Study on Sensing Mechanism of Volatile Organic Compounds Using Pt-Loaded ZnO Nanocrystals.

Understanding the surface chemistry of target gases on sensing materials is essential for designing high-performance gas sensors. Here, we report the effect of Pt-loading on the sensing of volatile organic compounds (VOCs) with ZnO gas sensors, demonstrated by diffuse reflection infrared Fourier transform (DRIFT) spectroscopy. Pt-loaded ZnO nanocrystals (NCs) of 13~22 nm are synthesized using the hot soap method. The synthesized powder is deposited on an alumina substrate by screen-printing to form a particulate gas sensing film. The 0.1 wt% Pt-loaded ZnO NC sensor shows the highest sensor response to acetone and ethanol at 350 °C, while the responses to CO and H2 are small and exhibit good selectivity to VOCs. The gas sensing mechanism of ethanol with Pt-ZnO NCs was studied by in situ DRIFT spectroscopy combined with online FT-IR gas analysis. The results show that ethanol reacts with small Pt-loaded ZnO to produce intermediate species such as acetaldehyde, acetate, and carbonate, which generates a high sensor response to ethanol in air.

Submicroscopic deletions at 13q32.1 cause congenital microcoria.

Congenital microcoria (MCOR) is a rare autosomal-dominant disorder characterized by inability of the iris to dilate owing to absence of dilator pupillae muscle. So far, a dozen MCOR-affected families have been reported worldwide. By using whole-genome oligonucleotide array CGH, we have identified deletions at 13q32.1 segregating with MCOR in six families originating from France, Japan, and Mexico. Breakpoint sequence analyses showed nonrecurrent deletions in 5/6 families. The deletions varied from 35 kbp to 80 kbp in size, but invariably encompassed or interrupted only two genes: TGDS encoding the TDP-glucose 4,6-dehydratase and GPR180 encoding the G protein-coupled receptor 180, also known as intimal thickness-related receptor (ITR). Unlike TGDS which has no known function in muscle cells, GPR180 is involved in the regulation of smooth muscle cell growth. The identification of a null GPR180 mutation segregating over two generations with iridocorneal angle dysgenesis, which can be regarded as a MCOR endophenotype, is consistent with the view that deletions of this gene, with or without the loss of elements regulating the expression of neighboring genes, are the cause of MCOR.

Efficacy of reduced dose of pegfilgrastim in Japanese breast cancer patients receiving dose-dense doxorubicin and cyclophosphamide therapy.

BACKGROUND: This retrospective study aimed to evaluate the efficacy of a 3.6-mg dose of pegfilgrastim for primary prophylaxis in Japanese breast cancer patients receiving dose-dense chemotherapy. METHODS: Patients treated with adjuvant or neoadjuvant chemotherapy for early-stage breast cancer at the Tokyo-West Tokushukai Hospital were included in this analysis. Because 6 mg pegfilgrastim has not yet been approved for use in Japan, we compared the outcomes of a dose-dense doxorubicin and cyclophosphamide regimen plus 3.6 mg pegfilgrastim support with a conventional dose epirubicin and cyclophosphamide regimen. The incidence of febrile neutropenia, relative dose intensity, dose delay, dose reduction, regimen change and hospitalization because of neutropenia were assessed. RESULTS: From November 2013 to March 2016, 97 patients with stage I-III invasive breast cancer were analyzed (dose-dense doxorubicin and cyclophosphamide plus 3.6-mg pegfilgrastim group, n  =  41; epirubicin and cyclophosphamide group, n  =  56; median ages, 49.0 and 48.5 years, respectively). Febrile neutropenia occurred during the first chemotherapy cycle in 7 of 56 patients (12.5%) in the epirubicin and cyclophosphamide group and 0 of 41 patients in the dose-dense doxorubicin and cyclophosphamide group (P  =  0.02). The average relative dose intensities were 97.9% and 96.8%, respectively (P  =  0.28), with corresponding dose delay rates of 4.9% (2/41) and 16.1% (9/56), respectively (P  =  0.11) and dose reduction rates of 0% (0/41) and 7.1% (4/56), respectively (P  =  0.16). CONCLUSIONS: Our results indicate the efficacy of a 3.6-mg pegfilgrastim dose for the primary prevention of febrile neutropenia in dose-dense doxorubicin- and cyclophosphamide-treated Japanese breast cancer patients.

[Factors affecting adherence of breast cancer patients to adjuvant hormonal therapy and validation of the evaluation method].

BACKGROUND: The long-term use of hormonal therapy is important for the treatment of patients with breast cancer. Therefore, we evaluated the methods used for measuring adherence and examined factors that influence compliance. Our goal was to improve overall adherence to the treatment. METHODS: Retrospective analyses by using electronic medical records and questionnaires were performed on 294 patients with breast cancer. The patients were classified into 2 groups based on the mean number of days when a dose was missed over a period of 28 days: group A(range, 0-3 days, n=272)and group B (range, B4 days, n=22). Factors that may influence adherence, including age, duration of hormonal therapy, the drug administered in hormonal therapy, the surgical method, axillary lymph node dissection, and adjuvant chemotherapy, were compared between both groups. RESULTS: The adherence rates calculated from electronic medical records and questionnaires were similar. The proportion of patients younger than 50 years was 30% in group A and 50% in group B(p<0.05). Additionally, there was a difference in the duration of hormone therapy(752 days vs 981 days in groups A and B, respectively; p< 0.05). Additional factors that are related to low-risk cancer-related procedures, such as breast conserving surgery, may also be linked to poor adherence. CONCLUSION: Young age and long duration of hormonal therapy are possibly related to poor adherence. Therefore, pharmacists should identify and manage these patients to increase adherence.

Deletion of the angiotensin II type 1a receptor prevents atherosclerotic plaque rupture in apolipoprotein E-/- mice.

OBJECTIVE: Angiotensin II is involved in the genesis of atherosclerosis. As the role of the angiotensin II type 1a (AT(1a)) receptor in plaque rupture is poorly understood, we assessed the hypothesis that the AT(1a)receptor contributes to atherosclerotic plaque rupture. METHODS AND RESULTS: Atherosclerotic plaque rupture was induced by carotid artery ligation for 4 weeks followed by polyethylene cuff placement around the carotid in apolipoprotein E (ApoE)(-/-) and ApoE(-/-) AT(1a)(-/-) mice. The incidence of plaque rupture at 4 days after cuff placement was 72% in ApoE(-/-) mice compared with 24% in ApoE(-/-) AT(1a)(-/-) mice (P<0.01). Lipid accumulation, macrophage infiltration, expression of inflammatory cytokines, nicotinamide adenine dinucleotide phosphate-oxidase activity, and matrix metalloproteinase-9 activity in atherosclerotic plaque were markedly attenuated in ApoE(-/-) AT(1a)(-/-) compared with ApoE(-/-) mice. Oxidized low-density lipoprotein inhibited macrophage migration in ApoE(-/-) macrophages. In contrast, oxidized low-density lipoprotein-induced macrophage trapping was abolished in ApoE(-/-) AT(1a)(-/-) macrophages, and this was associated with decreased CD36 expression and focal adhesion kinase activity. CONCLUSIONS: Conclusion- These results suggest that blocking the AT(1) receptor may reduce atherosclerotic plaque rupture and that AT(1a) receptor-mediated macrophage trapping, inflammation, oxidative stress, and matrix metalloproteinase activation may play crucial roles in plaque vulnerability.

Single Crystallization of Cs4PbBr6 Perovskite from Supersaturated Organic Solutions Optimized Through Solubility Studies.

We demonstrate the fabrication of millimeter-sized single crystals of 0D-Cs4PbBr6 grown in a supersaturated solution consisting of organic solvents without HBr (aq). One of the precursors, CsBr, was dissolved in ethylene glycol (EG) mixed with dimethyl sulfoxide, which is a good solvent for the other precursor, PbBr2. At a solvent ratio of 20 vol % EG, the solubility of cesium bromide decreased and the title compound, Cs4PbBr6, was selectively formed, whereas, with an EG ratio of 80 vol %, 3D-CsPbBr3 was formed. A phase diagram (solubility curve) of Cs4PbBr6 in the mixed solvent containing 20 vol % EG was obtained by visually observing dissolution and crystal precipitation while changing the temperature. Because the solubility was proportional to the temperature, the solubility curve demonstrated an upper critical solution phenomenon. The solubility near the boiling point of the solution (150 °C) was approximately 0.14 M. A single crystal of Cs4PbBr6 was formed by growing a seed crystal in a supersaturated solution on the low-temperature side of the solubility curve. X-ray analysis established the crystal structure; a fluorescence emission at 520 nm with a full width at half maximum of 20 nm confirms the composition of the single crystal to be Cs4PbBr6.

Selective Detection of CO Using Proton-Conducting Graphene Oxide Membranes with Pt-Doped SnO2 Electrocatalysts: Mechanistic Study by Operando DRIFTS.

To reduce the risk of carbon monoxide (CO) poisoning, there is a strong need for small, compact gas sensors to detect and monitor CO at ppm concentrations. In this study, we focused on detecting CO with electrochemical sensors based on proton-conducting graphene oxide (GO) nanosheets at room temperature. We found that a Ce-doped GO nanosheet membrane fitted with the sensing electrode composed of Pt (10 wt %)-doped SnO2 nanocrystals exhibits an excellent sensor response to CO at 25 °C. Pt doping of SnO2 nanocrystals has made it possible to detect CO more selectively than H2 and ethanol. The CO detection mechanism is analyzed by operando diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS), Fourier transform infrared gas cell measurements, and comprehensive density functional theory-based calculations. The results revealed that adsorption of CO occurs predominantly on Pt sites, and the adsorbed CO is anodically oxidized at the interface between the sensing electrode and proton-conducting membrane, generating the selective sensor response. The strong adsorption of CO was realized with Pt (10 wt %)-doped SnO2 nanocrystals, as revealed by the DRIFTS analysis and temperature-programed desorption technique.

Renin inhibitors inhibited the activity of recombinant human renin but not activity in healthy human plasma.

BACKGROUND: Activity of renin substrate cleavage (renin-like activity) was measured in vitro in plasma samples obtained from healthy human volunteers. METHODS: Renin-like activity was determined using FRET (Fluorescence Resonance Energy Transfer) human renin substrate. Recombinant human renin and human plasma showed dose-dependent cleavage activity of FRET human renin substrate. RESULTS: Activity of recombinant human renin was completely inhibited by either a peptidergic or a non-peptidergic renin inhibitor. However, renin-like activity in human plasma was not inhibited by these renin inhibitors. In a mixture of recombinant renin and human plasma, renin inhibitors inhibited only that part of the activity caused by recombinant renin, while the activity in plasma still remained. Human plasma did not show cleavage activity of rat FRET renin substrate. Native human prorenin showed cleavage activity of human renin substrate. This activety was also completely inhibited by renin inhibitors. Immunoprecipitation with anti-renin or anti-prorenin antibodies did not reduce the activity in human plasma. Renin-like activity in human plasma was abolished by degeneration of protein when sample was heated to 95 degrees C. Activity of both recombinant renin and human plasma was significantly inhibited by a protease inhibitor cocktail. CONCLUSIONS: These results suggest that the activity of renin substrate cleavage in human plasma is not mainly caused by the renin or prorenin molecule, but probably by other proteases.

Irbesartan increased PPARγ activity in vivo in white adipose tissue of atherosclerotic mice and improved adipose tissue dysfunction.

The effect of the PPARγ agonistic action of an AT(1) receptor blocker, irbesartan, on adipose tissue dysfunction was explored using atherosclerotic model mice. Adult male apolipoprotein E-deficient (ApoEKO) mice at 9 weeks of age were treated with a high-cholesterol diet (HCD) with or without irbesartan at a dose of 50mg/kg/day for 4 weeks. The weight of epididymal and retroperitoneal adipose tissue was decreased by irbesartan without changing food intake or body weight. Treatment with irbesartan increased the expression of PPARγ in white adipose tissue and the DNA-binding activity of PPARγ in nuclear extract prepared from adipose tissue. The expression of adiponectin, leptin and insulin receptor was also increased by irbesartan. These results suggest that irbesartan induced activation of PPARγ and improved adipose tissue dysfunction including insulin resistance.

Bone marrow AT1 augments neointima formation by promoting mobilization of smooth muscle progenitors via platelet-derived SDF-1{alpha}.

OBJECTIVE: Bone marrow (BM)-derived endothelial progenitor cells (EPCs) and vascular smooth muscle progenitor cells (VPCs) contribute to neointima formation, whereas the angiotensin II (Ang II) type 1 receptor (AT(1))-mediated action on BM-derived progenitors remains undefined. METHODS AND RESULTS: A wire-induced vascular injury was performed in the femoral artery of BM-chimeric mice whose BM was repopulated with AT(1)-deficient (BM-Agtr1(-/-)) or wild-type (BM-Agtr1(+/+)) cells. Neointima formation was profoundly reduced by 38% in BM-Agtr1(-/-) mice. Although the number of circulating EPCs (Sca-1(+)Flk-1(+)) and extent of reendothelialization did not differ between the 2 groups, the numbers of both circulating VPCs (c-Kit(-)Sca-1(+)Lin(-)) and tissue VPCs (Sca-1(+)CD31(-)) incorporated into neointima were markedly decreased in BM-Agtr1(-/-) mice. The accumulation of aggregated platelets and their content of stromal cell-derived factor-1alpha (SDF-1alpha) were significantly reduced in BM-Agtr1(-/-) mice, accompanied by a decrease in the serum level of SDF-1alpha. Thrombin-induced platelets aggregation was dose-dependently inhibited (45% at 0.1 IU/mL, P<0.05) in Agtr1(-/-) platelets compared with Agtr1(+/+) platelets, accompanied by the reduced expression and release of SDF-1alpha. CONCLUSIONS: The BM-AT(1) receptor promotes neointima formation by regulating the mobilization and homing of BM-derived VPCs in a platelet-derived SDF-1alpha-dependent manner without affecting EPC-mediated reendothelialization.

Angiotensin II type 1 receptor-associated protein prevents vascular smooth muscle cell senescence via inactivation of calcineurin/nuclear factor of activated T cells pathway.

Emerging new research suggests that the functions of the angiotensin (Ang) II type 1 (AT(1)) receptor are regulated in a complex manner. AT(1) receptor-associated protein (ATRAP) has been reported to reduce AT(1) receptor signaling with enhancement of AT(1) receptor internalization and to regulate the calcineurin/nuclear factor of activated T cells (NFAT) pathway. We examined the possibility that ATRAP could attenuate AT(1) receptor-mediated vascular senescence via inactivation with the calcineurin/NFAT pathway. Ang II stimulation significantly increased senescence-associated beta-galactosidase (SA-beta-gal)-stained cells, oxidative stress, and expression of p53 and p21 in wild-type (WT) vascular smooth muscle cells (VSMC). Moreover, in WT VSMC, Ang II stimulation enhanced NFAT transcriptional activity, which was prevented by CAML-siRNA treatment. NFAT-siRNA treatment attenuated Ang-II-increased SA-beta-gal activity and p53 and p21 expression. Treatment with a calcineurin activity inhibitor, cyclosporin A, reduced Ang-II-induced NFAT transcriptional activity and senescent VSMC. In contrast, VSMC prepared from ATRAP transgenic (ATRAP-Tg) mice exhibited attenuation of Ang-II-induced SA-beta-gal activity, oxidative stress, NFAT transcriptional activity, and expression of p53 and p21. Moreover, ATRAP-Tg VSMC showed a more reduction of Ang-II-induced NFAT transcriptional activity by CAML-siRNA treatment than WT VSMC. Furthermore, we demonstrated that in ATRAP-Tg VSMC, NFAT activity and senescent cells induced by ultraviolet irradiation were decreased compared with those in WT VSMC. Treatment with an AT(1) receptor blocker, valsartan, blocked these senescent cells but did not change NFAT activity in both cells. These results suggest that ATRAP negatively regulates VSMC senescence by reducing AT(1) receptor signaling, and that ATRAP-mediated inactivation of the calcineurin/NFAT pathway could be at least partly involved in prevention of VSMC senescence, irrespective of AT(1) receptor blockade in some conditions.

Exaggeration of focal cerebral ischemia in transgenic mice carrying human Renin and human angiotensinogen genes.

BACKGROUND AND PURPOSE: We examined the possibility that activation of the human brain renin-angiotensin system is involved in enhancement of ischemic brain damage using chimeric transgenic mice with human renin (hRN) and human angiotensinogen (hANG) genes. METHODS: Chimeric (hRN/hANG-Tg) mice were generated by mating of hRN and hANG transgenic mice. Permanent occlusion of the middle cerebral artery (MCA) by an intraluminal filament technique induced focal ischemic brain lesions. RESULTS: hRN/hANG-Tg mice showed higher angiotensin II levels in the plasma and brain. The ischemic brain area at 24 hours after MCA occlusion was significantly enlarged in hRN/hANG-Tg mice with an enhanced neurological deficit compared to that in wild-type, hRN-Tg and hANG-Tg mice. The reduction of cerebral blood flow in the periphery region of the MCA territory after MCA occlusion was markedly exaggerated in hRN/hANG-Tg mice. Superoxide anion production in the brain and arteries was also increased significantly in hRN/hANG-Tg mice even before MCA occlusion and was further enhanced after MCA occlusion. Treatment with an AT(1) receptor blocker, valsartan (3.0 mg/kg per day), for 2 weeks significantly reduced the ischemic brain area and improved the neurological deficit after MCA occlusion in hRN/hANG-Tg mice, similar to those in wild-type, hRN-Tg, and hANG-Tg mice, with restoration of cerebral blood flow in the peripheral region and decreases in superoxide anion production and blood pressure. CONCLUSIONS: These results indicate that activation of the human renin-angiotensin system exaggerates ischemic brain damage mainly through stimulation of the AT(1) receptor and marked reduction of cerebral blood flow and enhanced oxidative stress.

New insights into the regulation of angiotensin receptors.

PURPOSE OF REVIEW: Angiotensin (Ang) II exerts its important physiological functions through two distinct receptor subtypes, type 1 (AT1) and type 2 (AT2) receptors. Recently, evidence has accumulated showing new mechanisms of regulation of Ang II receptor subtype functions beyond the classical actions of receptors for Ang II. These emerging concepts of regulation of Ang II receptors and a new insight into future drug discovery are discussed in this review. RECENT FINDINGS: New paradigms concerning functional regulation of the Ang receptors such as dimerization of Ang II receptors or other receptors and several novel receptor interacting proteins that interact with the intracellular C-terminal domain of the Ang II receptor have been reviewed, especially in terms of the pathophysiological roles of Ang II receptor functions. Moreover, ligand-independent receptor activation systems such as mechanical stretch for the AT1 receptor and agonistic antibodies against the AT1 receptor have also been highlighted. SUMMARY: Recently, new evidence has accumulated showing the existence of several novel receptor interacting proteins and various Ang II receptor activation mechanisms such as dimerization and mechanical stretch-induced activation, which differ from classical Ang II receptor signaling. These findings may provide new potent therapeutic targets for the treatment of cardiovascular disease.

Temporary pretreatment with the angiotensin II type 1 receptor blocker, valsartan, prevents ischemic brain damage through an increase in capillary density.

BACKGROUND AND PURPOSE: We investigated the effect of temporary treatment with a nonhypotensive dose of valsartan on ischemic brain damage in C57BL/6 mice. METHODS: We separated the mice into 3 groups of valsartan treatment before middle cerebral artery (MCA) occlusion: (1) for 4 weeks: Val (2W, 2W); (2) for 2 weeks followed by its cessation for 2 weeks: Val (2W, -); and (3) no treatment for 4 weeks: Val (-, -). RESULTS: Ischemic volume, DNA damage, superoxide production, and mRNA levels of monocyte chemoattractant protein-1 and tumor necrosis factor-alpha on the ipsilateral side after 24 hours of MCA occlusion were significantly reduced in both Val (2W, 2W) and Val (2W, -) mice compared with those in Val (-, -) mice, whereas these parameters were larger in Val (2W, -) mice than in Val (2W, 2W) mice. Moreover, mice in both the Val (2W, 2W) and Val (2W, -) groups exhibited an increase in cerebral blood flow in the peripheral territory of the MCA 1 hour after MCA occlusion, with increases in endothelial nitric oxide synthase activation and nitric oxide production. Before MCA occlusion, treatment with valsartan did not influence superoxide production or mRNA levels of monocyte chemoattractant protein-1 and tumor necrosis factor-alpha in the brain. However, the capillary density in the brain in both Val (2W, 2W) and Val (2W, -) mice was increased before MCA occlusion. CONCLUSIONS: Our results suggest that temporary valsartan treatment could protect against ischemic brain damage even after its cessation, at least in part due to an increase in capillary density.

Deletion of angiotensin II type 2 receptor attenuates protective effects of bone marrow stromal cell treatment on ischemia-reperfusion brain injury in mice.

BACKGROUND AND PURPOSE: Protective effects of bone marrow stromal cells (MSCs) on ischemic brain damage have been highlighted. We examined the possibility that deletion of AT(2) receptor could attenuate the cerebroprotective effects of MSC using AT(2) receptor-deficient mice (Agtr2 (-)) and the effect of selective AT(1) receptor blocker. METHODS: Wild-type mice (Agtr2 (+)) were subjected to 3 hours of focal brain ischemia followed by reperfusion (ischemia-reperfusion injury). Simultaneously, Agtr2 (+)-MSC, Agtr2 (-)-MSC, or saline was injected through the tail vein. RESULTS: Survival rates at 6 days after ischemia-reperfusion injury were as follows: approximately 50% in saline-injected mice, 80% in Agtr2 (+)-MSC-injected mice, and 20% in Agtr2 (-)-MSC-injected mice. Neurological deficit after ischemia-reperfusion injury was improved in Agtr2 (+)-MSC-injected mice, but not in Agtr2 (-)-MSC-injected mice. After 48 hours of ischemia-reperfusion injury, brain infarct size was reduced in Agtr2 (+)-MSC-injected mice, but not in Agtr2 (-)-MSC-injected mice. Moreover, brain edema was significantly ameliorated in Agtr2 (+)-MSC-treated mice but not in Agtr2 (-)-MSC-treated mice. Furthermore, the increase in mRNA expression of tumor necrosis factor-alpha and monocyte chemoattractant protein-1 in the ischemic brain was less in Agtr2 (+)-MSC-treated mice in the ipsilateral site, but was similar in the contralateral hemisphere. Tumor necrosis factor-alpha level was increased in both the contralateral hemisphere and ipsilateral hemisphere of Agtr2 (-)-MSC-treated mice. In contrast, monocyte chemoattractant protein-1 levels tended to increase Agtr2 (-)-MSC-treated mice without a significant difference. Treatment of MSC with an AT(1) receptor blocker, valsartan, significantly improved survival rates in Agtr2 (-)-MSC-injected mice. CONCLUSIONS: These results suggest that AT(2) receptor signaling in MSC attenuated brain damage and neurological deficit (deleted).

Angiotensin II and III suppress food intake via angiotensin AT(2) receptor and prostaglandin EP(4) receptor in mice.

Intracerebroventricularly administered angiotensin (Ang) II and III dose-dependently suppressed food intake in mice and their anorexigenic activities were inhibited by AT(2) receptor-selective antagonist. Ang II did not suppress food intake in AT(2) receptor-knockout mice, while it did significantly in wild-type and AT(1) receptor-knockout mice. The suppression of food intake in AT(1) receptor-knockout mice was smaller than that in wild-type. The anorexigenic activities of Ang II and III were also blocked by a selective antagonist for prostaglandin EP(4) receptor. Taken together, centrally administered Ang II and III may decrease food intake through AT(2) receptor with partial involvement of AT(1) receptor, followed by EP(4) receptor activation, which is a novel pathway regulating food intake.

Telmisartan prevented cognitive decline partly due to PPAR-gamma activation.

Telmisartan is a unique angiotensin receptor blocker (ARB) and partial agonist of peroxisome proliferator-activated receptor (PPAR)-gamma. Here, we investigated the preventive effect of telmisartan on cognitive decline in Alzheimer disease. In ddY mice, intracerebroventricular injection of Abeta 1-40 significantly attenuated their cognitive function evaluated by shuttle avoidance test. Pretreatment with a non-hypotensive dose of telmisartan significantly inhibited such cognitive decline. Interestingly, co-treatment with GW9662, a PPAR-gamma antagonist, partially inhibited this improvement of cognitive decline. Another ARB, losartan, which has less PPAR-gamma agonistic effect, also inhibited Abeta-injection-induced cognitive decline; however the effect was smaller than that of telmisartan and was not affected by GW9662. Immunohistochemical staining for Abeta showed the reduced Abeta deposition in telmisartan-treated mice. However, this reduction was not observed in mice co-administered GW9662. These findings suggest that ARB has a preventive effect on cognitive impairment in Alzheimer disease, and telmisartan, with PPAR-gamma activation, could exert a stronger effect.

The renin-angiotensin system contributes to renal fibrosis through regulation of fibrocytes.

BACKGROUND: The renin-angiotensin system is a major pathway in the pathogenesis of cardiovascular and renal diseases. Bone marrow-derived fibrocytes, which are dual positive for CD45 and type I collagen, are now considered to contribute to the pathogenesis of various fibrotic diseases. We hypothesized that fibrocytes might contribute to renal fibrosis by an angiotensin II dependent pathway. RESULTS: In murine models of renal fibrosis, angiotensin II type 2 receptor (AT2R)-deficient mice, when compared with wild-type mice, showed increased renal fibrosis and fibrocyte infiltration with a concomitant upregulation of renal transcripts of procollagen type I (alpha) (COL1A1). Fibrocyte numbers in the bone marrow also were increased in AT2R-deficient mice. By contrast, pharmacological inhibition of angiotensin II type 1 receptor (AT1R) with valsartan reduced the degree of renal fibrosis and the number of fibrocytes in both the kidney and the bone marrow. In isolated human fibrocytes, inhibition of AT2R signaling increased the angiotensin II-stimulated expression of type I collagen, whereas inhibition of AT1R decreased collagen synthesis. These results suggest that AT1R/AT2R signaling may contribute to the pathogenesis of renal fibrosis by at least two mechanisms: by regulating the number of fibrocytes in the bone marrow, and by activation of fibrocytes.

Blockade of AT1 receptor improves adipocyte differentiation in atherosclerotic and diabetic models.

BACKGROUND: The roles of the angiotensin (Ang) II type 1 (AT(1)) receptor in the changes in white adipose tissue were explored in an animal model of atherosclerosis using apolipoprotein E-deficient (ApoEKO) mice. METHODS: Apolipoprotein E-deficient (ApoEKO) mice and KK-A(y) mice were used. Expression of markers for adipocyte differentiation and inflammation was determined by real-time reverse-transcription polymerase chain reaction. RESULTS: Adipose tissue weight and adipocyte size in epididymal white adipose tissue were increased in ApoEKO mice and KK-A(y) mice. In the adipose tissue of these models, expression of adiponectin and peroxisome proliferator-activated receptor-gamma (PPARgamma), which induce adipocyte differentiation, and expression of transcription factors of adipocyte differentiation, such as CCAAT-enhancer-binding protein-alpha (C/EBPalpha) and aP2, were decreased. Expression of inflammatory markers and nicotinamide adenine dinucleotide phosphate oxidase subunits was also increased. Deletion of AT(1)a receptor in ApoEKO mice and administration of an AT(1) receptor blocker, valsartan, to KK-A(y) mice reduced epididymal adipose tissue weight and adipocyte size significantly. Blockade of the AT(1) receptor also reduced the expression of inflammatory chemokines and oxidative stress markers. Moreover, AT(1)a receptor deletion in ApoEKO mice and AT(1) receptor blockade in KK-A(y) mice prevented the decrease in expression of adiponectin, PPARgamma, C/EBPalpha, and aP2. Valsartan also increased glucose uptake induced by insulin in adipose tissue of KK-A(y) mice. CONCLUSIONS: These results suggest that enlargement and weakened differentiation of adipocytes are observed in atherosclerosis and diabetes, and that AT(1) receptor blockade prevented adipocyte enlargement and promoted adipocyte differentiation in these models.

Akt-FOXO3a signaling affects human endothelial progenitor cell differentiation.

Here we address the effect of Akt signaling on endothelial progenitor cells (EPCs). Human peripheral blood mononuclear cells (PBMCs) were cultured on fibronectin-coated dishes in EPC differentiation medium. PBMCs differentiated in a series of three steps: proliferation for foci formation, tight attachment to the dishes in the early stages of differentiation, and maturation in the late stages. In Western blot analysis, Akt expression was attenuated in the early stages of differentiation and was gradually upregulated during EPC maturation. Forkhead box-containing protein, class O 3a (FOXO3a), an Akt downstream target, was downregulated through phosphorylation in the late stages of EPC differentiation. Adenovirus-mediated overexpression of activated FOXO3a in PBMCs markedly increased the number of cell foci but reduced the number of DiI-acetyl LDL EPCs that appear at later time points. These data suggest that Akt/FOXO3a signaling is an important regulator of EPC maturation.