilepsy in the world. The pig is the natural intermediate host, harboring the larvae or cysticerci.

Involvement of SMAD4, but not of SMAD2, in transforming growth factor-beta1-induced trophoblast expression of matrix metalloproteinase-2.

Matrix metalloproteinases (MMPs) play crucial roles in extravillous trophoblast invasion. In the present study, we examined the possible role of Smad4 and Smad2 in transforming growth factor (TGF)-beta1-induced MMP-2 expression, using the well-established invasive extravillous trophoblast cell line HTR-8/SVneo. Recombinant sense Smad4 or Smad2 retroviral vectors were constructed by inserting full-length Smad4 or Smad2 cDNA into pLXSN retroviral vector.

Role of pro-IGF-II processing by proprotein convertase 4 in human placental development.

Fetal growth restriction (intrauterine growth restriction, IUGR) is a leading cause of perinatal mortality. However, the causes of aberrant development of the placenta and, thus, of the fetus, are not currently known. Insulin-like growth factor II (IGF-II) has been shown to be an important regulator of fetoplacental growth.

Comparisons of brain, uterus, and liver mRNA expression for cytochrome p450s, DNA methyltransferase-1, and catechol-o-methyltransferase in prepubertal female Sprague-Dawley rats exposed to a mixture of aryl hydrocarbon receptor agonists.

Non-ortho polychlorinated biphenyls (PCBs), polychlorinated dibenzodioxins (PCDDs), and polychlorinated dibenzofurans (PCDFs) are ubiquitous environmental contaminants that exert their toxicity mostly through activation of the aryl-hydrocarbon receptor (AhR), and are referred to as AhR agonists. The objective was to study, by real time reverse-transcriptase-polymerase chain reaction (RT-PCR), the effects of postnatal exposure to a reconstituted mixture of AhR agonists present in breast milk (3 non-ortho PCBs, 6 PCDDs, and 7 PCDFs, referred to here-in-after as AhRM) on mRNA expression of estrogen receptor (ERalpha), enzymes involved with the metabolism of estrogens [catechol-o-methyltransferase (Comt), cytochrome P450 (Cyp)1A1, 1B1 and 2B1], and DNA methyltransferase-1 (Dnmt1), in brain areas, liver and uterus of immature female rats. Neonates were exposed by gavage during postnatal day (PND) 1-20 with dosages equivalent to 1, 10, 100, and 1000 times the estimated average human exposure level, and were sacrificed at PND 21.

Fas ligand expression by maternal decidual cells is negatively correlated with the abundance of leukocytes present at the maternal-fetal interface.

The abundance of leukocytes at the maternal-fetal interface could influence the fate and invasion of extravillous trophoblasts. However, the mechanism(s) involved in determining the number of leukocytes present at the maternal-fetal interface as well as the nature of the interactions between invading fetal trophoblasts, maternal leukocytes and decidual cells are not well understood. In the present studies, we examined Fas ligand (FasL)/Fas expression at the maternal-fetal interface in human placental tissues of early pregnancy by immunohistochemistry.

A case of primary malignant pericardial mesothelioma.

Primary malignant pericardial mesothelioma (PMPM) is an exceedingly rare tumour. One of the largest necropsy series gave an incidence of primary pericardial tumours of 0.0022%, of which mesothelioma is the most common type.

A soluble Nogo receptor differentially affects plasticity of spinally projecting axons.

In the central nervous system, regeneration of injured axons and sprouting of intact axons are suppressed by myelin-derived molecules that bind to the Nogo receptor (NgR). We used a soluble form of the NgR (sNgR), constructed as an IgG of the human NgR extracellular domain, to manipulate plasticity of uninjured primary afferent and descending monoaminergic projections to the rat spinal cord following dorsal rhizotomy. Rats with quadruple dorsal rhizotomies were treated with intrathecal sNgR or saline, or were left untreated for 2 weeks.

Nodal induces apoptosis and inhibits proliferation in human epithelial ovarian cancer cells via activin receptor-like kinase 7.

Human epithelial ovarian cancer is the most lethal female cancer. Hormones and growth factors, including the TGF-beta superfamily, have been suggested to play a role in ovarian tumorigenesis. The biological effects of TGF-beta superfamily are mediated by type I and type II serine/threonine kinase receptors and by intracellular Smad proteins.

Lack of effects of postnatal exposure to a mixture of aryl hydrocarbon-receptor agonists on the development of methylnitrosourea-induced mammary tumors in sprague-dawley rats.

There are concerns that early life exposure to organochlorines, including aryl hydrocarbon receptor (AhR) agonists, may lead to long-term effects and increase the risk of developing breast cancer. Our objective was to test if postnatal exposure to a mixture of 2,3,7,8-tetrachlorodibenzodioxin (TCDD)-like chemicals would modulate the development of methylnitrosourea (MNU)-induced mammary tumors. Females received by gavage a mixture containing 3 non-ortho-polychlorinated biphenyls (PCBs), 6 polychlorinated dibenzodioxins (PCDDs), and 7 polychlorinated dibenzofurans (PCDFs), at 1, 5, 10, 15, and 20d of age.