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101.
102.
Tokuhiro K Ikawa M Benham AM Okabe M 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(10):3850-3855
A disintegrin and metalloproteinase 3 (ADAM3) is a sperm membrane protein critical for both sperm migration from the uterus into the oviduct and sperm primary binding to the zona pellucida (ZP). Here we show that the testis-specific protein disulfide isomerase homolog (PDILT) cooperates with the testis-specific calreticulin-like chaperone, calsperin (CALR3), in the endoplasmic reticulum and plays an indispensable role in the disulfide-bond formation and folding of ADAM3. Pdilt(-/-) mice were male infertile because ADAM3 could not be folded properly and transported to the sperm surface without the PDILT/CALR3 complex. Peculiarly we find that not only Pdilt(-/-), but also Adam3(-/-), spermatozoa effectively fertilize eggs when the eggs are surrounded in cumulus oophorus. These findings reveal that ADAM3 requires testis-specific private chaperones to be folded properly and that the principle role of ADAM3 is for sperm migration into the oviduct but not for the fertilization event. Moreover, the importance of primary sperm ZP binding, which has been thought to be a critical step in mammalian fertilization, should be reconsidered. 相似文献
103.
Hashizume O Shimizu A Yokota M Sugiyama A Nakada K Miyoshi H Itami M Ohira M Nagase H Takenaga K Hayashi J 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(26):10528-10533
It has been hypothesized that respiration defects caused by accumulation of pathogenic mitochondrial DNA (mtDNA) mutations and the resultant overproduction of reactive oxygen species (ROS) or lactates are responsible for aging and age-associated disorders, including diabetes and tumor development. However, there is no direct evidence to prove the involvement of mtDNA mutations in these processes, because it is difficult to exclude the possible involvement of nuclear DNA mutations. Our previous studies resolved this issue by using an mtDNA exchange technology and showed that a G13997A mtDNA mutation found in mouse tumor cells induces metastasis via ROS overproduction. Here, using transmitochondrial mice (mito-mice), which we had generated previously by introducing G13997A mtDNA from mouse tumor cells into mouse embryonic stem cells, we provide convincing evidence supporting part of the abovementioned hypothesis by showing that G13997A mtDNA regulates diabetes development, lymphoma formation, and metastasis--but not aging--in this model. 相似文献
104.
105.
Shiro Matsubara Koichi Kondo Keizo Sugaya Kazuhito Miyamoto 《Clinical rheumatology》2012,31(10):1493-1498
Dermatomyositis (DM) and polymyositis (PM) are often refractory to conventional therapy with corticosteroids sometimes combined with immune-suppressing agents and can lead to severe disability if these treatments are unsuccessful. In this prospective, open, non-randomized study, we examined the efficacy of tacrolimus (FK506), an immunosuppressant, in nine patients with DM (n?=?5) or PM (n?=?4) who did not respond to previous therapy. Outcomes included compound muscle strength, ambulatory status, and serum creatine kinase activity measured at intervals after starting tacrolimus. At 6?months after the introduction of tacrolimus, all five patients with DM and three patients with PM showed clinical improvements. Patients with a disease duration of <4?years and those with trough level of tacrolimus >5?ng/ml tended to have better outcomes than those with longer disease duration or lower trough levels. There were no side effects other than moderate hypertension and aggravation of diabetes mellitus. Tacrolimus was beneficial in the majority of patients with PM or DM refractory to corticosteroid therapy. It was also effective in four patients who were previously treated with other immunosuppressants or intravenous immunoglobulin combined with corticosteroids. These results warrant further studies as to the efficacy of tacrolimus compared to other immunosuppressing agents. 相似文献
106.
Akira Shimada Tomohiko Taki Daisuke Koga Ken Tabuchi Akio Tawa Ryoji Hanada Masahiro Tsuchida Keizo Horibe Ichiro Tsukimoto Souichi Adachi Seiji Kojima Yasuhide Hayashi 《International journal of hematology》2012,96(4):469-476
The prognostic value of WT1 mRNA expression in pediatric acute myeloid leukemia (AML) remains controversial. A sample of newly diagnosed (n?=?158) AML patients from the Japanese Childhood AML Cooperative Treatment Protocol, AML 99, were simultaneously analyzed for WT1 expression, cytogenetic abnormalities and gene alterations (FLT3, KIT, MLL, and RAS). WT1 expression (including more than 2,500 copies/??gRNA) was detected in 122 of the 158 (77.8?%) initial diagnostic AML bone marrow samples (median 45,500 copies/??gRNA). Higher WT1 expression was detected in French American British (FAB)-M0, M3, M7 and lower expression in M4 and M5. Higher WT1 expression was detected in AML with inv(16), t(15;17) and Down syndrome and lower in AML with 11q23 abnormalities. Multivariate analyses demonstrated that FLT3-internal tandem duplication (ITD), KIT mutation, MLL-partial tandem duplication were correlated with poor prognosis; however, higher WT1 expression was not. FLT3-ITD was correlated with WT1 expression and prognosis. Furthermore, 74 WT1 expression after induction chemotherapy was analyzed. Higher WT1 expression after induction chemotherapy was significantly correlated with M1 or M2/M3 marrow, FLT3-ITD and poor prognosis. Multivariate analyses in 74 AML patients revealed that FLT3-ITD, MLL-PTD, and KIT mutations were associated with poor prognosis; however, NRAS Mutation, KRAS mutation and high WT1 expression (>10,000 copies/??gRNA) did not show poor prognosis. Our findings suggest that higher WT1 expression at diagnosis does not correlate with poor prognosis, but that WT1 expression after induction chemotherapy is considered to be a useful predictor of clinical outcome in pediatric AML. 相似文献
107.
Hirokazu Kakuda Keizo Kanasaki Daisuke Koya Noboru Takekoshi 《Clinical and experimental nephrology》2013,17(2):240-247
Background
Chronic kidney disease (CKD) is a serious health problem worldwide. Therapies that can halt the progression of CKD are limited, and the identification of new strategies for CKD treatment is therefore important. Pitavastatin, one of the newest statins introduced to the market, has been shown to exhibit some beneficial effects on renal and endothelial function.Method
We enrolled 12 healthy volunteers for our study. With or without pitavastatin administration, creatinine clearance (Ccr), urinary albumin excretion, lipid status, and oxidative stress markers were evaluated in acute and early phases after administration of the drug.Results
A single pitavastatin administration increased Ccr and reduced oxidative stress parameters, such as 8-OHdG levels and isoprostane production, within 6 h, without altering lipid status in healthy participants. A two-week treatment with pitavastatin lowered total and LDL cholesterol and triglycerides but not HDL cholesterol at 7 and 14 days. This change in lipid profile is associated with enhanced Ccr and the suppression of oxidative stress parameters. Urinary albumin excretion was reduced after either acute or chronic administration of pitavastatin, although this effect was not yet significant.Conclusion
We found that pitavastatin augmented Ccr and reduced oxidative stress parameters in healthy subjects. These data suggest that pitavastatin affects renal outcomes in both lipid status-dependent and -independent manners. These observations suggest that pitavastatin treatment could be beneficial for CKD patients. 相似文献108.
Fibrillin is a primary component of elastin-associated microfibrils. Since microfibrils are distributed rather ubiquitously in embryonic tissues, attention has focused on the types of cells responsible for producing fibrillin. To clarify this issue, we employed monensin-induced perturbation of secretory activity in embryonic primary cultures, as this would allow examination of both the secreted protein and the formation of extracellular fibrils in the same culture. Micromasses of avian limb bud mesoderm, its ectodermal covering and several explants from other sources were cultured in the presence and absence of monensin, and evaluated immunohistochemically using antibodies against fibrillin and cell lineage markers. The results indicated that monensin perturbation induced intracellular accumulation of fibrillin and prevented the formation of microfibrils. It was shown specifically that not only mesodermally derived fibrogenic cells and myogenic cells of skeletal and smooth muscle cell lineage, but also epithelial-type cells such as endothelial and ectodermal cells, are producers of fibrillin. This dual cellular origin of fibrillin at the ectomesenchymal interface is considered significant for understanding the formation and remodeling of microfibrils originating from the basal lamina. 相似文献
109.
Utsunomiya T Shimada M Rikimaru T Hasegawa H Yamashita Y Hamatsu T Yamasaki M Kaku S Yamada K Sugimachi K 《Hepato-gastroenterology》2003,50(53):1609-1613
BACKGROUND/AIMS: The antioxidant and anti-inflammatory properties of sesamin (a non-fat constituent of sesame oil) have been attributed to an increased accumulation of dihomo-y-linolenic acid, a precursor of 1-series prostaglandins, and the decreasing production of proinflammatory 2-series prostaglandins and 4-series leukotrienes by inhibiting the delta-5 desaturase activity. We investigated the effects of a diet containing sesamin on hepatic ischemia-reperfusion injury in rats. METHODOLOGY: After feeding rats either a basal diet (control group) or a diet supplemented with sesamin (sesamin group) for 14 days, the rats underwent 60 minutes of partial hepatic ischemia and 3 hours of reperfusion. The phospholipid fatty acid composition of both liver and lung tissue specimens were then analyzed. The plasma levels of leukotriene B4 and PCOOH (phosphatidylcholine hydroperoxide) were also determined. RESULTS: The consumption of the dietary sesamin resulted in a significant increase in the dihomo-y-linolenic acid content in the tissue phospholipids of the liver and lung specimens. The amounts of polyunsaturated fatty acids in the lungs subjected to the ischemia-reperfusion injury were well preserved in the animals from the sesamin group. Despite a lack of differences in the levels of arachidonic acid, the plasma levels of leukotriene B4 in the rats fed dietary sesamin (88 +/- 15 pg) tended to be lower (P = 0.07) than those fed the control diet (110 +/- 20 pg). Furthermore, the plasma concentrations of PCOOH in the sesamin group (130 +/- 62 pmol) were also significantly lower (P < 0.05) than those in the control group (223 +/- 33 pmol). CONCLUSIONS: These findings indicate that a diet containing sesamin may thus reduce hepatic ischemia-reperfusion injury by inducing both antioxidant and anti-inflammatory activities. 相似文献
110.
Hidenori Ichiyasu Akiko Yamamura Mitsuko Honda Shinichiro Okamoto Kaori Tsumori Tatsuya Okamoto Keizo Sato Mitsuhiro Matsumoto Hirotsugu Kohrogi 《Nihon Kokyūki Gakkai zasshi》2006,44(10):754-760
A 74-year-old woman was treated with steroid and cyclosporine A for hypersensitivity pneumonia. To examine the causes of general fatigue and increased levels of beta-D glucan in serum, she was admitted to our hospital. Chest computed tomography (CT) scan revealed nodular opacity with a well-defined margin in the right S1. 67Ga scintigraphy image showed high uptake in the left thigh and CT showed circularly enhanced lesions in the thigh. An ultrasonography-guided needle aspiration and biopsy of the muscle abscess allowed isolation of Aspergillus fumigatus and evidence of necrotic tissues around the granuloma formation. We therefore diagnosed invasive aspergillosis. Because of the poor response to initial therapy with micafungin and itraconazole for 4 weeks, we treated her with voliconazole (VCZ). Spectacular regression of lung lesions and muscle abscesses was rapidly achieved. Furthermore, the high level of beta-D glucan in serum decreased gradually. This case suggests that administration of VCZ can be recommended for deep seated mycoses. 相似文献