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1.
Int J Mol Sci ; 24(17)2023 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-37685978

RESUMO

The role of psoralen (PS), a major active component extracted from Psoralea corylifolia L. seed, in renal fibrosis is still unclear. Thus, the objective of this study was to evaluate the effects of PS on the development and progression of renal fibrosis induced by unilateral ureteral obstruction (UUO) in a mouse model. Mice were divided into four groups: PS (20 mg/kg, i.g., n = 5), PS + sham (n = 5), UUO (n = 10), and PS + UUO (n = 10). PS was intragastrically administered 24 h before UUO and continued afterwards for 7 days. All mice were killed 7 days post UUO. Severe tubular atrophy, tubular injury, and tubulointerstitial fibrosis (TIF) were significantly developed in UUO mice. A higher expression of transforming growth factor-ß1 (TGF-ß1) was accompanied by elevated levels of α-smooth muscle actin (α-SMA) and phosphorylated Smad2/3 (pSmad2/3) at 7 days post UUO. However, PS treatment reduced tubular injury, interstitial fibrosis, and the expression levels of TGF-ß1, α-SMA, and pSmad2/3. Furthermore, the levels of macrophages (represented by F4/80 positive cells) and the inflammasome, reflected by inflammasome markers such as nucleotide-binding and oligomerization domain-like receptors protein 3 (NLRP3) and cleaved caspase1 (cCASP-1), were significantly decreased by PS treatment. These results suggest that PS merits further exploration as a therapeutic agent in the management of chronic kidney disease (CKD).


Assuntos
Furocumarinas , Insuficiência Renal Crônica , Obstrução Ureteral , Animais , Camundongos , Transição Epitelial-Mesenquimal , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Fator de Crescimento Transformador beta1 , Obstrução Ureteral/complicações , Obstrução Ureteral/tratamento farmacológico , Modelos Animais de Doenças , Fibrose
2.
Int J Mol Sci ; 23(3)2022 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-35163466

RESUMO

Ischemia-reperfusion injury (IRI) is a major cause of acute kidney injury (AKI) and progression to chronic kidney disease (CKD). However, no effective therapeutic intervention has been established for ischemic AKI. Endothelial progenitor cells (EPCs) have major roles in the maintenance of vascular integrity and the repair of endothelial damage; they also serve as therapeutic agents in various kidney diseases. Thus, we examined whether EPCs have a renoprotective effect in an IRI mouse model. Mice were assigned to sham, EPC, IRI-only, and EPC-treated IRI groups. EPCs originating from human peripheral blood were cultured. The EPCs were administered 5 min before reperfusion, and all mice were killed 72 h after IRI. Blood urea nitrogen, serum creatinine, and tissue injury were significantly increased in IRI mice; EPCs significantly improved the manifestations of IRI. Apoptotic cell death and oxidative stress were significantly reduced in EPC-treated IRI mice. Administration of EPCs decreased the expression levels of NLRP3, cleaved caspase-1, p-NF-κB, and p-p38. Furthermore, the expression levels of F4/80, ICAM-1, RORγt, and IL-17RA were significantly reduced in EPC-treated IRI mice. Finally, the levels of EMT-associated factors (TGF-ß, α-SMA, Snail, and Twist) were significantly reduced in EPC-treated IRI mice. This study shows that inflammasome-mediated inflammation accompanied by immune modulation and fibrosis is a potential target of EPCs as a treatment for IRI-induced AKI and the prevention of progression to CKD.


Assuntos
Injúria Renal Aguda/prevenção & controle , Células Progenitoras Endoteliais/transplante , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Injúria Renal Aguda/metabolismo , Animais , Apoptose/efeitos dos fármacos , Nitrogênio da Ureia Sanguínea , Células Cultivadas , Creatinina/sangue , Modelos Animais de Doenças , Células Progenitoras Endoteliais/citologia , Células Progenitoras Endoteliais/imunologia , Células Progenitoras Endoteliais/metabolismo , Humanos , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Traumatismo por Reperfusão/imunologia , Traumatismo por Reperfusão/metabolismo
3.
Intern Med ; 61(2): 151-158, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34248121

RESUMO

Objective Human microRNA-185 (miR-185) has been reported to act as a regulator of fibrosis and angiogenesis in cancer. However, miR-185 has not been investigated in patients with ST-segment elevation myocardial infarction (STEMI). We hypothesized that the changes in miR-185 levels in STEMI patients are related to the processes of myocardial healing and remodeling. Methods Between January 2011 and December 2013, 145 patients with STEMI (65.9±11.6 years old; 41 women) were enrolled. Initial and discharge serum samples collected from 20 patients with STEMI and mixed sera from 8 healthy controls were analyzed by a microarray. A quantitative reverse transcription polymerase chain reaction (RT-qPCR) analysis of miR-185 was performed in all 145 patients. The correlation between the miR-185 levels and the clinical, laboratory, angiographic, and echocardiographic parameters was analyzed. Results The microarray analysis revealed a biphasic pattern in miR-185 levels, with an initial decrease followed by an increase at discharge. The miR-185 levels at discharge were significantly correlated with the troponin-I, CK-MB, and area under the curve of CK-MB levels. There was a positive correlation between the transforming growth factor-ß and miR-185 levels at discharge (ρ=0.242, p=0.026). A high wall motion score index and a low ejection fraction, as measured by echocardiography, and high B-type natriuretic peptide level at one month after STEMI were related to high miR-185 levels. Conclusion Our results showed that elevated miR-185 levels at the late stage of STEMI were related to a large amount of myocardial injury and adverse remodeling.


Assuntos
MicroRNAs , Infarto do Miocárdio com Supradesnível do Segmento ST , Idoso , Biomarcadores , Creatina Quinase Forma MB , Feminino , Humanos , MicroRNAs/genética , Pessoa de Meia-Idade , Infarto do Miocárdio com Supradesnível do Segmento ST/genética , Troponina I
4.
J Clin Med ; 10(4)2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33670117

RESUMO

The immunologic aspects of radiation pneumonitis (RP) are unclear. We analyzed variations in cytokine profiles between patients with grade (Gr) 0-1 and Gr ≥ 2 RP. Fifteen patients undergoing concurrent chemoradiotherapy for non-small cell lung cancer were included. Blood samples of 9 patients with Gr 0-1 and 6 with Gr ≥ 2 RP were obtained from the Biobank. Cytokine levels were evaluated using an enzyme linked immunosorbent assay at before radiotherapy (RT) initiation, 1, 3, and 6 weeks post-RT initiation, and 1 month post-RT completion. Concentrations of granulocyte colony-stimulating factor (G-CSF), interleukin (IL)-6, IL-10, IL-13, IL-17, interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and transforming growth factor (TGF)-ß were analyzed; none were related to the occurrence of Gr ≥ 2 RP at pre-RT initiation. At 3 weeks, relative changes in the G-CSF, IL-6, and IFN-γ levels differed significantly between the groups (p = 0.026, 0.05 and 0.026, respectively). One month post-RT completion, relative changes of IL-17 showed significant differences (p = 0.045); however, relative changes in TNF-α, IL-10, IL-13, and TGF-ß, did not differ significantly. Evaluation of changes in IL-6, G-CSF, and IFN-γ at 3 weeks after RT initiation can identify patients pre-disposed to severe RP. The mechanism of variation in cytokine levels in relation to RP severity warrants further investigation.

5.
Laryngoscope ; 131(5): E1400-E1407, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-32990335

RESUMO

OBJECTIVES: The Janus kinase/signal transducer and activator of transcription (JAK-STAT) pathway play a key role in immune modulation, especially in the polarization of T helper cells. JAK inhibitors reduce inflammation by inhibiting the phosphorylation of STAT. We investigated whether a JAK inhibitor, tofacitinib, can reduce inflammation in a mouse model of chronic rhinosinusitis with nasal polyps (CRSwNP). METHODS: An eosinophilic CRSwNP model was induced using 4-week-old BALB/c mice. The therapeutic effects of topical tofacitinib were compared with the effects of triamcinolone acetonide (TAC). Polyp formation and eosinophilic infiltration were assessed by histology. Levels of phosphorylated STAT (pSTAT), eosinophil cationic protein, and eotaxin were measured by immunohistochemistry. Gene expression levels of GATA-3 was measured using quantitative PCR. The production of cytokines in sinonasal tissues, including interleukin IL-4, IL-5, IL-12, and interferon-γ, were measured using enzyme-linked immunosorbent assays (ELISA). RESULTS: Topical tofacitinib administration significantly reduced the number of polyp-like lesions and the degree of eosinophilic infiltration, with an efficacy comparable with that of systemic TAC administration. Similarly, the levels of pSTAT6, eosinophil cationic protein, and eotaxin decreased with tofacitinib treatment. Tofacitinib decreased the gene expression level of GATA-3. Lastly, tofacitinib significantly decreased IL-4 and IL-5 production to a similar extent as that by systemic or topical TAC administration. Tofacitinib, but not TAC, significantly increased the production of interferon-γ. CONCLUSION: Topical tofacitinib administration may be an effective treatment for eosinophilic CRSwNP by inhibiting phosphorylation of STATs. LEVEL OF EVIDENCE: N/A. Laryngoscope, 131:E1400-E1407, 2021.


Assuntos
Eosinofilia/tratamento farmacológico , Pólipos Nasais/tratamento farmacológico , Piperidinas/administração & dosagem , Pirimidinas/administração & dosagem , Rinite/tratamento farmacológico , Sinusite/tratamento farmacológico , Adjuvantes Imunológicos/administração & dosagem , Administração Intranasal , Animais , Doença Crônica/tratamento farmacológico , Citocinas/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Eosinofilia/complicações , Eosinofilia/imunologia , Eosinofilia/patologia , Eosinófilos/imunologia , Humanos , Janus Quinases/metabolismo , Masculino , Camundongos , Mucosa Nasal/citologia , Mucosa Nasal/efeitos dos fármacos , Mucosa Nasal/imunologia , Mucosa Nasal/patologia , Pólipos Nasais/complicações , Pólipos Nasais/imunologia , Pólipos Nasais/patologia , Rinite/complicações , Rinite/imunologia , Rinite/patologia , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Sinusite/complicações , Sinusite/imunologia , Triancinolona Acetonida/administração & dosagem
6.
Oxid Med Cell Longev ; 2020: 7627934, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33299530

RESUMO

Contrast-induced acute kidney injury (CI-AKI) is the third most common cause of hospital-acquired renal failure, with an incidence of 11%. However, the disease mechanism remains unclear, and no effective treatment is available. Paricalcitol has been reported to be effective in animal models of kidney injury. We hypothesized that paricalcitol could play a renoprotective role against CI-AKI. Rats were divided into control, paricalcitol, contrast, and paricalcitol-plus-contrast groups. We used a previously published protocol to produce CI-AKI. Paricalcitol (0.3 µg/kg) was administered intraperitoneally before 24 h and 30 min before indomethacin. We used HK-2 cells to evaluate the effects of paricalcitol on mitophagy and senescence. Ioversol triggered renal dysfunction, increasing blood urea nitrogen and serum creatinine. Significant tubular damage, increased 8-OHdG expression, and apoptosis were apparent. Ioversol injection induced high expression levels of the mitophagy markers Pink1, Parkin, and LC3 and the senescence markers ß-galactosidase and p16INK4A. Paricalcitol pretreatment prevented renal dysfunction and reduced tissue damage by reducing both mitophagy and senescence. Cellular morphological changes were found, and expression of LC3B and HMGB1 was increased by ioversol in HK-2 cells. Paricalcitol countered these effects. This study showed that mitochondria might drive injury phenotypes in CI-AKI, and that paricalcitol protects against CI-AKI by decreasing mitochondrial damage.


Assuntos
Injúria Renal Aguda/tratamento farmacológico , Ergocalciferóis/farmacologia , Mitocôndrias/efeitos dos fármacos , Mitofagia/efeitos dos fármacos , Injúria Renal Aguda/induzido quimicamente , Animais , Meios de Contraste/efeitos adversos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/metabolismo , Masculino , Mitocôndrias/metabolismo , Ratos , Ubiquitina-Proteína Ligases/efeitos dos fármacos
7.
Int J Mol Sci ; 21(11)2020 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-32531940

RESUMO

Radioiodine (RI) therapy is known to cause salivary gland (SG) dysfunction. The effects of antioxidants on RI-induced SG damage have not been well described. This study was performed to investigate the radioprotective effects of alpha lipoic acid (ALA) administered prior to RI therapy in a mouse model of RI-induced sialadenitis. Four-week-old female C57BL/6 mice were divided into four groups (n = 10 per group): group I, normal control; group II, ALA alone (100 mg/kg); group III, RI alone (0.01 mCi/g body weight, orally); and group IV, ALA + RI (ALA at 100 mg/kg, 24 h and 30 min before RI exposure at 0.01 mCi/g body weight). The animals in these groups were divided into two subgroups and euthanized at 30 or 90 days post-RI treatment. Changes in salivary 99mTc pertechnetate uptake and excretion were tracked by single-photon emission computed tomography. Salivary histological examinations and TUNEL assays were performed. The 99mTc pertechnetate excretion level recovered in the ALA treatment group. Salivary epithelial (aquaporin 5) cells of the ALA + RI group were protected from RI damage. The ALA + RI group exhibited more mucin-containing parenchyma and less fibrotic tissues than the RI only group. Fewer apoptotic cells were observed in the ALA + RI group compared to the RI only group. Pretreatment with ALA before RI therapy is potentially beneficial in protecting against RI-induced salivary dysfunction.


Assuntos
Lesões Experimentais por Radiação/prevenção & controle , Protetores contra Radiação/farmacologia , Glândulas Salivares/efeitos da radiação , Sialadenite/prevenção & controle , Ácido Tióctico/farmacologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Aquaporina 5/metabolismo , Peso Corporal/efeitos dos fármacos , Peso Corporal/efeitos da radiação , Senescência Celular/efeitos dos fármacos , Senescência Celular/efeitos da radiação , Ensaio de Imunoadsorção Enzimática , Feminino , Radioisótopos do Iodo/efeitos adversos , Camundongos Endogâmicos C57BL , Lesões Experimentais por Radiação/etiologia , Radioterapia/efeitos adversos , Radioterapia/métodos , Saliva/efeitos dos fármacos , Saliva/efeitos da radiação , Glândulas Salivares/efeitos dos fármacos , Glândulas Salivares/fisiopatologia , Sialadenite/etiologia , Testes de Função Tireóidea
8.
Int J Mol Sci ; 21(10)2020 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-32414157

RESUMO

Acute kidney injury (AKI) is the most common condition in hospitalized patients. As ischemia/reperfusion-induced AKI (IR-AKI) is as a major contributor to end-stage disease, an effective therapeutic intervention for IR-AKI is imperative. Erythropoietin (EPO) is a potent stimulator of erythroid progenitor cells and is significantly upregulated during hypoxia. Here, we investigated the renoprotective effects of EPO in an IR-AKI mouse model. Mice were assigned to sham, EPO only, and IR only groups, and the IR group was treated with EPO prior to injury. EPO was administered twice at 30 min prior to bilateral renal artery occlusion, and 5 min before reperfusion, with all mice sacrificed 24 h after IR-AKI. The serum was harvested for renal functional measurements. The kidneys were subjected to histological evaluation, and the biochemical changes associated with renal injury were assessed. EPO significantly attenuated the renal dysfunction associated with IR-AKI, as well as tissue injury. Apoptotic cell death and oxidative stress were significantly reduced in EPO-treated mice. Macrophage infiltration and expression of ICAM-1 and MCP-1 were also significantly reduced in EPO-treated mice. Furthermore, the expression of inflammasome-related factors (NLRP1, NLRP3, and caspase-1 cleavage), via the activation of the COX-2 and NF-B signaling pathways were significantly reduced following EPO treatment. To our knowledge, this is the first study to demonstrate that inflammasome-mediated inflammation might be a potential target of EPO as a treatment for ischemic AKI.


Assuntos
Injúria Renal Aguda/tratamento farmacológico , Eritropoetina/genética , Rim/efeitos dos fármacos , Traumatismo por Reperfusão/tratamento farmacológico , Injúria Renal Aguda/genética , Injúria Renal Aguda/patologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/genética , Caspase 1/genética , Hipóxia Celular/genética , Ciclo-Oxigenase 2/genética , Modelos Animais de Doenças , Células Precursoras Eritroides/efeitos dos fármacos , Eritropoetina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamassomos/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/patologia
9.
Int J Mol Sci ; 21(7)2020 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-32218158

RESUMO

Radiation therapy is a standard treatment for patients with head and neck cancer. However, radiation exposure to the head and neck induces salivary gland (SG) dysfunction. Alpha lipoic acid (ALA) has been reported to reduce radiation-induced toxicity in normal tissues. In this study, we investigated the effect of ALA on radiation-induced SG dysfunction. Male Sprague-Dawley rats were assigned to the following treatment groups: control, ALA only (100 mg/kg, intraperitoneally), irradiation only, and ALA administration 24 h or 30 min prior to irradiation. The neck area, including SGs, was irradiated evenly at 2 Gy/min (total dose, 18 Gy) using a photon 6 MV linear accelerator. The rats were sacrificed at 2, 6, 8, and 12 weeks after irradiation. Radiation decreased SG weight, saliva secretion, AQP5 expression, parasympathetic innervation (GFRα2 and AchE expression), regeneration potentials (Shh and Ptch expression), salivary trophic factor levels (brain-derived neurotrophic factor and neurturin), and stem cell expression (Sca-1). These features were restored by treatment with ALA. This study demonstrated that ALA can rescue radiation-induced hyposalivation by preserving parasympathetic innervation and regenerative potentials.


Assuntos
Lesões Experimentais por Radiação/tratamento farmacológico , Glândulas Salivares/efeitos dos fármacos , Ácido Tióctico/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Masculino , Tamanho do Órgão/efeitos dos fármacos , Lesões Experimentais por Radiação/patologia , Ratos Sprague-Dawley , Glândulas Salivares/patologia
10.
Clin Exp Reprod Med ; 46(3): 132-139, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31405270

RESUMO

OBJECTIVE: Vitamin D-binding protein (VDBP) mediates various biological processes in humans. The goal of this study was to investigate whether VDBP gene polymorphisms could predispose Korean women to endometriosis. METHODS: We prospectively enrolled women with endometriosis (n = 16) and healthy controls (n = 16). Total serum 25-hydroxyl vitamin D (25(OH)D) concentrations were measured using an Elecsys vitamin D total kit. Levels of bioavailable and free 25(OH)D were calculated. Concentrations of VDBP were measured using a vitamin D BP Quantikine ELISA kit. DNA was extracted using a DNeasy blood & tissue kit. Two singlenucleotide polymorphisms (SNPs; rs4588 and rs7041) in GC, the gene that codes for VDBP, were analyzed using a TaqMan SNP genotyping assay kit. The functional variant of VDBP was determined based on the results of the two SNPs. RESULTS: Gravidity and parity were significantly lower in the endometriosis patients than in the control group, but serum CA-125 levels and the erythrocyte sedimentation rate were significantly higher. Total serum 25(OH)D levels in the endometriosis patients were significantly lower than in the control group. However, serum bioavailable 25(OH)D, free 25(OH)D, and VDBP levels did not differ significantly between the endometriosis and control groups. The genotypes and allele frequencies of GC were similar in both groups. CONCLUSION: Korean women with endometriosis had lower total serum 25(OH)D concentrations than controls. Neither serum VDBP concentrations nor polymorphisms in the gene coding for VDBP were associated with endometriosis. Further studies are needed to investigate the pathophysiology and clinical implications of 25(OH)D and VDBP in endometriosis.

11.
Neurol Sci ; 40(8): 1597-1605, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30982131

RESUMO

BACKGROUND: Meningitis is an inflammatory process involving meninges. It is difficult to diagnose because of the absence of a diagnostic biomarker. We first report here the possibility of cerebrospinal fluid (CSF) vitamin D-binding protein (VDBP) as a new biomarker for the diagnosis of meningitis. METHODS: This prospective study enrolled a total of 102 subjects (58 patients with non-neurologic disease, 17 patients with meningitis, and 27 patients with other neurologic diseases) from 2017 to 2018. CSF and blood samples were collected in pairs. Total 25(OH)D in CSF and serum and VDBP levels in serum were measured. GC genotyping was also performed to determine polymorphisms of rs4588 and rs7041. CSF total 25(OH)D and VDBP levels were compared with serum total 25(OH)D and VDBP levels according to disease (meningitis vs. non-meningitis). Receiver operating characteristic (ROC) analysis for the diagnosis of meningitis using CSF VDBP level was performed. RESULTS: Mean CSF VDBP and serum VDBP levels of all patients were 1.48 ± 1.32 and 181.28 ± 56.90 µg/mL, respectively. CSF VDBP level in the meningitis disease group (3.20 ± 1.49 µg/mL) was significantly (P < 0.001) higher than that in other disease groups. According to ROC curve analysis, the appropriate cut-off value for CSF VDBP was 1.96 µg/mL, showing sensitivity of 82.4% and specificity of 85.9%. AUC of CSF VDBP was 0.879 (95% CI: 0.789-0.962). CONCLUSIONS: CSF VDBP level showed very good diagnostic performance. It could be used as a potential biomarker for the diagnosis of meningitis.


Assuntos
Biomarcadores/líquido cefalorraquidiano , Meningite/líquido cefalorraquidiano , Meningite/diagnóstico , Proteína de Ligação a Vitamina D/líquido cefalorraquidiano , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sensibilidade e Especificidade , Adulto Jovem
12.
PLoS One ; 14(3): e0213389, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30889212

RESUMO

Epidemiological investigations have suggested that serum 25-hydroxyvitamin D [25(OH)D] level has significantly inverse associations with various neurological and neurodegenerative diseases. However, little is known about 25(OH)D level in human cerebrospinal fluid (CSF). Thus, the aim of this study was to determine correlations of 25(OH)D level in CSF with serum total, bioavailable, and free 25(OH)D levels. This observational study enrolled a total of 117 subjects (58 patients with non-neurologic disease and 59 patients with neurologic disease) from 2017 to 2018. CSF and blood samples were collected in pairs. Total 25(OH)D levels in CSF and serum and vitamin D binding protein (VDBP) levels in serum were measured. We also performed GC genotyping for polymorphisms of rs4588 and rs7041 to calculate bioavailable and free 25(OH)D levels. CSF total 25(OH)D levels were compared with serum total, bioavailable, and free 25(OH)D levels. Mean total 25(OH)D concentrations in CSF and serum of all patients were 37.14 ± 7.71 and 25.72 ± 12.37 ng/mL, respectively. The mean total 25(OH)D concentration in CSF was generally 1.4-fold higher than that in the serum. Total 25(OH)D concentrations in CSF showed weakly positive but significant correlations with serum total, bioavailable, and free 25(OH)D concentrations (P = 0.022, P = 0.033, and P = 0.026, respectively). Serum total 25(OH)D concentration was also correlated with serum VDBP concentration (P = 0.017). However, total 25(OH)D levels in CSF of non-neurologic disease group and neurologic disease group were similar. Total 25(OH)D level in CSF has weakly positive but significant correlations with serum total, bioavailable, and free 25-hydroxy vitamin D levels in the Korean population. The distribution of CSF total 25(OH)D in Korean neurologic and non-neurologic disease patients was presented.


Assuntos
Vitamina D/análogos & derivados , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Disponibilidade Biológica , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso/sangue , Doenças do Sistema Nervoso/líquido cefalorraquidiano , Doenças do Sistema Nervoso/genética , Polimorfismo de Nucleotídeo Único , República da Coreia , Vitamina D/sangue , Vitamina D/líquido cefalorraquidiano , Proteína de Ligação a Vitamina D/sangue , Proteína de Ligação a Vitamina D/genética , Adulto Jovem
13.
Int J Endocrinol ; 2019: 9120467, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30774661

RESUMO

BACKGROUND: Bioavailable 25-hydroxy vitamin D (25(OH)D) has been suggested for the accurate determination of vitamin D status. The purpose of this study was to determine the utility of bioavailable 25(OH)D in assessing vitamin D status when vitamin D-binding protein (VDBP) was significantly altered by pregnancy and liver cirrhosis (LC). The role of genotyping of GC, a gene encoding VDBP, in the determination of bioavailable 25(OH)D concentration in a Korean population was also evaluated. METHODS: This prospective study enrolled a total of 136 subjects (53 healthy controls, 45 patients with LC, and 38 pregnant women) from 2017 to 2018. The concentrations of total 25(OH)D and VDBP were measured, and bioavailable 25(OH)D concentrations were calculated. GC genotyping was performed to determine rs4588 and rs7041 polymorphisms. Clinical and laboratory data were compared among the three groups of subjects. RESULTS: Median VDBP and total 25(OH)D concentrations were 165.2 µg/ml and 18.5 ng/ml in healthy controls, 76.9 µg/ml and 10.5 ng/ml in patients with LC, and 368.9 µg/ml and 17.7 ng/ml in pregnant women, respectively. Compared with controls, patients diagnosed with LC had significantly lower VDBP and total 25(OH)D concentrations (all P < 0.001) while pregnant women had significantly higher VDBP concentrations (P < 0.001). Although total 25(OH)D concentrations in pregnant women were similar to those in controls (P = 0.394), their bioavailable 25(OH)D concentrations were significantly lower (1.2 vs. 3.0 ng/ml; P < 0.001). Among all the three groups combined, the genotype-specific bioavailable 25(OH)D and the genotype-independent bioavailable 25(OH)D concentrations did not differ significantly (P = 0.299). CONCLUSIONS: Our study has demonstrated that bioavailable 25(OH)D concentration reflects vitamin D status more accurately than the total 25(OH)D concentration, especially in pregnant women. In addition, GC genotyping did not significantly affect bioavailable 25(OH)D concentration. Therefore, if VDBP concentration is significantly altered, the measurement of bioavailable 25(OH)D concentration might facilitate the accurate determination of vitamin D status. However, GC genotyping might be unnecessary.

14.
Laryngoscope ; 129(8): E266-E271, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30675728

RESUMO

OBJECTIVES: Poor wound healing as reflected by the development of synechia and osteitis after endoscopic sinus surgery may trigger disease recurrence. Animal models provide insights into the pathogenesis of poor wound healing and may aid in the development of new therapeutics. Here, we established a mouse model of nasal wound healing and confirmed its utility. STUDY DESIGN: Animal study. METHODS: Unilateral intranasal wounds were induced using a small interdental brush in 6-week-old C57BL/6 mice. Forty-five mice were divided into three groups (each n = 15): one control and two experimental groups (intranasal vs. intraperitoneal dexamethasone). Mice were sacrificed on days 2, 14, and 28 after injury (each n = 5). Serial changes in nasal wound histopathology were described, and intergroup differences were analyzed. RESULTS: On day 2, mucosal detachment, hemorrhage, and exudate were observed. On day 14, synechiae featuring neo-osteogenesis (bone lacunae, osteoblasts, and multinucleated osteoclasts) between the septum and the maxilloturbinate were prominent, followed by wound maturation on day 28: fewer lacunae and smaller osteoblasts. Macrophages were evident only on day 2, and lymphocytes were predominant on day 28. The amount of exudate on day 2 and the synechial area on day 28 were significantly reduced in mice that received dexamethasone systemically compared with control mice, with similar trends in those treated intranasally. CONCLUSION: Our mouse model of nasal wound healing was characterized by the development of bony synechia and neo-osteogenesis, not soft-tissue synechia. The model may be useful in the assessment of novel therapeutics to prevent those wounds. LEVEL OF EVIDENCE: NA Laryngoscope, 129:E266-E271, 2019.


Assuntos
Anti-Inflamatórios/administração & dosagem , Dexametasona/administração & dosagem , Ferida Cirúrgica/tratamento farmacológico , Cicatrização/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL , Mucosa Nasal/cirurgia , Procedimentos Cirúrgicos Nasais
15.
PLoS One ; 13(11): e0207090, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30408092

RESUMO

There is evidence that pepsin can aggravate tonsil hypertrophy. Pepstatin is a potent inhibitor of pepsin activity and could protect patients against reflux tonsil hypertrophy by inhibiting pepsin. We examined the effects of pepstatin on the development of tonsil hypertrophy to investigate pepsin's role in the pathogenesis of tonsil lesions. We investigated whether pepstatin suppresses pepsin-mediated lymphocyte proliferation in tonsil hypertrophy. Forty-nine children with tonsil hypertrophy and twenty-two adults with tonsillitis were recruited to the study prior to surgery. Tonsil tissue from each patient was harvested and assessed for changes in the number of lymphocytes and macrophages in the presence of pepsin and pepstatin. We found that the proportions of CD4- and CD14-positive cells were significantly lower (p < 0.05), but that the proportions of CD19- and CD68-positive cells were significantly higher (p < 0.05), in children than in adults. There were significantly more CD4-positive cells after pepsin treatment, but these numbers were reduced by pepstatin. The levels of both interleukin-2 (IL-2) and interferon gamma (IFN-γ) increased significantly in response to pepsin, but were reduced when pepsin was inhibited by pepstatin. The level of IL-10 is reduced in pepsin-treated CD4 cells and the level is restored by pepstatin. IL-2 blocking reduced the increased CD4 cell number by pepsin. But, an additive or a synergic effect is not founded in combined with IL-2 blocking and pepstatin. Pepsin-positive cells did not co-localize with CD20 and CD45 cells, but they were found surrounding CD20- and CD45-positive hypertrophic tonsil cells. Pepsin-positive cells co-localized with CD68-positive cells. It is probable that pepsin from extraesophageal reflux aggravates tonsil hypertrophy and pepstatin exerts a protective effect by inhibiting pepsin activity.


Assuntos
Tonsila Palatina/metabolismo , Pepsina A/metabolismo , Pepstatinas/metabolismo , Doenças Faríngeas/metabolismo , Adolescente , Adulto , Envelhecimento/metabolismo , Criança , Pré-Escolar , Feminino , Humanos , Hipertrofia/metabolismo , Técnicas In Vitro , Interferon gama/metabolismo , Interleucina-10/metabolismo , Interleucina-2/metabolismo , Linfócitos/metabolismo , Linfócitos/patologia , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Tonsila Palatina/crescimento & desenvolvimento , Tonsila Palatina/patologia , Tonsila Palatina/cirurgia , Doenças Faríngeas/patologia , Doenças Faríngeas/cirurgia
16.
Clin Exp Emerg Med ; 5(3): 192-198, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30269455

RESUMO

OBJECTIVE: Dapsone (diaminodiphenyl sulfone, DDS) is currently used to treat leprosy, malaria, dermatitis herpetiformis, and other diseases. It is also used to treat pneumocystis pneumonia and Toxoplasma gondii infection in HIV-positive patients. The most common adverse effect of DDS is methemoglobinemia from oxidative stress. Ascorbic acid is an antioxidant and reducing agent that scavenges the free radicals produced by oxidative stress. The present study aimed to investigate the effect of ascorbic acid in the treatment of DDS induced methemoglobinemia. METHODS: Male Sprague-Dawley rats were divided into three groups: an ascorbic acid group, a methylene blue (MB) group, and a control group. After DDS (40 mg/kg) treatment via oral gavage, ascorbic acid (15 mg/kg), MB (1 mg/kg), or normal saline were administered via tail vein injection. Depending on the duration of the DDS treatment, blood methemoglobin levels, as well as the nitric oxide levels and catalase activity, were measured at 60, 120, or 180 minutes after DDS administration. RESULTS: Methemoglobin concentrations in the ascorbic acid and MB groups were significantly lower compared to those in the control group across multiple time points. The plasma nitric oxide levels and catalase activity were not different among the groups or time points. CONCLUSION: Intravenous ascorbic acid administration is effective in treating DDS-induced methemoglobinemia in a murine model.

17.
Oncotarget ; 8(42): 72739-72747, 2017 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-29069822

RESUMO

PURPOSE: Radiotherapy is currently one of the main treatment modalities for head and neck cancer; however, it also results in severe toxicity to the normal tissue, to the detriment of patients. This study aimed to investigate whether alpha lipoic acid (ALA) could protect against radiation-induced oral mucositis in a rat model. RESULTS: On post-irradiation days 4 and 7, the epithelial layer on oral mucosa showed pronounced injury (shortening of the layer) and it is diminished by ALA pretreatment before radiation. Hif-1a expression was significantly induced in the radiation group on days 4, 7, and 28. GLUT1 expression was also induced by radiation at all time points, and the expression levels peaked on day 28. Phosphorylated p53 level was significantly higher in the radiation group on days 4 and 7, and Bax protein expression was significantly higher in the same group on day 4 than ALA-pretreated radiation group. TUNEL-positive staining was significantly lower in the ALA-pretreated radiation group. MATERIALS AND METHODS: Rats were assigned to one of the following four groups: control, ALA only (100 mg/kg, i.p.), irradiated, and ALA administered 24 h and 30 min prior to irradiation, with the neck area including the oral mucosa evenly irradiated with 2 Gy per minute (total dose, 18 Gy) using a photon 6-MV linear accelerator. Rats were sacrificed 4, 7, 28, or 56 days after radiation. CONCLUSIONS: The results show that ALA can be used to ameliorate radiation-induced oral mucositis with head and neck cancer.

18.
Sci Rep ; 7: 46065, 2017 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-28378840

RESUMO

The epithelial-to-mesenchymal transition (EMT) is one of mechanisms that induce renal interstitial fibrosis. Understanding EMT in renal fibrosis has important therapeutic implications for patients with kidney disease. Alpha-lipoic acid (ALA) is a natural compound with antioxidant properties. Studies for ALA are performed in acute kidney injury with renal tubular apoptosis, renal inflammation, and oxidative stress. We investigated the effects of ALA on EMT-mediated renal interstitial fibrosis in mice with unilateral ureteral obstruction (UUO). UUO mice developed severe tubular atrophy and tubulointerstitial fibrosis, with a robust EMT response and ECM deposition after 7 postoperative days. In contrast, ALA-treated UUO mice showed only moderate injury and minimal fibrosis and also larger reductions in the expression of ECM proteins, inflammatory factors, and EMT markers. ALA was shown to be involved in the suppression of infiltrating macrophages associated with EMT and the progression of interstitial fibrosis. It also lessened the destruction of the tubular basement membrane, by reducing the expression of matrix metalloproteinases. This is the first study to show that ALA modulates EMT in a UUO mouse model. Our results suggest that ALA merits further exploration as a therapeutic agent in the prevention and treatment of chronic kidney disease.


Assuntos
Transição Epitelial-Mesenquimal , Ácido Tióctico/uso terapêutico , Obstrução Ureteral/tratamento farmacológico , Obstrução Ureteral/patologia , Animais , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Fibrose , Inflamação/patologia , Molécula 1 de Adesão Intercelular/metabolismo , Rim/efeitos dos fármacos , Rim/patologia , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Fosforilação/efeitos dos fármacos , Transdução de Sinais , Proteínas Smad/metabolismo , Ácido Tióctico/farmacologia , Fator de Crescimento Transformador beta1/metabolismo , Obstrução Ureteral/enzimologia
19.
Int Forum Allergy Rhinol ; 6(11): 1139-1144, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27309728

RESUMO

BACKGROUND: Although topical corticosteroids are considered a safe and effective drug for allergic rhinitis (AR), some AR patients do not show sufficient symptomatic improvement by use of topical corticosteroids. Topical cyclosporine is a safe and effective drug for patients with allergic conjunctivitis, particularly for those with steroid-resistant allergic conjunctivitis. We investigated the anti-inflammatory effects of intranasal cyclosporine for AR using a mouse model. METHODS: After establishment of allergic inflammation in 5-week-old BALB/c mice, cyclosporine was administered intranasally 3 times per week for 2 weeks. To confirm its anti-inflammatory effects, triamcinolone acetonide (TAC) was utilized as a control drug. Histopathologic changes were evaluated using Sirius red and Giemsa staining for eosinophilic and mast cell infiltration, respectively. The levels of cytokines in sinonasal tissues, including tumor necrosis factor (TNF), interleukin (IL)-4, IL-5, and IL-13, were assessed based on a cytometric bead array. RESULTS: The degree of eosinophilic infiltration was significantly decreased by instillation of cyclosporine, the potency being similar to TAC. However, the number of mast cells was not decreased by cyclosporine or TAC. The levels of TNF, IL-4, IL-5, and IL-13 were significantly decreased after treatment with cyclosporine. CONCLUSION: The anti-inflammatory effects of topical cyclosporine for AR were equivalent to those of topical corticosteroids. Topical cyclosporine may be useful for the treatment of AR, although human studies are required.


Assuntos
Anti-Inflamatórios/administração & dosagem , Ciclosporina/administração & dosagem , Rinite Alérgica/tratamento farmacológico , Administração Intranasal , Animais , Anti-Inflamatórios/uso terapêutico , Contagem de Células , Ciclosporina/uso terapêutico , Citocinas/imunologia , Modelos Animais de Doenças , Eosinófilos , Mastócitos , Camundongos Endogâmicos BALB C , Mucosa Nasal/citologia , Mucosa Nasal/imunologia , Mucosa Nasal/patologia , Rinite Alérgica/imunologia , Rinite Alérgica/patologia
20.
PLoS One ; 11(4): e0152336, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27058240

RESUMO

BACKGROUND: Gastroesophageal reflux is associated with numerous pathologic conditions of the upper aerodigestive tract. Gastric pepsin within reflux contributes to immunologic reactions in the tonsil. In this study, we aimed to find the relationships between pepsin and tonsillar hypertrophy. METHODS AND FINDING: We explored the notion whether tonsillar hypertrophy was due to pepsin-mediated gastric reflux in tonsil hypertrophy. Fifty-four children with tonsil hypertrophy and 30 adults with tonsillitis were recruited before surgical treatment. Blood and tonsil tissues from each patient were harvested for analysis of changes in lymphocyte and macrophage numbers coupled with histological and biochemical analysis. Pepsin was expressed at different levels in tonsil tissues from each tonsillar hypertrophy. Pepsin-positive cells were found in the crypt epithelium, surrounding the lymphoid follicle with developing fibrosis, and also surrounding the lymphoid follicle that faced the crypt. And also, pepsin staining was well correlated with damaged tonsillar squamous epithelium and TGF-ß1 and iNOS expression in the tonsil section. In addition, pepsin and TGF-ß1-positive cells were co-localized with CD68-positive cells in the crypt and surrounding germinal centers. In comparison of macrophage responsiveness to pepsin, peripheral blood mononuclear cells (PBMNCs) were noticeably larger in the presence of activated pepsin in the child group. Furthermore, CD11c and CD163-positive cells were significantly increased by activated pepsin. However, this was not seen for the culture of PBMNCs from the adult group. CONCLUSIONS: The lymphocytes and monocytes are in a highly proliferative state in the tonsillar hypertrophy and associated with increased expression of pro-inflammatory factors as a result of exposure to stomach reflux pepsin.


Assuntos
Hipertrofia/patologia , Macrófagos/patologia , Tonsila Palatina/patologia , Pepsina A/farmacologia , Estômago/patologia , Tonsilite/patologia , Adulto , Western Blotting , Movimento Celular , Sobrevivência Celular , Células Cultivadas , Criança , Pré-Escolar , Feminino , Imunofluorescência , Fármacos Gastrointestinais/farmacologia , Humanos , Hipertrofia/induzido quimicamente , Técnicas Imunoenzimáticas , Imunoprecipitação , Macrófagos/efeitos dos fármacos , Masculino , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estômago/efeitos dos fármacos , Tonsilite/induzido quimicamente
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