In the subgranular zone (SGZ) of the hippocampus, neurogenesis persists throughout life and is upregulated following ischemia. Accumulating evidence suggests that enhanced neurogenesis stimulated by ...ischemic injury contributes to recovery after stroke. However, the mechanisms underlying the upregulation of neurogenesis are unclear. We have demonstrated that a neuropeptide, pituitary adenylate cyclase-activating polypeptide (PACAP), exerts a wide range of effects on neural stem cells (NSCs) during neural development. Here, we examined the effects of endogenous and exogenous PACAP in adult NSCs of the SGZ. Immunostaining showed expression of the PACAP receptor PAC1R in nestin-positive NSCs of adult naive mice. PACAP injection into the lateral ventricle increased bromodeoxyuridine (BrdU)-positive proliferative cells in the SGZ. These data suggest that PACAP promoted the proliferation of NSCs. In global ischemia model mice, the number of BrdU-positive cells was increased in wild-type mice but not in PACAP heterozygous knockout mice. The BrdU-positive cells that increased in number after ischemia were immunopositive for SOX2, a marker of NSCs, and differentiated into NeuN-positive mature neurons at 4 weeks after ischemia. These findings suggest that PACAP contributes to the proliferation of NSCs and may be associated with recovery after brain injury.
Osteoarthritis （OA） is the most common joint disease associated with articular cartilage destruction. Matrix metalloproteinase-13 （MMP-13） and a disintegrin and thrombospondin motif-5 （ADAMTS-5）, ...which are enzymes that degrade the extracellular matrix, promote OA pathogenesis. We have recently shown that hydrogen peroxide-inducible clone-5 （Hic-5）, a mechanical stress-responsive adaptor molecule, promotes OA by inducing the expression of MMP-13 and ADAMTS-5 in chondrocytes in response to proinflammatory cytokines and mechanical stress. In this review, we discuss the potential of Hic-5 to be a therapeutic target for OA and the relevance of the focal adhesion molecules vinculin and talin to OA using single-cell data.
Abstract Objectives Hepcidin-25 serves as a key peptide in the regulation of iron homeostasis and inflammation. It remains unknown whether hepcidin-25 plays an adverse role in atherosclerotic ...diseases. The aim of this study was to investigate whether hepcidin-25 is involved in the pathophysiology of coronary plaque vulnerability. Methods and Results Serum hepcidin-25 levels were quantitatively determined by the LC–MS/MS assay system. Peripheral blood was collected from patients with acute myocardial infarction (MI, n = 33) and patients with stable angina pectoris (sCAD, n = 19). The levels of hepcidin-25, IL-6, and CRP were significantly higher in the patients with acute MI than in the patients with sCAD. Coronary blood was aspirated from the culprit arteries via a thrombectomy catheter in 16 of the MI patients. Serum from the aspirates contained higher levels of hepcidin-25 and IL-6 compared with the peripheral blood. In immunohistochemical staining, the macrophages of the plaques in the solid component of the aspirates were immunoreactive for hepcidin-25. To confirm the clinical observation, an in vitro study was performed using human macrophages and coronary endothelial cells. The hepcidin gene and protein were detected in the cultured macrophages but not in the endothelial cells. Hepcidin-25 exposure induced ferroportin degradation and reduced the survival rate of endothelial cells. Conclusions The results of the present study demonstrated that circulating hepcidin-25 and IL-6 were both elevated in the acute phase of MI and that hepcidin-25 released from plaque macrophages and other cell sources contributed to the plaque instability by inducing endothelial cell death.
Objectives: To determine whether decreased serum insulin‐like growth factor‐1 (IGF‐1) levels could be a risk factor for dementia in older people.
Design: Case control study.
Setting: Showa University ...Karasuyama Hospital, Tokyo, Japan.
Participants: A total of 436 Japanese elderly subjects: 106 patients with Alzheimer's disease (AD), 103 patients with vascular dementia (VaD), and 227 age‐matched controls without dementia.
Mesurements: Serum concentrations of IGF‐1 and atherogenic lipoproteins, carotid artery intima‐media thickness (IMT), and plaques were determined.
Results: Mini‐Mental State Examination (MMSE) scores were positively correlated with serum IGF‐1 concentrations as well as mean blood pressure or body mass index and were negatively correlated with age, serum low‐density lipoprotein cholesterol and lipoprotein(a) concentrations, and carotid IMT. Serum IGF‐1 concentrations had a significant inverse correlation with carotid IMT. Analysis across the IGF‐1 quartiles revealed a threshold effect of low IGF‐1 on MMSE score in subjects with the IGF‐1 levels of 140 ng/mL or less (50% percentile) versus those with IGF‐1 levels greater than 140 ng/mL. Multiple logistic regression concerning AD and VaD retained serum IGF‐1 concentrations of 140 ng/mL or less and carotid IMT of 0.9 mm or more. Patients with AD and VaD had significantly lower IGF‐1 concentrations and greater mean IMT than nondemented controls.
Conclusion: These results suggest that decreased serum IGF‐1 level and the progression of carotid atherosclerosis could play a role as independent risk factors for dementia.
The COS-7 (CV-1 in Origin with SV40 genes) cells are known as non-steroidogenic cells because they are derived from kidney cells and the kidney is defined as a non-steroidogenic organ. Therefore, ...COS-7 cells are used for transfection experiments to analyze the actions of functional molecules including steroids. However, a preliminary study suggested that COS-7 cells metabolize
Htestosterone to
Handrostenedione. These results suggest that COS-7 cells are able to metabolize steroids. Therefore, the present study investigated the expression of steroidogenic enzymes and the metabolism of steroids in COS-7 cells. RT-PCR analyses demonstrated the expressions of several kinds of steroidogenic enzymes, such as cytochrome P450 side-chain cleavage enzyme, 3β-hydroxysteroid dehydrogenase/Δ
-Δ
isomerase, cytochrome P450 7α-hydroxylase, cytochrome P450 17α-hydroxylase/17,20-lyase, 17β-hydroxysteroid dehydrogenase, 5α-reductase, cytochrome P450 21-hydroxylase, cytochrome P450 11β-hydroxylase, and cytochrome P450 aromatase in COS-7 cells. In addition, steroidogenic enzymes 3β-HSD, P4507α, 5α-reductase, P450c17, P450c21, P450c11β, and 17β-HSD actively metabolized various steroids in cultured COS-7 cells. Finally, we demonstrated that 17β-HSD activity toward androstenedione formation was greater than other steroidogenic enzyme activities. Our results provide new evidence that COS-7 cells express a series of steroidogenic enzyme mRNAs and actively metabolize a variety of steroids.
Calpains are Ca
2+
-dependent intracellular proteases that play central roles in the post-translational processing of functional proteins. In mammals, calpain proteolytic systems comprise the ...endogenous inhibitor calpastatin as well as 15 homologues of the catalytic subunits and two homologues of the regulatory subunits. Recent pharmacological and gene targeting studies in experimental animal models have revealed the contribution of conventional calpains, which consist of the calpain-1 and -2 isozymes, to atherosclerotic diseases. During atherogenesis, conventional calpains facilitate the CD36-dependent uptake of oxidized low-density lipoprotein (LDL), and block cholesterol efflux through ATP-binding cassette transporters in lesional macrophages, allowing the expansion of lipid-enriched atherosclerotic plaques. In addition, calpain-6, an unconventional non-proteolytic calpain, in macrophages reportedly potentiates pinocytotic uptake of native LDL, and attenuates the efferocytic clearance of apoptotic and necrotic cell corpses from the lesions. Herein, we discuss the recent progress that has been made in our understanding of how calpain contributes to atherosclerosis, in particular focusing on macrophage cholesterol handling.
1 Department of Biochemistry and 2 Department of Anatomy I, Showa University School of Medicine, Tokyo, Japan
Submitted 16 April 2008
; accepted in final form 22 November 2008
Leptin is an adipose ...tissue-derived hormone implicated in atherosclerosis and macrophage foam cell formation. The current study was conducted to examine the effect of leptin on cholesteryl ester accumulation in human monocytes/macrophages. Exogenously added leptin at 5 nM during differentiation of monocytes into macrophages for 7 days accelerated acetylated LDL (acetyl-LDL)-induced cholesteryl ester accumulation by 30–50%. Leptin did not affect endocytic uptake of acetyl-LDL; however, it increased ACAT activity 1.8-fold and ACAT-1 protein expression 1.9-fold. Among the four ACAT-1 mRNA transcripts, two shorter transcripts (2.8 and 3.6 kb) were upregulated 1.7-fold upon leptin treatment. The enhanced expression of ACAT-1 protein by leptin was suppressed by inhibitors of Janus-activated kinase2 (JAK2) and phosphatidylinositol 3-kinase (PI3K). HDL-mediated cholesterol efflux was suppressed by leptin, which was canceled by K-604, an ACAT-1 inhibitor. Expression of long form of leptin receptor was upregulated during monocytic differentiation into macrophages and sustained after differentiation. Thus, the results suggest that leptin accelerates cholesteryl ester accumulation in human monocyte-derived macrophages by increasing ACAT-1 expression via JAK2 and PI3K, thereby suppressing cholesterol efflux.
leptin receptor; acyl-coenzyme A:cholesterol acyltransferase-1; acyl-coenzyme A:cholesterol acyltransferase inhibitor; atherosclerosis
Address for reprint requests and other correspondence: S. Hongo, Dept. of Biochemistry, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan (e-mail: shongo{at}med.showa-u.ac.jp )
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