The Role of Autophagy in Maintaining Pregnancy

Autophagy is an evolutionarily conserved process in eukaryotes by which cytoplasmic cargo sequestered inside double-membrane vesicles is delivered to the lysosome for degradation. In early pregnancy, trophoblasts and the fetus experience hypoxic and low-nutrient conditions; nevertheless, extravillous trophoblasts (EVTs) invade the uterine myometrium up to one-third of its depth and migrate along the lumina of spiral arterioles, replacing the maternal endothelial lining. An enhancement of autophagy induced by physiological hypoxia takes part in the invasion and vascular remodeling in EVTs. On the other hand, soluble endoglin, which increased in sera in preeclamptic cases, suppresses EVT-invasion or -vascular remodeling by inhibiting autophagy In vitro. In addition, a substance selectively degraded by autophagy, p62/SQSTM1, accumulates in EVT cells in preeclamptic placental biopsy samples showing impaired autophagy in vivo. Thus, alternation of autophagy could affect fates of mothers and babies. Recently increasing evidence of modulating autophagy has accumulated during pregnancy. In this chapter, we introduce the role of autophagy in embryogenesis, implantation, and maintaining pregnancy

A securitização da imigração japonesa na Segunda Guerra Mundial: uma análise comparativa entre Brasil e Estados Unidos

O presente artigo tem como objetivo analisar de forma comparativa a securitização que os governos brasileiro e estadunidense perpetuaram contra as populações nipo-brasileira e nipoestadunidense, através de um discurso securitizador e medidas excepcionais que tratavam esses cidadãos como uma ameaça existencial para a segurança nacional e os valores sóciodemocráticos ocidentais. Apresentam-se os fundamentos da teoria da securitização; com a definição dos cinco elementos fundamentais para a ocorrência desse processo. São demonstrados também breves históricos de como o Brasil e os Estados Unidos chegaram à decisão de ―proteger-se‖ contra os japoneses em seus países. Em seguida, são indicadas as medidas excepcionais tomadas contra os japoneses, bem como a forma como se deu a construção de um discurso pejorativo e de ameaça existencial para com esses cidadãos. Por fim, serão evidenciadas as medidas reparadoras (ou falta dessas) que os governos tomaram anos após o ocorrido, bem como de que forma esse tratamento dos japoneses possivelmente afetou essa porção da população em ambos os países

Effects of empagliflozin in patients with chronic kidney disease from Japan: exploratory analyses from EMPA–KIDNEY

Background: EMPA–KIDNEY assessed the effects of empagliflozin 10 mg once daily vs. placebo in 6609 patients with chronic kidney disease (CKD) at risk of progression, including 612 participants from Japan. Methods: Eligibility required an estimated glomerular filtration rate (eGFR) of ≥ 20  Results: Japanese participants had higher levels of albuminuria and eGFR than those from non-Japan regions. During a median of 2.0 year follow-up, a primary outcome occurred in 432 patients (13.1%) in the empagliflozin group and in 558 patients (16.9%) in the placebo group (hazard ratio [HR], 0.72, 95% confidence interval [95%CI] 0.64–0.82; P  Conclusions: Empagliflozin safely reduced the risk of “kidney disease progression or cardiovascular death” in patients with CKD, with consistent effects in participants from Japan

Neutrophil Depletion Exacerbates Pregnancy Complications, Including Placental Damage, Induced by Silica Nanoparticles in Mice

Recent advances in nanotechnology have led to the development of nanoparticles with innovative functions in various fields. However, the biological effects of nanoparticles—particularly those on the fetus—need to be investigated in detail, because several previous studies have shown that various nanoparticles induce pregnancy complications in mice. In this regard, our previous findings in mice suggested that the increase in peripheral neutrophil count induced by treatment with silica nanoparticles with a diameter of 70 nm (nSP70) may play a role in the associated pregnancy complications. Therefore, here, we sought to define the role of neutrophils in nSP70-induced pregnancy complications. The peripheral neutrophil count in pregnant BALB/c mice at 24 h after treatment with nSP70 was significantly higher than in saline-treated mice. In addition, maternal body weight, uterine weight, and the number of fetuses in nSP70-treated mice pretreated with anti-antibodies, which deplete neutrophils, were significantly lower than those in nSP70-treated mice pretreated with phosphate-buffered saline or isotype-matched control antibodies. Histology revealed that neutrophil depletion increased nSP70-induced placental damage from the decidua through the spongiotrophoblast layer and narrowed spiral arteries in the placentae. In addition, depletion of neutrophils augmented nSP70-induced cytotoxicity to fetal vessels, which were covered with endothelium. The rate of apoptotic cell death was significantly higher in the placentae of anti-nSP70-treated mice than in those from mice pretreated with isotype-matched control antibodies. Therefore, impairment of placental vessels and apoptotic cell death due to nSP70 exposure is exacerbated in the placentae of nSP70-treated mice pretreated with anti-antibodies. Depletion of neutrophils worsens nSP70-induced pregnancy complications in mice; this exacerbation was due to enhanced impairment of placental vessels and increased apoptotic cell death in maternal placentae. Our results provide basic information regarding the mechanism underlying silica-nanoparticle-induced pregnancy complications

PDZRN3 Negatively Regulates BMP-2–induced Osteoblast Differentiation through Inhibition of Wnt Signaling

PDZRN3, a member of the PDZ domain–containing RING finger family of proteins plays an important role in negative feedback control of BMP-2–induced osteoblast differentiation in C2C12 mouse mesenchymal progenitor cells through inhibition of Wnt–β-catenin signaling

Regulation of matrix metalloproteinase-13 and tissue inhibitor of matrix metalloproteinase-1 gene expression by WNT3A and bone morphogenetic protein-2 in osteoblastic differentiation

During bone remodeling, degradation of skeletal connective tissue is regulated, at least in part, by the balance between matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinase (TIMPs), their natural inhibitors. Recently, the Wnt signaling pathway has been demonstrated to play a crucial role in the regulation of bone formation. Here, we investigated a potential role for Wnt signaling and functional cross-talk with bone morphogenetic protein (BMP)-2 in mRNA expression of MMPs, TIMPs and bone matrix proteins in pluripotent C2C12 cells. To assess the functional contribution of Wnt signaling, we have generated C2C12 cell lines stably over-expressing Wnt3a or Wnt5a, and then treated these cells with BMP-2 for 24 h. In these cultures, MMP-13 mRNA expression was induced by BMP-2 in Wnt3a over-expressing C2C12 (Wnt3a-C2C12) cells but not in either Wnt5a over-expressing C2C12 (Wnt5a-C2C12) cells or vehicle-transfected C2C12 cells. MMP-13 mRNA was induced in these cells by addition of BMP-2 for 12 h and the enhancement lasted up to 48 h. These effects were observed in a dose-dependent manner. Enzymatic activity of MMP-13 also induced in Wnt3a-C2C12 cells by addition of BMP-2. However, membrane type-1 matrix metalloproteinase (MT1-MMP) and MMP-2 mRNA expression was not affected by either Wnt3a or BMP-2. In contrast, TIMP-1 mRNA expression was suppressed by BMP-2 in Wnt3a-C2C12 cells but not in Wnt5a-C2C12 cells. Our results show that expression of MMP-13 and TIMP-1 is regulated by Wnt signaling combined with BMP-2 in osteoblastic differentiation, and this signaling may in part mediate MMP-13 and TIMP-1 production during bone formation and/or remodeling

Cross-talk between Wnt and bone morphogenetic protein (BMP)- 2 signalling in differentiation pathway of C2C12 myoblasts

Loss of function of the Wnt co-receptor, lipoprotein receptor-related protein 5, decreases bone formation, and a point mutation in this gene results in high bone mass, indicating the importance of this signalling pathway in bone formation. However, the exact mechanism is currently unknown. We examined a potential role for Wnt signalling and functional cross-talk of bone morphogenetic protein (BMP)-2 in osteoblast differentiation. To assess the contribution of Wnt, we generated C2C12 cells overexpressing Wnt3a or Wnt5a and treated these with BMP-2. We showed that expression of matix extracellular phosphoglycoprotein was induced by BMP-2 in Wnt3a over-expressing C2C12 cells but not in Wnt5a over-expressing C2C12 cells. Overexpression of Wnt3a blocked BMP-2-induced inhibition of myotube formation in C2C12 cells when switched to low mitogen medium. In these cultures, expression of inhibitor of DNA binding/differentiation (Id) 1, a basic helix-loop-helix protein induced by BMP-2, decreased in stable Wnt3a, but not Wnt5a, expressing cells. This suppression is mediated by a GC rich region of the BMP-2 responsive element of the Id1 gene promoter and interaction between Smad1/4 and β-catenin is crucial for Wnt-mediated suppression of the BMP-2 response in C2C12 cells. Overexpression of the inhibitor of canonical Wnt signalling, Dickkopf, inhibits this suppression. In contrast, BMP-2 or Smad1/4 up-regulated Wnt3a or activated β-catenin-induced lymphoid enhancing factor 1/T cell factor-dependent transcriptional activity. These findings identify functional cross-talk of Id1 expression between Wnt and BMP signalling and demonstrate a novel mechanism for Wnt regulation of the BMP-2 response, linking Id1 expression to Wnt/β-catenin signalling