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ABSTRACT: Melanocortins, adrenocorticotropic hormone (ACTH) and α-, β-, and γ-melanocyte-stimulating hormone (MSH) are produced in the placenta and secreted into embryos/fetuses. ACTH concentrations are higher in fetal plasma than in maternal plasma and peak at mid-gestation in rats, whereas ACTH production starts in the anterior lobe of the fetal pituitary at later stages. Melanocortin receptors (MC1-5R), receptors for ACTH and α-, β- and γ-MSH, are expressed in various adult organs. The specific function of these receptors has been well examined in the hypothalamic-pituitary-adrenocortical (HPA) axis and the HPA axis-like network in the skin, and anti-inflammatory effects for white blood cells have also been investigated. MC2R and/or MC5R are also expressed in the testis, lung, kidney, adrenal, liver, pancreas, brain and blood cells at different stages in mouse and rat embryos/fetuses. Melanocortins in embryos and fetuses promote maturation of the HPA axis and also contribute to the development of lung, testis, brain and blood cells. Recently, a unique ACTH function was revealed in fetuses: placental ACTH, which is secreted by the maternal leukemia inhibitory factor (LIF), and induces LIF secretion from fetal nucleated red blood cells. Finally, the maternal LIF-placental ACTH-fetal LIF signal relay regulates the LIF level and promotes neurogenesis in fetuses, which suggests that ACTH acts as a signal transducer or effector for fetal development in the maternal-fetal signal pathway.
Congenital Anomalies 06/2011; 51(2):47-54.
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ABSTRACT: Leukemia inhibitory factor (LIF) promotes the proliferation of neuronal progenitor cells in the cerebrum. However, it remains unclear how fetal LIF level is regulated. Here we show evidence that maternal LIF signals drive fetal LIF levels via the placenta, thereby promoting neurogenesis in the fetal brain in rats. Chronological changes showed that LIF concentration in fetal sera (FS) and fetal cerebrospinal fluid peaked at gestational day (GD) 15.5, after the peak of maternal LIF at GD14.5. LIF injection into rat dams at GD15.5 increased the level of ACTH in FS and subsequently increased LIF levels in FS and fetal cerebrospinal fluid. The elevation of fetal LIF after LIF injection into dams was inhibited by in utero injection of anti-ACTH antibody into fetuses. Cultured syncytiotrophoblasts, which express the LIF receptor and glycoprotein 130, were induced to secrete ACTH and up-regulate Pomc expression by the addition of LIF. Nucleated red blood cells from fetuses at GD15.5, but not GD13.5 or GD17.5, displayed LIF secretion in response to ACTH. Moreover, injection of LIF into dams at GD13.5 or GD17.5 did not result in elevation of ACTH or LIF in fetuses. The labeling index of 5-bromo-2'-deoxyuridine-positive cells in the ventricular zone of the cerebral neocortex increased 24 h after injection of LIF into dams at GD15.5 but not GD13.5 or GD17.5. These results suggest that in rats maternal LIF induces ACTH from the placenta, which in turn induces fetal nucleated red blood cells to secrete LIF that finally increases neurogenesis in fetuses around GD15.
Endocrinology 02/2010; 151(4):1853-62. · 4.46 Impact Factor
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Hiroki Shimada,
Kei-Ichi Hirai,
Eriko Simamura,
Toshihisa Hatta,
Hiroki Iwakiri,
Keiji Mizuki,
Taizo Hatta,
Tatsuya Sawasaki,
Satoko Matsunaga,
Yaeta Endo,
Shigeomi Shimizu
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ABSTRACT: Paraquat (PQ), a herbicide used worldwide, causes fatal injury to organs upon high dose ingestion. Treatments for PQ poisoning are unreliable, and numerous deaths have been attributed inappropriate usage of the agent. It is generally speculated that a microsomal drug-metabolizing enzyme system is responsible for PQ toxicity. However, recent studies have demonstrated cytotoxicity via mitochondria, and therefore, the cytotoxic mechanism remains controversial. Here, we demonstrated that mitochondrial NADH-dependent PQ reductase containing a voltage-dependent anion channel 1 (VDAC1) is responsible for PQ cytotoxicity. When mitochondria were incubated with NADH and PQ, superoxide anion (O(2)(*)) was produced, and the mitochondria ruptured. Outer membrane extract oxidized NADH in a PQ dose-dependent manner, and oxidation was suppressed by VDAC inhibitors. Zymographic analysis revealed the presence of VDAC1 protein in the oxidoreductase, and the direct binding of PQ to VDAC1 was demonstrated using biotinylated PQ. VDAC1-overexpressing cells showed increased O(2)(*) production and cytotoxicity, both of which were suppressed in VDAC1 knockdown cells. These results indicated that a VDAC1-containing mitochondrial system is involved in PQ poisoning. These insights into the mechanism of PQ poisoning not only demonstrated novel physiological functions of VDAC protein, but they may facilitate the development of new therapeutic approaches.
Journal of Biological Chemistry 09/2009; 284(42):28642-9. · 4.77 Impact Factor
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ABSTRACT: Although the celiac artery is a common trunk of the left gastric, splenic, and common hepatic arteries, its branching pattern varies. Indeed, even among anatomy textbooks, there is disagreement on which pattern is standard. In the present study, we identified the standard pattern of celiac artery branching by examining 186 Japanese cadavers. Celiac arteries with the three main branches were found in 91.4% (170/186) of the cadavers. These 170 cases were then classified into 4 types (Types I-IV). Type I, in which the first branch was the left gastric artery, accounted for 132 cases (71.0%). Thirty-one cases (16.7%) were Type II, in which the three main arteries branched out at the same vertebral level. Type III, in which the common hepatic artery was the first branch, accounted for 4 cases (2.2%). Finally, 3 cases (1.6%) were Type IV, in which the splenic artery was the first branch. These findings suggest that the Type I phenotype is the standard branching pattern of the celiac artery in Japanese. The artery's developmental process was also discussed.
Anatomical Science International 04/2009; 84(1):7-10.
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ABSTRACT: The authors recently demonstrated that the mitochondrial voltage-dependent anion channel 1 (VDAC1) is involved in the sensitivity of cancer cells to furanonaphthoquinone (FNQ). The aim of the present study was to investigate whether mitochondrial VDAC1 reduces quinone antitumor drugs. The VDAC1 purified by immunoprecipitation reduced FNQ in the presence of nicotinamide adenine dinucleotide (NADH) and produced H(2)O(2). Blue native polyacrylamide gel electrophoresis demonstrated that the band that reduced FNQ NADH-dependently mainly included VDAC1. Because H(2)O(2) generation in catalyzing FNQ with NADH caused mitochondrial damage, the cytotoxic activity of FNQ was induced by VDAC1. In the quinone antitumor drugs, menadione (VK3), adriamycin and mitomycin C, mitochondrial VDAC1 bioreductively activated VK3. These results demonstrate that mitochondrial VDAC1 is a pharmacologic target for the treatment of tumor.
Anatomical science international / Japanese Association of Anatomists 01/2009; 83(4):261-6. · 0.83 Impact Factor
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ABSTRACT: The present report describes an anomalous case of the right vertebral artery arising as the last branch of the aortic arch identified in a 76-year-old Japanese male cadaver during dissection in the anatomical laboratory of Kanazawa Medical University. The aortic arch itself coursed normally but the right vertebral artery was uniquely situated at the fourth branch next to the brachiocephalic artery, the left common carotid artery, and the left subclavian artery. The anomalous right vertebral artery branched into the esophageal branch, the prevertebral branch, and the second right posterior intercostal artery, and finally entered the first costotransverse foramen at the thoracic region as it passed upward through the first to the seventh transverse foramina of the cervical vertebra. The left vertebral artery was normal. The development of the right vertebral artery may be described as follows: (i) the distal portion of the right dorsal aorta, which usually disappears, persisted and became united, via post-costal longitudinal anastomosis; (ii) the right dorsal aorta between the seventh and eighth intersegmental arteries lost its connection to the main structure; and (iii) the fusion of the originally paired dorsal aorta extended around the 11th segment, which was two segments away from the normal portion of the structure.
Anatomical science international / Japanese Association of Anatomists 01/2009; 83(4):314-8. · 0.83 Impact Factor
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ABSTRACT: Recently, it was demonstrated that some anti-cancer agents used mitochondrial voltage-dependent anion channels (VDAC1-3 isoforms) as their pharmacological target. VDACs are expressed more highly in cancer cells than normal cells; thus the VDAC-dependent cytotoxic agents can have cancer-selectivity. Furanonaphthoquinones (FNQs) induced caspase-dependent apoptosis via the production of NADH-dependent reactive oxygen species (ROS) by VDAC1. The ROS production and the anti-cancer activity of FNQs were increased by VDAC1 overexpression. Meanwhile, erastin induced RAS-RAF-MEK-dependent non-apoptotic cell death via VDAC2. On the other hand, VDACs were needed for transporting ATP to hexokinase (HK), which was highly expressed in cancer cells. We hypothesized that the high glycolysis might induce up-regulation of VDAC. In this review, we propose that VDACs are novel candidates for effective pharmacological targets of anti-cancer drugs.
Journal of Bioenergetics 09/2008; 40(3):213-7. · 2.81 Impact Factor
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ABSTRACT: The mitochondrial production of reactive oxygen species has been implicated in the anticancer activity of furanonaphthoquinone. However, the mechanism of the activation remains elusive. In the current study, we found that treatment of HeLa cells with 2-methyl-5(or -8)-hydroxy-furanonaphthoquinone (FNQ13) induces mitochondrial swelling, followed by apoptosis. This toxic effect of FNQ13 was reduced by the radical scavengers alpha-tocopherol and trolox. Cytochemical experiments in isolated mitochondria showed that a combination of FNQ13 and NADH induces the production of H(2)O(2) at the exterior mitochondrial membrane surface. This production of H(2)O(2) was reduced by an antibody to the voltage-dependent anion channel (VDAC). Overexpression of the VDAC by transfection with vdac1 cDNA increased the production of H(2)O(2) by HeLa cells, whereas transfection with a small interfering RNA to VDAC reduced FNQ13-induced H(2)O(2) production and cell death due to an almost complete knockdown of VDAC expression. We also found significant correlations between the expression of VDAC and the induction of H(2)O(2) production and cell death by FNQ13 in 11 human cancer cell lines. These results indicate that the anticancer activity of furanonaphthoquinones depends on the production of reactive oxygen species by mitochondrial permeability transition pores including the VDAC.
Cancer biology & therapy 12/2006; 5(11):1523-9. · 2.64 Impact Factor
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ABSTRACT: The mechanisms of the antitumor reactions of 2-methylnaphtho[2,3-b]furan-4,9-dione (FNQ3) to human lung adenocarcinoma A549 cells were investigated. A549 cells that received 1.25 microg/ml FNQ3 (IC(50) at 0.35 microg/ml) developed intensive mitochondrial H(2)O(2) production at 1 h. Selective structural mitochondrial swelling, alteration of mitochondrial membrane potential, and cytochrome c and caspase-9 release from the mitochondria occurred 18-24 h later. alpha-Tocopherol inhibited the alteration of both mitochondrial permeability and the leakage of procaspase-9. The caspase-9 was then activated in the cytosol. The expression of Bcl-2 oncoprotein was suppressed by FNQ3, and resulted in apoptosis. The higher dose of 5 microg/ml induced necrosis via severe mitochondrial breakage. These results showed that FNQ3 targets the mitochondria of A549 cells to produce a reactive oxygen species resulting in apoptosis and necrosis.
Cancer Detection and Prevention 02/2003; 27(1):5-13. · 2.52 Impact Factor
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ABSTRACT: We examined the paraquat detoxicative system in mouse livers. The survival rate of mice receiving 50 mg/kg paraquat was 41% at 7 days and significantly rose to 88, 64, 69% with pretreatment with phenytoin, phenobarbital, and rifampicin, respectively. Phenytoin induced activity in NADPH-cytochrome P450 reductase, CYP3A, CYP2B, and CYP2C that was 3 to 4 times higher than that of the controls. Phenobarbital induced CYP2B and rifampicin induced CYP3A, respectively, in addition to NADPH-cytochrome P450 reductase. 3-Methylcholanthrene did not induce these enzymes and did not alter the survival rate. All the mice pretreated with CoCl(2) (a CYP synthesis inhibitor) or SKF 525-A (a CYP inhibitor) were dead after 5 days, and troleandomycin (a CYP3A-specific inhibitor) also reduced the survival rate. When cell homogenates were incubated with paraquat and NADPH, paraquat decreased and its metabolic intermediate paraquat-monopyridone was formed. Troleandomycin inhibited the decrease in paraquat and increased the monopyridone. After making a subfraction of the homogenate, monopyridone was produced in the postmicrosomal 105,000g supernatant, but not in the microsomes. The pretreatment of mice with phenytoin decreased the monopyridone in the postmitochondrial fraction, but did not affect the supernatant. These results indicated that paraquat was first metabolized in the postmicrosomal supernatant into monopyridone, and that may have been subsequently hydroxylated by the microsomes. Repeated intravenous injections of alpha-tocopherol to paraquat-loaded mice significantly reduced the paraquat mortality and when these mice were pretreated with rifampicin, 100% of them survived. These studies demonstrate that postmitochondrial fractions play an important role in paraquat detoxication metabolism, and that the combination of CYP induction and alpha-tocopherol administration is highly useful for the survival of paraquat-exposed mice.
Archives of Biochemistry and Biophysics 07/2002; 402(1):149-57. · 2.93 Impact Factor
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ABSTRACT: The possible protection of cultured human cells from acute dioxin injury by antioxidants was investigated. The most potent dioxin, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), caused vacuolization of the smooth endoplasmic reticulum and Golgi apparatus in cultured human conjunctival epithelial cells and cervical cancer cells. Subsequent nuclear damage included a deep irregular indentation resulting in cell death. A dosage of 30-40 ng/mL TCDD induced maximal intracellular production of H2O2 at 30 minutes and led to severe cell death (0-31% survival) at two hours. A dose of 1.7 mM alpha-tocopherol or 1 mM L-dehydroascorbic acid significantly protected human cells against acute TCDD injuries (78-97% survivals), but vitamin C did not provide this protection. These results indicate that accidental exposure to fatal doses of TCDD causes cytoplasmic free radical production within the smooth endoplasmic reticular systems, resulting in severe cytotoxicity, and that vitamin E and dehydroascorbic acid can protect against TCDD-induced cell damage.
International Journal for Vitamin and Nutrition Research 06/2002; 72(3):147-53. · 0.88 Impact Factor
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ABSTRACT: The cell spreading ability of human lung cancer cells on collagen substrata was examined in comparison with normal human tracheal epithelial cells. Plastic dishes or multiwells were coated with type I, III or IV collagen gel at a concentrate of 200 g/cm2. Ninety per cent of the normal cells were round on all collagens. Adenocarcinoma RERF-LC-MS and VMRC-LCD cell lines and squamous cell carcinoma VMRC-LCP cell line, which metastasize weakly after intrasplenic transplantation in nude mice, spread relatively poorly. Adenocarcinoma, A549 and SK-LU-1 and squamous cell carcinoma Calu-1 cell lines, which were highly metastatic to liver, spread well. Adenocarcinoma ABC-1 cell line, which is moderately metastatic to liver in nude mice, spread moderately. On type III collagen, three adenocarcinoma cell lines (A549, ABC-1 and VMRC-LCD) gradually started to contract after initial spreading and became round at 24 h. These results suggest that there may be a correlation between the degree of malignancy of human lung cancer cells and their spreading ability on collagen substrata, and that the cell spreading ability may be regulated by type III collagen in some lung cancer cells.
Clinical and Experimental Metastasis 10/1991; 9(6):517-527. · 3.52 Impact Factor
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ABSTRACT: Regeneration of the sciatic nerve in transplanted nerve grafts in which laminin was inactivated was examined electron microscopically. Nerve grafts for transplantation were obtained from close cloned donor Wistar rats; 1-cm nerve segments of the sciatic nerve were frozen and thawed to kill the Schwann cells. Control recipient rats received grafts treated with normal rabbit serum to repair the artificially-made complete defect of the right sciatic nerve, and the experimental group of rats received grafts doubly treated with normal serum and rabbit anti-laminin antiserum. In the control grafts regenerating axons grew almost completely through the inside of the basal lamina scaffolds (92%) and adhered to the structure, while in the anti-laminin antiserum treated grafts the axons were present outside (52%) and inside (48%) the scaffolds simultaneously. In this case, the adhesion of axons to the scaffolds was obscure. Axons were associated with and without Schwann cells both inside and outside the basal lamina scaffolds. No unassociated Schwann cells were observed. The maximal number of axons in a 2 mm portion of the antiserum-treated grafts was approximately 250 axons per 100 × 100 μm square and 520 in the control at 15 days. At 30 days, almost the same number of axons was found at the distal (8 mm) portion of both groups. The growth in the former was delayed for 3 days. These results indicate that regenerating peripheral nerve axons may enter the basal lamina scaffolds and grow well because of the neurotrophic function of laminin present at the inner side of Schwann cell basal lamina.
Brain Research.
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ABSTRACT: Wistar rats (close cloned strain) were used to investigate the effect of endogenous laminin and fibronectin on axons, Schwann cells and perineurial cells in the regenerating peripheral nervous system (PNS). Sciatic nerve grafts obtained from donor rats were frozen, thawed and treated with rabbit anti-rat laminin or anti-fibronectin antiserum. Control grafts were treated with normal rabbit serum alone. One cm long portions of the sciatic nerve of the recipient rats were replaced with grafts. At 15 days after transplantation the number of regenerated axons in the laminin- and fibronectin-depleted grafts was half of that in the control. The growing axons in the laminin-depleted grafts did not recognize the basal lamina scaffolds (BLS) remaining in the basal lamina tubes, while in the control and fibronectin-depleted grafts 90% or more of axons grew inside the BLS. Elongation of axons always preceded migration of Schwann cells with the lattter subsequently adhering to and wrapping around the former. Perineurium-forming fibroblastic cells recognized the combination of axons and Schwann cells and formed perineurial fasciculi around them. These fibroblastic cells did not recognize empty BLS but responded to them only when fibronectin was depleted. Macrophages sometimes closely faced the naked axons which elongated outside the BLS. These results suggest that in the early stages of nerve regeneration endogenous laminin and fibronectin not only regulate the growth of regenerating nerve fibers, but also exert a positive influence on perineurial cells and macrophages, both of which play important roles in nerve tissue injury and repair.
Brain Research.
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ABSTRACT: Although the intracellular toxic sites of paraquat, a herbicide toxic to human bodies, have remained unclear for a long time, we recently demonstrated paraquat-induced mitochondrial injury in rat lung and liver in vivo . In the present study, cultured human lung cells (A549 adenocarcinoma cell line) which received 0.15 mM paraquat (equivalent to 40 mg/kg i.v.) showed selective mitochondrial breakage at 6–24 hr and died at 36–48 hr. These results suggest that mitochondria are the initial toxic site of paraquat in vitro as well as in vivo in contrast to the previously proposed microsome theory.
