57 research outputs found
The Role of PPARs in Cancer
Peroxisome proliferator-activated receptors (PPARs) are ligand-activated
transcription factors that belong to the nuclear hormone receptor superfamily.
PPARĪ± is mainly
expressed in the liver, where it activates fatty acid catabolism. PPARĪ± activators have been used to treat dyslipidemia, causing a reduction in plasma triglyceride
and elevation of high-density lipoprotein cholesterol. PPARĪ“ is expressed ubiquitously and is
implicated in fatty acid oxidation and keratinocyte differentiation. PPARĪ“ activators
have been proposed for the treatment of metabolic disease. PPARĪ³2 is expressed
exclusively in adipose tissue and plays a pivotal role in adipocyte differentiation.
PPARĪ³ is involved in glucose metabolism through the improvement of insulin sensitivity
and represents a potential therapeutic target of type 2 diabetes. Thus PPARs are molecular
targets for the development of drugs treating metabolic syndrome. However, PPARs also play
a role in the regulation of cancer cell growth. Here, we review the function of PPARs in tumor
growth
Inverse electron demand asymmetric cycloadditions of cyclic carbonyl ylides catalyzed by chiral Lewis acids-Scope and limitations of diazo and olefinic substrates
High enantioselectivities (94ā96% ee) were obtained for the inverse electron-demand 1,3-dipolar cycloadditions between cyclohexyl vinyl ether and 2-benzopyrylium-4-olate generated via Rhā(OAc)ā-catalyzed decomposition of o-methoxycarbonyl-Ī±-diazoacetophenone. The reactions were effectively catalyzed by Eu(OTf)ā, Ho(OTf)ā, or Gd(OTf)ā complexes (10 mol %) of chiral 2,6-bis[(4S,5S)-4,5-diphenyl-2-oxazolinyl]pyridine. The reactions with the other electron-rich dipolarophiles such as allyl alcohol, 2,3-dihydrofuran, and butyl-tert-butyldimethylsilylketene acetal showed moderate enanantioselectivities (60ā73% ee). Good to high enantioselectivities (73ā97% ee) were also obtained for the cycloadditions between 3-acyl-2-benzopyrylium-4-olates, generated from methyl 2-(2-diazo-1,3-dioxoalkyl)benzoates and butyl or cyclohexyl vinyl ethers, in the presence of binaphthyldiimine (BINIM)āNi(II) complexes (10 mol %). Under similar conditions, the reaction between methyl 2-(2-diazo-1,3-dioxohexyl)benzoate and 2,3-dihydrofuran was highly endo-selective, and moderately enantioselective (70% ee). For the BINIMāNi(II)-catalyzed reactions of cyclohexyl vinyl ether, the use of an epoxyindanone as the 3-acyl-2-benzopyrylium-4-olate precursor revealed that the chiral Lewis acid can function as a catalyst for asymmetric induction. The scope of the cyclic carbonyl ylides was extended to those generated from 1-diazo-2,5-pentanedione derivatives, which were reacted with butyl or TBS vinyl ether and catalyzed using the (4S,5S)-Pybox-4,5-PhāāLu(OTf)ā complex to give good levels of asymmetric inductions (75ā84% ee).ArticleTetrahedron. 66(16):3070-3089 (2010)journal articl
Low magnetic field promotes recombinant human BMP-2-induced bone formation and influences orientation of trabeculae and bone marrow-derived stromal cells
Effects of high magnetic fields [MFs, ā„ 1 T (T)] on osteoblastic differentiation and the orientation of cells or matrix proteins have been reported. However, the effect of low MFs (< 1 T) on the orientation of bone formation is not well known. This study was performed to verify the effects of low MFs on osteoblastic differentiation, bone formation, and orientation of both cells and newly formed bone. An apparatus was prepared with two magnets (190 mT) aligned in parallel to generate a parallel MF. In vitro, bone marrow-derived stromal cells of rats were used to assess the effects of low MFs on cell orientation, osteoblastic differentiation, and mineralization. A bone morphogenetic protein (BMP)-2-induced ectopic bone model was used to elucidate the effect of low MFs on microstructural indices, trabecula orientation, and the apatite c-axis orientation of newly formed bone. Low MFs resulted in an increased ratio of cells oriented perpendicular to the direction of the MF and promoted osteoblastic differentiation in vitro. Moreover, in vivo analysis demonstrated that low MFs promoted bone formation and changed the orientation of trabeculae and apatite crystal in a direction perpendicular to the MF. These changes led to an increase in the mechanical strength of rhBMP-2-induced bone. These results suggest that the application of low MFs has potential to facilitate the regeneration of bone with sufficient mechanical strength by controlling the orientation of newly formed bone.Okada R., Yamato K., Kawakami M., et al. Low magnetic field promotes recombinant human BMP-2-induced bone formation and influences orientation of trabeculae and bone marrow-derived stromal cells. Bone Reports, 14, 100757. https://doi.org/10.1016/j.bonr.2021.100757
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Mitochondrial Abnormality Facilitates Cyst Formation in Autosomal Dominant Polycystic Kidney Disease
ABSTRACT Autosomal dominant polycystic kidney disease (ADPKD) constitutes the most inherited kidney disease. Mutations in the PKD1 and PKD2 genes, encoding the polycystin 1 and polycystin 2 Ca2+ ion channels, respectively, result in tubular epithelial cell-derived renal cysts. Recent clinical studies demonstrate oxidative stress to be present early in ADPKD. Mitochondria comprise the primary reactive oxygen species source and also their main effector target; however, the pathophysiological role of mitochondria in ADPKD remains uncharacterized. To clarify this function, we examined the mitochondria of cyst-lining cells in ADPKD model mice (Ksp-Cre PKD1flox/flox) and rats (Han:SPRD Cy/+), demonstrating obvious tubular cell morphological abnormalities. Notably, the mitochondrial DNA copy number and peroxisome proliferator-activated receptor Ī³ coactivator 1Ī± (PGC-1Ī±) expression were decreased in ADPKD model animal kidneys, with PGC-1Ī± expression inversely correlated with oxidative stress levels. Consistent with these findings, human ADPKD cyst-derived cells with heterozygous and homozygous PKD1 mutation exhibited morphological and functional abnormalities, including increased mitochondrial superoxide. Furthermore, PGC-1Ī± expression was suppressed by decreased intracellular Ca2+ levels via calcineurin, p38 mitogen-activated protein kinase (MAPK), and nitric oxide synthase deactivation. Moreover, the mitochondrion-specific antioxidant MitoQuinone (MitoQ) reduced intracellular superoxide and inhibited cyst epithelial cell proliferation through extracellular signal-related kinase/MAPK inactivation. Collectively, these results indicate that mitochondrial abnormalities facilitate cyst formation in ADPKD
Two Distinct Mechanisms Underlying Ī³Ī“ T Cell-Mediated Regulation of Collagen Type I in Lung Fibroblasts
Idiopathic pulmonary fibrosis is a chronic intractable lung disease, leading toćrespiratory failure and death. Although anti-fibrotic agents delay disease progression, they are not considered curative treatments, and alternative modalities have attracted attention. We examined the effect of human Ī³Ī“ T cells on collagen type I in lung fibroblasts. Collagen type I was markedly reduced in a Ī³Ī“ T cell number-dependent manner following treatment with Ī³Ī“ T cells expanded with tetrakis-pivaloxymethyl 2-(thiazole-2-ylamino) ethylidene-1,1-bisphosphonate (PTA) and interleukin-2. Collagen type I levels remained unchanged on addition of Ī³Ī“ T cells to the culture system through a trans-well culture membrane, suggesting that cellācell contact is essential for reducing its levels in lung fibroblasts. Re-stimulating Ī³Ī“ T cells with (E)-4-hydroxy-3-methylbut-2-enyl diphosphate (HMBPP) reduced collagen type I levels without cellācell contact, indicating the existence of HMBPP-induced soluble anti-fibrotic factors in Ī³Ī“ T cells. Adding anti-interferon-Ī³ (IFN-Ī³)-neutralizing mAb restored collagen type I levels, demonstrating that human Ī³Ī“ T cell-derived IFN-Ī³ reduces collagen type I levels. Conversely, interleukin-18 augmented Ī³Ī“ T cell-induced suppression of collagen type I. Therefore, human Ī³Ī“ T cells reduce collagen levels in lung fibroblasts via two distinct mechanisms; adoptive Ī³Ī“ T cell transfer is potentially a new therapeutic candidate
Novel SPEF2 Variant in a Japanese Patient with Primary Ciliary Dyskinesia: A Case Report and Literature Review
Primary ciliary dyskinesia (PCD) is a genetic and congenital disease associated with an abnormal ciliary ultrastructure and function and is estimated to affect 1 in 15,000ā20,000 individuals. A PCD diagnosis can be achieved by genotyping. Here, we performed whole-exome analysis for the diagnosis of PCD and described the detailed clinical characteristics of the case. A 39-year-old Japanese woman with sinusitis and bronchiectasis without situs inversus had had upper and lower respiratory symptoms since childhood and had received long-term macrolide therapy without an accurate diagnosis. A moderate deterioration of cilia function was observed by high-speed video microscopy analysis; additionally, the number of cells with moving cilia was fewer than that in patients without PCD. Electron microscopy revealed no apparent structural abnormalities. We performedwhole-exome analysis and identified novel biallelic variants of SPEF2 in the homozygous state (c.1860_1861insCT).We confirmed the absence of SPEF2 protein expression in the cilia of the nasal mucosa using fluorescent immunostaining. Accordingly, she was diagnosed as having PCD with the SPEF2 variant. The present case suggests that the deterioration of cilia function is moderate, the number of respiratory cells with moving cilia might be reduced, and the respiratory condition could be severe in patients with PCD with the SPEF2 variant
Inverse electron demand asymmetric cycloadditions of cyclic carbonyl ylides catalyzed by chiral Lewis acidsāScope and limitations of diazo and olefinic substrates
Imaging evaluation of continuous extrapleural intercostal nerve block for minimally invasive cardiac surgery: a case report
Abstract Background Spinal nerve block is difficult with minimally invasive cardiac surgery (MICS), because of the risk of serious bleeding complications due to full heparinization. Continuous extrapleural intercostal nerve block (CEINB) is a postoperative pain treatment for intercostal thoracotomy, with fewer complications. Here, we report a case in which imaging evaluation of CEINB with contrast medium was conducted to anatomically confirm the spread of local anesthetics after MICS. Case presentation A 65-year-old woman with severe mitral regurgitation underwent mitral valve plasty under general anesthesia via right-sided mini-thoracotomy. A CEINB catheter was placed before the incision was closed, without creating a conventional extrapleural pocket. We conducted an imaging evaluation with a contrast medium via the inserted catheter and confirmed sufficient spread around the intercostal nerve area. In addition, postoperative pain was well controlled by the nerve block. Conclusions Imaging evaluation of CEINB with contrast medium could increase analgesic quality and decrease complications post-MICS
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