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BACKGROUND AND AIMS: In obesity and type 2 diabetes mellitus, leptin promotes insulin resistance and contributes to the progression of NASH via activation of hepatic stellate cells (HSCs). However, the pathogenic mechanisms that trigger HSC activation in leptin-deficient obesity are still unknown. This study aimed to determine how HSC-targeting lipocalin-2 (LCN2) mediates the transition from simple steatosis to NASH. APPROACH AND RESULTS: Male wild-type (WT) and ob/ob mice were fed a high-fat diet (HFD) for 20 weeks to establish an animal model of NASH with fibrosis. Ob/ob mice were subject to caloric restriction or recombinant leptin treatment. Double knockout (DKO) mice lacking both leptin and lcn2 were also fed an HFD for 20 weeks. In addition, HFD-fed ob/ob mice were treated with gadolinium trichloride to deplete Kupffer cells. The LX-2 human HSCs and primary HSCs from ob/ob mice were used to investigate the effects of LCN2 on HSC activation. Serum and hepatic LCN2 expression levels were prominently increased in HFD-fed ob/ob mice compared with normal diet-fed ob/ob mice or HFD-fed WT mice, and these changes were closely linked to liver fibrosis and increased hepatic α-SMA/matrix metalloproteinase 9 (MMP9)/signal transducer and activator of transcription 3 (STAT3) protein levels. HFD-fed DKO mice showed a marked reduction of α-SMA protein compared with HFD-fed ob/ob mice. In particular, the colocalization of LCN2 and α-SMA was increased in HSCs from HFD-fed ob/ob mice. In primary HSCs from ob/ob mice, exogenous LCN2 treatment induced HSC activation and MMP9 secretion. By contrast, LCN2 receptor 24p3R deficiency or a STAT3 inhibitor reduced the activation and migration of primary HSCs. CONCLUSIONS: LCN2 acts as a key mediator of HSC activation in leptin-deficient obesity via α-SMA/MMP9/STAT3 signaling, thereby exacerbating NASH.
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Diabetes Mellitus Tipo 2 , Hepatopatia Gordurosa não Alcoólica , Animais , Humanos , Masculino , Camundongos , Dieta Hiperlipídica , Células Estreladas do Fígado/metabolismo , Leptina , Lipocalina-2/metabolismo , Fígado/patologia , Metaloproteinase 9 da Matriz/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade/metabolismoRESUMO
Chemotherapy-induced cachexia causes severe metabolic abnormalities independently of cancer and reduces the therapeutic efficacy of chemotherapy. The underlying mechanism of chemotherapy-induced cachexia remains unclear. Here we investigated the cytarabine (CYT)-induced alteration in energy balance and its underlying mechanisms in mice. We compared energy balance-associated parameters among the three groups of mice: CON, CYT, and PF (pair-fed mice with the CYT group) that were intravenously administered vehicle or CYT. Weight gain, fat mass, skeletal muscle mass, grip strength, and nocturnal energy expenditure were significantly lowered in the CYT group than in the CON and PF groups. The CYT group demonstrated less energy intake than the CON group and higher respiratory quotient than the PF group, indicating that CYT induced cachexia independently from the anorexia-induced weight loss. Serum triglyceride was significantly lower in the CYT group than in the CON group, whereas the intestinal mucosal triglyceride levels and the lipid content within the small intestine enterocyte were higher after lipid loading in the CYT group than in the CON and PF groups, suggesting that CYT inhibited lipid uptake in the intestine. This was not associated with obvious intestinal damage. The CYT group showed increased zipper-like junctions of lymphatic endothelial vessel in duodenal villi compared to that in the CON and CYT groups, suggesting their imperative role in the CYT-induced inhibition of lipid uptake. CYT worsens cachexia independently of anorexia by inhibiting the intestinal lipid uptake, via the increased zipper-like junctions of lymphatic endothelial vessel.
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Antineoplásicos , Caquexia , Camundongos , Animais , Caquexia/induzido quimicamente , Citarabina/farmacologia , Anorexia/etiologia , Intestino Delgado/metabolismo , Triglicerídeos , LipídeosRESUMO
Doxorubicin (DOX) is an effective anticancer drug with the side effect of irreparable cardiomyopathy. Lipocalin-2 (LCN2) has been identified as an important regulator of oxidative stress and inflammation in cardiovascular disease pathophysiology. Here, we demonstrate that LCN2 deletion increases autophagic flux in the DOX-treated hearts. Mice were injected intraperitoneally six times with 30 mg/kg DOX. Echocardiography showed that DOX-treated wild-type (WT) mice had markedly weaker cardiac function compared to saline-treated WT mice. In DOX-treated LCN2 knockout (KO) mice, cardiac function was partially restored. Histological analysis showed a reduction in cardiomyocyte diameter in DOX-treated WT mice that was ameliorated in DOX-treated LCN2KO mice. Cardiac levels of phosphorylated signal transducer and activator of transcription 3, LCN2, heme oxygenase-1, and NAD (P) H dehydrogenase were markedly greater in DOX-treated WT mice than in DOX-treated LCN2KO mice. Light chain 3B (LC3B)II expression was higher in DOX-treated WT mice, but lower in DOX-treated LCN2KO mice when compared to saline-treated WT mice. Less co-localization of LC3B and lysosomal-associated membrane protein 1 was observed in DOX-treated WT mice than in DOX-treated LCN2KO mice. LCN2 co-localized with LC3B-stained cells in the DOX-treated WT mouse heart, but not in the DOX-treated LCN2KO mouse heart. These findings indicate that the cardiotoxic effect of DOX is due to autophagosome accumulation mediated by LCN2 upregulation and that LCN2 may inhibit autophagic flux, leading to DOX-induced cardiomyopathy.
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Cardiomiopatias/induzido quimicamente , Cardiomiopatias/patologia , Doxorrubicina/efeitos adversos , Lipocalina-2/deficiência , Animais , Autofagossomos/metabolismo , Autofagia , Feminino , Deleção de Genes , Lipocalina-2/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Biológicos , Miocárdio/metabolismo , Miocárdio/patologia , Estresse Oxidativo , Fosforilação , Fator de Transcrição STAT3/metabolismoRESUMO
Obesity-induced adipocyte apoptosis promotes inflammation and insulin resistance. Src homology domain-containing inositol 5'-phosphatase 1 (SHIP1) is a key factor of apoptosis and inflammation. However, the role of SHIP1 in obesity-induced adipocyte apoptosis and autophagy is unclear. We found that diet-induced obesity (DIO) mice have significantly greater crown-like structures and terminal deoxynucleotidyl transferase deoxyuridine triphosphate (dUTP) nick-end labeling (TUNEL)-positive cells than ob/ob or control mice. Using RNA sequencing (RNA-seq) analysis, we identified that the apoptosis- and inflammation-related gene Ship1 is upregulated in DIO and ob/ob mice compared with control mice. In particular, DIO mice had more SHIP1-positive macrophages and lysosomal-associated membrane protein 1 (LAMP1) as well as a higher B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax)/Bcl-2 ratio compared with ob/ob or control mice. Furthermore, caloric restriction attenuated adipose tissue inflammation, apoptosis, and autophagy by reversing increases in SHIP1-associated macrophages, Bax/Bcl2-ratio, and autophagy in DIO and ob/ob mice. These results demonstrate that DIO, not ob/ob, aggravates adipocyte inflammation, apoptosis, and autophagy due to differential SHIP1 expression. The evidence of decreased SHIP1-mediated inflammation, apoptosis, and autophagy indicates new therapeutic approaches for obesity-induced chronic inflammatory diseases.
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Inflamação/genética , Obesidade/genética , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteína X Associada a bcl-2/genética , Adipócitos/metabolismo , Adipócitos/patologia , Tecido Adiposo/crescimento & desenvolvimento , Tecido Adiposo/patologia , Animais , Apoptose/genética , Autofagia/genética , Dieta Hiperlipídica , Humanos , Inflamação/patologia , Resistência à Insulina/genética , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Camundongos Obesos , Obesidade/patologiaRESUMO
Radioisotopes are widely used in the fields of medicine, science, and industry. The growing demand for medical radioisotopes has driven research on alternative production methods. In particular, both isotopes of 67Cu and 68Ge play vital roles in the medical environment in many countries to be used in the radio-immunotherapy and the positron emission tomography imaging, respectively. This study designed a multi-target system consisting of two Zn and one Ga2O3 plates to enable simultaneous production of the medical radioisotopes 67Cu and 68Ge using 100 MeV proton beams. To understand the thermal effect on the multi-targets, we examined the distribution of energy absorbed in each solid plate target when exposed to an accelerated proton beam through the thermal-fluid analysis based on ANSYS simulation. For confirming thermal stability for two Zn targets and one Ga2O3 target, the modified water flow path inside the multi-target system was designed effectively with the controlled distribution of multiple sub-holes between main inlet and the following four channels. It was confirmed that the newly designed multi-target system of Zn and Ga2O3 solid plates shows higher thermal stability than the case of uniform distribution of water inlet, which means it could be exposed to a higher current beam of 7.57% to decrease the processing time.
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Intermittent fasting (IF), an alternating pattern of dietary restriction, reduces obesity-induced insulin resistance and inflammation. However, the crosstalk between adipose tissue and the hippocampus in diabetic encephalopathy is not fully understood. Here, we investigated the protective effects of IF against neuroinflammation and cognitive impairment in high-fat diet(HFD)-fed mice. Histological analysis revealed that IF reduced crown-like structures and adipocyte apoptosis in the adipose tissue of HFD mice. In addition to circulating lipocalin-2 (LCN2) and galectin-3 (GAL3) levels, IF reduced HFD-induced increases in LCN2- and GAL3-positive macrophages in adipose tissue. IF also improved HFD-induced memory deficits by inhibiting blood-brain barrier breakdown and neuroinflammation. Furthermore, immunofluorescence showed that IF reduced HFD-induced astrocytic LCN2 and microglial GAL3 protein expression in the hippocampus of HFD mice. These findings indicate that HFD-induced adipocyte apoptosis and macrophage infiltration may play a critical role in glial activation and that IF reduces neuroinflammation and cognitive impairment by protecting against blood-brain barrier leakage.
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Disfunção Cognitiva , Galectina 3 , Animais , Camundongos , Doenças Neuroinflamatórias , Dieta Hiperlipídica/efeitos adversos , Lipocalina-2 , Jejum Intermitente , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/prevenção & controleRESUMO
Cytochrome P450s (CYPs) regulate plant growth and stress responses by producing diverse primary and secondary metabolites. However, the function of many plant CYPs remains unknown because, despite their structural similarity, predicting the enzymatic activity of CYPs is difficult. In this study, one member of the CYP736A subfamily (CYP736A61) from tomatoes was isolated and characterized its enzymatic functions. CYP736A61 was successfully expressed in Escherichia coli through co-expression with molecular chaperones. The purified CYP736A61 showed hydroxylation activity toward 7-ethoxycoumarin, producing 7-hydroxycoumarin or 3-hydroxy 7-ethoxycoumarin. Further substrate screening revealed that dihydrochalcone and stilbene derivates (resveratrol and polydatin) are the substrates of CYP736A61. CYP736A61 also mediated the hydroxylation of resveratrol and polydatin, albeit with low activity. Importantly, CYP736A61 mediated the cleavage of resveratrol and polydatin as well as pinostilbene and pterostilbene. Interestingly, CY736A61 also converted phloretin to naringenin chalcone. These results suggest that CYP736A61 is a novel CYP enzyme with stilbene cleavage activity.
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Glucosídeos , Solanum lycopersicum , Estilbenos , Resveratrol , Estilbenos/química , Estilbenos/metabolismo , CatáliseRESUMO
BACKGROUND: Jawoongo (JW) is a topical herbal ointment that has been used as an alternative treatment option for atopic dermatitis. Topical ointments are known to have less bioavailability because the stratum corneum allows only lipophilic and low molecular weight drugs to pass across it. This study aimed to investigate whether applying microneedle patches (MNP) increases the therapeutic effect of 2,4-dinitrochlorobenzene (DNCB)+JW for atopic dermatitis by enhancing transdermal delivery. METHODS: Atopic dermatitis was induced by DNCB in BALB/c mice. The combination treatment of JW and MNP was estimated to study the effect of MNP in improving transdermal delivery. Histological analysis, quantitative real-time PCR (qPCR), and immunofluorescence were performed to verify the effect of MNP in enhancing the therapeutic effects of DNCB+JW on atopic dermatitis in mice. RESULTS: Both combination treatment and DNCB+JW treatment ameliorated histological alterations and reduced skin thickness and infiltration of CD4+ T cells in atopic dermatitis-like skin lesions in DNCB-exposed BALB/c mice. However, the improvement of histological alterations was better in the combination treatment, which was almost normal. Furthermore, the combination treatment exhibited a larger decrease in mRNA levels of IL-4, IL-6, IL-13, iNOS, and TNF-α, compared to DNCB+JW only. In addition, skin thickness and infiltration of CD4+ T cells in the sensitized skin were significantly lower using the combination treatment than using DNCB+JW only. CONCLUSION: Combination treatment with JW and MNP further decreased skin thickness and several inflammatory cytokines in atopic dermatitis like skin lesions compared to treatment using JW alone. These findings suggest that applying a dissolvable MNP after JW application could be useful for treating atopic dermatitis.
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Dermatite Atópica , Animais , Camundongos , Citocinas , Dermatite Atópica/induzido quimicamente , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/patologia , Dinitroclorobenzeno/efeitos adversos , Pele/patologiaRESUMO
We have developed a new analytical peak separation analysis for superposed [Formula: see text]-ray peaks on [Formula: see text]Cu and [Formula: see text]Ga to measure the [Formula: see text]Zn(p,2p)[Formula: see text]Cu and [Formula: see text]Zn(p,2n)[Formula: see text]Ga reactions, unlike in most previous works that were employing a radiochemical separation to measure them. Based on the nuclear data such as the [Formula: see text]-ray intensity and the half-life for each nuclide, we may develop a new analytical method that enables us to estimate the respective counts arising from each nuclide, thereby obtaining the nuclear reactions. The newly developed analytical method can universally be applied to separate the superposed [Formula: see text]-ray spectra of any two nuclides, especially superior in separating the nuclides with different half-lives. In comparison with the data in the literature, the two reactions in the present work are in good agreement with those of some previous works. In addition, we compared the present [Formula: see text]Zn(p,2n)[Formula: see text]Ga reaction without the peak separation to the data in the literature without the chemical separation, and find that a good agreement is evident, enhancing the reliability of the [Formula: see text]Zn(p,x)[Formula: see text]Zn and [Formula: see text]Zn(p,3n)[Formula: see text]Ga reactions, which are further measured in the present work.
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Zinco , Reprodutibilidade dos TestesRESUMO
Lipocalin-2 (LCN2) is an acute-phase protein that regulates inflammatory responses to bacteria or lipopolysaccharide (LPS). Although the bacteriostatic role of LCN2 is well studied, the function of LCN2 in acute lung damage remains unclear. Here, LCN2 knockout (KO) mice were used to investigate the role of LCN2 in LPS-treated mice with or without recombinant LCN2 (rLCN2). In addition, we employed patients with pneumonia. RAW264.7 cells were given LCN2 inhibition or rLCN2 with or without iron chelator deferiprone. LCN2 KO mice had a higher survival rate than wild-type (WT) mice after LPS treatment. In addition to elevated LCN2 levels in serum and bronchoalveolar lavage fluid (BALF), LPS treatment also increased LCN2 protein in alveolar macrophage lysates of BALF. LCN2 deletion attenuated neutrophil and macrophage infiltration in the lungs of LPS-treated mice as well as serum and BALF interleukin-6 (IL-6). Circulating proinflammatory cytokines and LCN2-positive macrophages were prominently increased in the BALF of pneumonia patients. In addition to increase of iron-stained macrophages in pneumonia patients, increased iron-stained macrophages and oxidative stress in LPS-treated mice were inhibited by LCN2 deletion. In contrast, rLCN2 pretreatment aggravated lung inflammation and oxidative stress in LPS-treated WT mice and then resulted in higher mortality. In RAW264.7 cells, exogenous LCN2 treatment also increased inflammation and oxidative stress, whereas LCN2 knockdown markedly diminished these effects. Furthermore, deferiprone inhibited inflammation, oxidative stress, and phagocytosis in RAW264.7 cells with high LCN2 levels, as well as LPS-induced acute lung injury in WT and LCN2 KO mice. Thus, these findings suggest that LCN2 plays a key role in inflammation and oxidative stress following acute lung injury and that LCN2 is a potential therapeutic target for pneumonia or acute lung injury.
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Lesão Pulmonar Aguda , Pneumonia , Animais , Camundongos , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/genética , Lesão Pulmonar Aguda/metabolismo , Deferiprona/efeitos adversos , Deferiprona/metabolismo , Inflamação/metabolismo , Ferro/metabolismo , Lipocalina-2/genética , Lipocalina-2/efeitos adversos , Lipopolissacarídeos/farmacologia , Pulmão/metabolismo , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Estresse Oxidativo/genética , Pneumonia/metabolismoRESUMO
BACKGROUND: Lipocalin-2 (LCN2) is an acute-phase protein that has been linked to insulin resistance, diabetes, and neuroinflammatory diseases. Triggering receptor expressed on myeloid cells-2 (TREM2) has been also implicated in microglia-mediated neuroinflammation. However, the potential role of LCN2 on TREM2 in diabetic mouse models is not fully understood. METHODS: We investigated hepatic and hippocampal TREM2 expressions in high-fat diet (HFD) and streptozotocin (STZ)-induced diabetic LCN2 knockout (KO) mice. RESULTS: In addition to increased serum LCN2 level, diabetic wild-type (WT) mice had insulin resistance and hepatic steatosis. However, LCN2 deletion attenuated these metabolic parameters in diabetic mice. We also found that LCN2 deletion reduced hepatic inflammation and microglial activation in diabetic mice. In particular, diabetic LCN2 KO mice had a reduction in hepatic and hippocampal TREM2 expressions compared with diabetic WT mice. Furthermore, we found that many TREM2-positive Kupffer cells and microglia in diabetic WT mice were reduced through LCN2 deletion. CONCLUSIONS: These findings indicate that LCN2 may promote hepatic inflammation and microglial activation via upregulation of TREM2 in diabetic mice.
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We have developed chelator-free copper-64-incorporated iron oxide (IO) nanoparticle (NPs) which have both magnetic and radioactive properties being applied to positron emission tomography (PET)-magnetic resonance imaging (MRI). We have found that the IO nanoparticles composed of radioactive isotope 64Cu may act as a contrast agent being a diagnostic tool for PET as well as a good T2 MRI nanoprobe due to their good r2/r1 ratio. Furthermore, we demonstrate that the 64Cu incorporation at the core of core-shell-structured IO NPs exhibits a good in vivo stability, giving us an insightful strategy for the design of a contrast agent for the PET-MRI system.
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This study evaluated the in vivo behavior and accumulation of silica particles in the form of wires, which were actively studied as drug carriers along with spheres, using positron emission tomography (PET). Wire-shaped silicon dioxide (SiO2) was synthesized at micro-size, using anodic aluminum oxide (AAO), a template, and folic acid (FA), which specifically binds folate receptors (FR) which are overexpressed in many cancers, and which was bound to the wire's surface to confirm its possible use as a cancer diagnostic agent. In addition, for evaluation using PET, the positron-emitting nuclide 89Zr (t1/2 = 3.3 days) was directly bonded to the hydroxyl group (-OH) on the particle surface. The diameter and shape of the synthesized silica microwires (SMWs) were confirmed using SEM and TEM, the chemical bonding of FA was confirmed through FT-IR and NMR, and the labeling of 89Zr was measured by means of radio-thin-layer chromatography (TLC) measurement. Folic acid-conjugated SMWs (FA-SMWs) were found to have a low receptor-mediated uptake in cell internalization evaluation, but in PET studies, FA-SMWs stayed longer at the tumor site. In conclusion, we successfully synthesized a homogeneous silica microwire for drug delivery, we confirmed that the FA-conjugated sample remains at the tumor site for a relatively longer time, and we have reported the characteristic in vivo behavior of 89Zr-FA-SMWs.
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We investigate the magnetic properties in carbonyl iron (CI) particles before and after Ni[Formula: see text] and H[Formula: see text] ion beam irradiation. Upon increasing temperatures, the saturation magnetization ([Formula: see text]) in hysteresis loops exhibits an anomalous increase at a high temperature for the unirradiated and the Ni[Formula: see text]-beam-irradiated samples, unlike in H[Formula: see text]-beam-irradiated sample. Moreover, the magnetization values at low and high temperatures are more intense after Ni[Formula: see text] beam irradiation, whereas after H[Formula: see text] beam irradiation those are remarkably suppressed. Hematite ([Formula: see text]-Fe[Formula: see text]O[Formula: see text]) phase introduced on the surface of our CI particles undergoes the Morin transition that was observed in our magnetization-temperature curves. The Morin transition causing canted antiferromagnetism above the Morin temperature was found in the unirradiated and Ni[Formula: see text]-beam-irradiated samples, but not in H[Formula: see text]-beam-irradiated sample. It is thus revealed that the CI particles undergoing the Morin transition cause the anomalous increase in [Formula: see text]. We may suggest that Ni[Formula: see text] ion beam increases uncompensated surface spins on the CI particles resulting in a more steep Morin transition and the intensified [Formula: see text]. Ion-beam irradiation may thus be a good tool for controlling the magnetic properties of CI particles, tailoring our work for future applications.
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Exendin-4 (Ex-4) is a glucagon-like peptide-1 receptor (GLP-1R) agonist that protects against brain injury. However, little is known about the effect of Ex-4 on kainic acid (KA)-induced seizures and hippocampal cell death. Therefore, this study evaluated the neuroprotective effects of Ex-4 pretreatment in a mouse model of KA-induced seizures. Three days before KA treatment, mice were intraperitoneally injected with Ex-4. We found that Ex-4 pretreatment reversed KA-induced reduction of GLP-1R expression in the hippocampus and attenuated KA-induced seizure score, hippocampal neuronal death, and neuroinflammation. Ex-4 pretreatment also dramatically reduced hippocampal lipocalin-2 protein in KA-treated mice. Furthermore, immunohistochemical studies showed that Ex-4 pretreatment significantly alleviated blood-brain barrier leakage. Finally, Ex-4 pretreatment stimulated hippocampal expression of phosphorylated cyclic adenosine monophosphate (cAMP) response element-binding protein (p-CREB), a known target of GLP-1/GLP-1R signaling. These findings indicate that Ex-4 pretreatment may protect against KA-induced neuronal damage by regulating GLP-1R/CREB-mediated signaling pathways.
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Morte Celular/efeitos dos fármacos , Exenatida/farmacologia , Hipocampo/efeitos dos fármacos , Doenças Neuroinflamatórias/tratamento farmacológico , Neurônios/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Exenatida/metabolismo , Hipocampo/metabolismo , Masculino , Camundongos , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Transdução de Sinais/efeitos dos fármacosRESUMO
The hippocampal cell death that follows kainic acid (KA)-induced seizures is associated with blood-brain barrier (BBB) leakage and oxidative stress. Lipocalin-2 (LCN2) is an iron-trafficking protein which contributes to both oxidative stress and inflammation. However, LCN2's role in KA-induced hippocampal cell death is not clear. Here, we examine the effect of blocking LCN2 genetically on neuroinflammation and oxidative stress in KA-induced neuronal death. LCN2 deficiency reduced neuronal cell death and BBB leakage in the KA-treated hippocampus. In addition to LCN2 upregulation in the KA-treated hippocampus, circulating LCN2 levels were significantly increased in KA-treated wild-type (WT) mice. In LCN2 knockout mice, we found that the expressions of neutrophil markers myeloperoxidase and neutrophil elastase were decreased compared to their expressions in WT mice following KA treatment. Furthermore, LCN2 deficiency also attenuated KA-induced iron overload and oxidative stress in the hippocampus. These findings indicate that LCN2 may play an important role in iron-related oxidative stress and neuroinflammation in KA-induced hippocampal cell death.
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Obesity and insulin resistance accelerate aging-related sarcopenia, which is associated with iron load and oxidative stress. Lipocalin-2 (LCN2) is an iron-binding protein that has been associated with skeletal muscle regeneration, but details regarding its role in obese sarcopenia remain unclear. Here, we report that elevated LCN2 levels in skeletal muscle are linked to muscle atrophy-related inflammation and oxidative stress in leptin-deficient ob/ob mice. RNA sequencing analyses indicated the LCN2 gene expression is enhanced in skeletal muscle of ob/ob mice with sarcopenia. In addition to muscular iron accumulation in ob/ob mice, expressions of iron homeostasis-related divalent metal transporter 1, ferritin, and hepcidin proteins were increased in ob/ob mice compared to lean littermates, whereas expressions of transferrin receptor and ferroportin were reduced. Collectively, these findings demonstrate that LCN2 functions as a potent proinflammatory factor in skeletal muscle in response to obesity-related sarcopenia and is thus a therapeutic candidate target for sarcopenia treatment.
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The associations of Internet addiction (IA) and smartphone addiction (SA) with mental health problems have been widely studied. We investigated the effects of IA and SA on depression and anxiety while adjusting for sociodemographic variables. In this study, 4854 participants completed a cross-sectional web-based survey including socio-demographic items, the Korean Scale for Internet Addiction, the Smartphone Addiction Proneness Scale, and the subscales of the Symptom Checklist 90 Items-Revised. The participants were classified into IA, SA, and normal use (NU) groups. To reduce sampling bias, we applied the propensity score matching method based on genetics matching. The IA group showed an increased risk of depression (relative risk 1.207; p < 0.001) and anxiety (relative risk 1.264; p < 0.001) compared to NUs. The SA group also showed an increased risk of depression (relative risk 1.337; p < 0.001) and anxiety (relative risk 1.402; p < 0.001) compared to NCs. These findings show that both, IA and SA, exerted significant effects on depression and anxiety. Moreover, our findings showed that SA has a stronger relationship with depression and anxiety, stronger than IA, and emphasized the need for prevention and management policy of the excessive smartphone use.
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Ansiedade/epidemiologia , Comportamento Aditivo/epidemiologia , Depressão/epidemiologia , Internet , Smartphone , Adulto , Ansiedade/psicologia , Comportamento Aditivo/psicologia , Estudos Transversais , Depressão/psicologia , Feminino , Humanos , Masculino , Saúde Mental , Pessoa de Meia-Idade , Pontuação de Propensão , República da Coreia , Risco , Inquéritos e Questionários , Adulto JovemRESUMO
PURPOSE: Sevelamer, a noncalcium phosphate binder, has been shown to attenuate the progression of vascular calcification and improve survival in patients with chronic kidney disease undergoing dialysis compared with calcium-based binders. Using real-world data from a cohort study and the Health Insurance Review and Assessment Service database, we conducted a cost-effectiveness analysis comparing sevelamer with calcium acetate in dialysis patients from the perspective of the National Health Insurance Service in South Korea. METHODS: Data (demographic, diagnostic, laboratory, and survival) from 4674 patients undergoing dialysis enrolled in a multicenter prospective cohort study conducted in South Korea between September 2008 and December 2012 were linked to phosphate binder use, hospitalization, and cost data available from the Health Insurance Review and Assessment Service database. After propensity score matching, a dataset comprising comparable patients treated with either sevelamer (n = 501) or calcium acetate (n = 501) was used in the cost-effectiveness analysis. A Markov model was used to estimate costs, life years, quality-adjusted life years (QALYs), and cost-effectiveness over each patient's lifetime. Forty-month treatment-specific overall survival (OS) data available from the dataset were extrapolated to lifetime survival with the use of regression analysis. FINDINGS: Patients had a mean age of 56.3 years and were treated with dialysis for a mean duration of 67.6 months. Compared with calcium acetate, sevelamer was associated with an incremental cost of South Korean Won (â©) 12,246,911 ($10,819) and a gain of 1.758 life years and 1.108 QALYs per patient. This outcome yielded incremental cost-effectiveness ratios of â©6,966,350 ($6154) and â©11,057,699 ($9768) per life year and QALY gained, respectively. Conclusions regarding sevelamer's cost-effectiveness were insensitive to alternative assumptions in time horizon, discount rate, hospitalization rate, costs, and health utility estimates, and they remained consistent in 100% of the model iterations, considering a willingness-to-pay threshold of â©31,894,720 ($28,176) per QALY gained. IMPLICATIONS: This analysis of real-world data found that sevelamer's higher cost relative to calcium acetate was adequately offset by improved survival among patients undergoing dialysis in South Korea. As such, sevelamer offers good value for money, representing a cost-effective alternative to calcium-based binders.
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Acetatos/economia , Quelantes/economia , Diálise Renal/economia , Insuficiência Renal Crônica/economia , Sevelamer/economia , Acetatos/uso terapêutico , Adulto , Idoso , Povo Asiático , Compostos de Cálcio/economia , Compostos de Cálcio/uso terapêutico , Quelantes/uso terapêutico , Análise Custo-Benefício , Feminino , Hospitalização/economia , Humanos , Masculino , Cadeias de Markov , Pessoa de Meia-Idade , Programas Nacionais de Saúde , Estudos Prospectivos , Anos de Vida Ajustados por Qualidade de Vida , Análise de Regressão , Insuficiência Renal Crônica/terapia , República da Coreia , Sevelamer/uso terapêuticoRESUMO
Prevalent anuric peritoneal dialysis (PD) patients usually have higher mortality than PD patients with residual urine volume. We aimed to evaluate the predictors of survival in anuric PD patients. Anuric PD patients (n = 505, <100 mL of daily urine) enrolled in Korean nationwide prospective cohort were analyzed. Survived and non-survived anuric PD patients were compared by propensity score matching analysis with a ratio of two to one. The propensity method was used to adjust for patient age, dialysis duration, and presence of diabetes. Among the total anuric PD patients, non-survived patients showed a significantly older age, higher incidence of diabetes, coronary artery disease, and arrhythmia, and lower serum creatinine and albumin. After propensity score matching, multivariate Cox regression analysis for patient survival showed a decreasing risk as serum albumin increased (HR = 0.347, p = 0.0094). Analysis using the receiver-operating-characteristic (ROC) curve showed that survival could be predicted with a sensitivity of 59.4% and a specificity of 63.2% using a cutoff value of 3.6 g/dL of serum albumin in unmatched total PD patients. The beneficial impact of high albumin level on death was significantly greater for patients with older age (≥50 years), no diabetes, low ultrafiltration (UF) volume (<1000 mL/day), and low levels of serum creatinine (<10 mg/dL), total cholesterol (<177.5 mg/dL), ferritin (<100 ng/mL), and high-sensitivity C-reactive protein (hs-CRP) (<0.1 mg/dL). Survival in anuric PD patients was associated with age, comorbidities, and nutritional factors such as creatinine and albumin. After adjustment by propensity score matching, serum albumin level was an independent predictor for survival in anuric PD patients.