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1.
Kidney Int ; 102(6): 1276-1290, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36049642

RESUMEN

Activated monocytes/macrophages promote glomerular injury, including crescent formation, in anti-glomerular basement membrane (GBM) glomerulonephritis. Disulfiram, an alcohol-aversion drug, inhibits monocyte/macrophage migration by inhibiting FROUNT, a cytosolic protein that enhances chemokine receptor signaling. Our study found that disulfiram at a human equivalent dose successfully blocked albuminuria and crescent formation with podocyte loss, and later stage kidney fibrotic lesions, in a rat model of anti-GBM glomerulonephritis. A disulfiram derivative, DSF-41, with more potent FROUNT inhibition activity, inhibited glomerulonephritis at a lower dose than disulfiram. Disulfiram markedly reduced the number of monocytes or macrophages at the early stage of glomerulonephritis and that of CD3+ and CD8+ lymphocytes at the established stage. Impaired pseudopodia formation was observed in the glomerular monocytes/macrophages of the disulfiram group; consistent with the in vitro observation that disulfiram blocked chemokine-dependent pseudopodia formation and chemotaxis of bone marrow-derived monocytes/macrophages. Furthermore, disulfiram suppressed macrophage activation as revealed by reduced expression of inflammatory cytokines and chemokines (TNF-α, CCL2, and CXCL9) and reduced CD86 and MHC class II expressions in monocytes/macrophages during glomerulonephritis. The dramatic reduction in monocyte/macrophage number might have resulted from disulfiram suppression of both the chemotactic response of monocytes/macrophages and their subsequent activation to produce cytokines and chemokines, which further recruit monocytes. Additionally, FROUNT was expressed in CD68+ monocytes/macrophages infiltrating the crescentic glomeruli in human anti-GBM glomerulonephritis. Thus, disulfiram can be a highly effective and safe drug for the treatment of glomerulonephritis by blocking the chemotactic responses of monocytes/macrophages and their activation status in the glomerulus.


Asunto(s)
Glomerulonefritis Membranoproliferativa , Glomerulonefritis , Ratas , Humanos , Animales , Disulfiram/farmacología , Disulfiram/uso terapéutico , Ratas Endogámicas WKY , Quimiocinas/metabolismo , Glomerulonefritis/tratamiento farmacológico , Glomerulonefritis/patología , Citocinas/metabolismo
2.
Am J Pathol ; 191(11): 1986-1998, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34390681

RESUMEN

Hyaluronan (HA)-binding protein involved in HA depolymerization (HYBID) is involved in cartilage destruction via HA depolymerization in human knee osteoarthritis. However, the role of HYBID in the progression of osteoarthritis remain elusive. This study sought to examine whether genetic depletion of Hybid could suppress surgically induced osteoarthritis of mouse knee joints. In osteoarthritis induced by medial collateral ligament transection with meniscus removal, articular cartilage destruction and osteophyte formation at the medial femoral-tibial joint were significantly inhibited in Hybid-deficient (Hybid-/-) mice compared with wild-type mice. Hybid was highly produced by synovial cells and articular chondrocytes in the osteoarthritis joints of wild-type mice. IL-1ß, IL-6, and tumor necrosis factor-α were up-regulated in the osteoarthritis joint tissues of both wild-type and Hybid-/- mice. Vascular density at the synovial and periosteal junction was significantly reduced in Hybid-/- mice compared with wild-type mice. High-molecular-weight HA accumulated in osteoarthritis joint tissues of Hybid-/- mice. Injections of high-molecular-weight HA to knee joints attenuated the cartilage destruction and osteophyte formation in wild-type mouse osteoarthritis group. Inhibition of cartilage destruction and osteophyte formation in Hybid-/- mice was also observed in destabilization of the medial meniscus model. These data are the first to demonstrate that cartilage destruction and osteophyte formation are suppressed in Hybid-/- mice and suggest that Hybid-mediated HA depolymerization is implicated for the progression of mechanically-induced knee osteoarthritis.


Asunto(s)
Ácido Hialurónico/metabolismo , Osteoartritis de la Rodilla/metabolismo , Osteoartritis de la Rodilla/patología , Animales , Cartílago Articular/metabolismo , Cartílago Articular/patología , Modelos Animales de Enfermedad , Ratones
3.
Clin Exp Nephrol ; 26(3): 216-225, 2022 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-34665348

RESUMEN

BACKGROUND: Low-vacuum scanning electron microscopy (LV-SEM) is applied to diagnostic renal pathology. METHODS: To demonstrate the usefulness of LV-SEM and to clarify the optimal conditions of pathology samples, we investigated the alterations of glomerular basement membrane (GBM) and podocytes in control and experimental active Heymann nephritis (AHN) rats by LV-SEM. RESULTS: On week 15 following induction of AHN, spike formation on GBM with diffuse deposition of IgG and C3 developed. Using LV-SEM, diffuse crater-like protrusions were clearly noted three-dimensionally (3D) on surface of GBM in the same specimens of light microscopy (LM) and immunofluorescence (IF) studies only after removal coverslips or further adding periodic acid-silver methenamine (PAM) staining. These 3D ultrastructural findings of GBM surface could be detected in PAM-stained specimens by LV-SEM, although true GBM surface findings could not be obtained in acellular glomeruli, because some subepithelial deposits remained on surface of GBM. Adequate thickness was 1.5-5 µm for 10% formalin-fixed paraffin-embedded (FFPE) and 5-10 µm for the unfixed frozen sections. The foot processes and their effacement of podocytes could be observed by LV-SEM using 10%FFPE specimens with platinum blue (Pt-blue) staining or double staining of PAM and Pt-blue. These findings were obtained more large areas in 2.5% glutaraldehyde-fixed paraffin-embedded (2.5%GFPE) specimens. CONCLUSION: Our findings suggest that LV-SEM is a useful assessment tool for evaluating the alterations of GBM and podocytes in renal pathology using routine LM and IF specimens, as well as 2.5%GFPE specimens.


Asunto(s)
Membrana Basal Glomerular , Podocitos , Animales , Membrana Basal Glomerular/patología , Humanos , Riñón/ultraestructura , Microscopía Electrónica de Rastreo , Podocitos/patología , Ratas , Vacio
4.
Skin Res Technol ; 28(1): 58-65, 2022 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-34455631

RESUMEN

BACKGROUND: Hyaluronan (HA) has a unique hydration capacity that contributes to firmness and bounciness of the skin. Epidermal HA declines with skin aging, which may lead to clinical signs of aging including skin wrinkles and loss of hydration and elasticity. Recently, we developed a new cosmetic agent 1-ethyl-ß-N-acetylglucosaminide (ß-NAG2), which enhances HA production in cultured human keratinocytes. The aim of this study was to explore antiaging potential of ß-NAG2 in reconstructed human epidermal models and human clinical trial. MATERIALS AND METHODS: The amount of HA in ß-NAG2-treated epidermal models by topical application was analyzed by enzyme-linked immunosorbent assay (ELISA)-like assay. A randomized, double-blind and placebo-controlled study was conducted in Japanese females (n = 33) by topically treating each side of the face with a lotion formulated with ß-NAG2 or placebo for 8 weeks. RESULTS: Topically applied ß-NAG2 dose dependently increased HA production in epidermal models. Treatment with ß-NAG2-formulated lotion significantly improved skin hydration and elasticity and reduced skin wrinkling in crow's foot areas when compared to the placebo formulation. CONCLUSION: Topically applied ß-NAG2 promoted epidermal HA production in vitro and showed antiwrinkle activity in vivo accompanying the improvement in skin hydration and elasticity. Our study provides a novel strategy for antiwrinkle care through ß-NAG2-induced epidermal HA production.


Asunto(s)
Ácido Hialurónico , Envejecimiento de la Piel , Epidermis , Femenino , Humanos , Queratinocitos , Piel
5.
Int J Mol Sci ; 23(5)2022 Feb 22.
Artículo en Inglés | MEDLINE | ID: mdl-35269567

RESUMEN

Hyaluronan (HA), an essential component of the extracellular matrix of the skin, is synthesized by HA synthases (HAS1-3). To date, epidermal HA has been considered a major player in regulating cell proliferation and differentiation. However, a previous study reported that depletion of epidermal HA by Streptomyces hyaluronidase (St-HAase) has no influence on epidermal structure and function. In the present study, to further explore roles of epidermal HA, we examined effects of siRNA-mediated knockdown of HAS3, as well as conventional HA-depletion methods using St-HAase and 4-methylumbelliferone (4MU), on epidermal turnover and architecture in reconstructed skin or epidermal equivalents. Consistent with previous findings, HA depletion by St-HAase did not have a substantial influence on the epidermal architecture and turnover in skin equivalents. 4MU treatment resulted in reduced keratinocyte proliferation and epidermal thinning but did not seem to substantially decrease the abundance of extracellular HA. In contrast, siRNA-mediated knockdown of HAS3 in epidermal equivalents resulted in a significant reduction in epidermal HA content and thickness, accompanied by decreased keratinocyte proliferation and differentiation. These results suggest that HAS3-mediated HA production, rather than extracellularly deposited HA, may play a role in keratinocyte proliferation and differentiation, at least in the developing epidermis in reconstructed epidermal equivalents.


Asunto(s)
Hialuronano Sintasas/genética , Ácido Hialurónico/metabolismo , Hialuronoglucosaminidasa/farmacología , Himecromona/farmacología , Queratinocitos/citología , Proteínas Bacterianas/farmacología , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Epidermis/efectos de los fármacos , Epidermis/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Humanos , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Streptomyces/enzimología
6.
J Biol Chem ; 295(8): 2483-2494, 2020 02 21.
Artículo en Inglés | MEDLINE | ID: mdl-31949043

RESUMEN

The immune-regulatory compound histamine is involved in the metabolism of the essential skin component hyaluronan (HA). We previously reported that histamine up-regulates the expression of HYBID (hyaluronan-binding protein involved in hyaluronan depolymerization, also called CEMIP or KIAA1199), which plays a key role in HA degradation. However, no information is available about histamine's effects on HA synthase (HAS) expression, the molecular sizes of HA species produced, and histamine receptors and their signaling pathways in skin fibroblasts. Moreover, histamine's effects on photoaged skin remain elusive. Here, we show that histamine increases HA degradation by up-regulating HYBID and down-regulating HAS2 in human skin fibroblasts in a dose- and time-dependent manner and thereby decreases the total amounts and sizes of newly produced HA. Histamine H1 blocker abrogated the histamine effects on HYBID up-regulation, HAS2 suppression, and HA degradation. Histamine H1 agonist exhibited effects on HA levels, composition, and breakdown similar to those of histamine. Of note, blockade of protein kinase Cδ or PI3K-Akt signaling abolished histamine-mediated HYBID stimulation and HAS2 suppression, respectively. Immunohistochemical experiments revealed a significant ∼2-fold increase in tryptase-positive mast cells in photoaged skin, where HYBID and HAS2 expression levels were increased and decreased, respectively, compared with photoprotected skin. These results indicate that histamine controls HA metabolism by up-regulating HYBID and down-regulating HAS2 via distinct signaling pathways downstream of histamine receptor H1. They further suggest that histamine may contribute to photoaged skin damage by skewing HA metabolism toward degradation.


Asunto(s)
Fibroblastos/metabolismo , Histamina/farmacología , Hialuronano Sintasas/metabolismo , Ácido Hialurónico/metabolismo , Hialuronoglucosaminidasa/metabolismo , Piel/citología , Línea Celular , Fibroblastos/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Hialuronano Sintasas/genética , Hialuronoglucosaminidasa/genética , Mastocitos/efectos de los fármacos , Mastocitos/metabolismo , Peso Molecular , Fosfatidilinositol 3-Quinasas/metabolismo , Proteína Quinasa C-delta/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores Histamínicos/metabolismo , Transducción de Señal/efectos de los fármacos , Envejecimiento de la Piel/efectos de los fármacos , Factores de Tiempo
7.
Biosci Biotechnol Biochem ; 85(6): 1433-1440, 2021 May 25.
Artículo en Inglés | MEDLINE | ID: mdl-33836055

RESUMEN

Regulation of hyaluronan (HA) is important for the maintenance of epidermal homeostasis. Here, we examined the mechanism by which 1-ethyl-ß-N-acetylglucosaminide (ß-NAG2), a newly developed N-acetylglucosamine (NAG) derivative, increases HA production in cultured human epidermal keratinocytes. When keratinocytes were treated with ß-NAG2, mRNA expression of HA synthase 3, which is responsible for HA production in human keratinocytes, was not influenced, but the intracellular level of UDP-NAG, a substrate used for HA synthesis, was increased. By using a synthetic substrate for ß-N-acetylglucosaminidase (ß-NAGase), keratinocytes were found to possess ß-NAGase activity, and treatment of o-(2-acetamido-2-deoxy-d-glucopyranosylidene) amino N-phenyl carbamate (PUGNAc), an inhibitor of ß-NAGase, abolished the release of NAG from ß-NAG2 in keratinocytes. Furthermore, PUGNAc attenuated the ß-NAG2-induced intracellular UDP-NAG and HA production in keratinocytes. These results suggest that ß-NAG2 is converted to NAG by endogenous ß-NAGase in keratinocytes, and the resulting NAG is further metabolized to UDP-NAG and utilized for HA production.


Asunto(s)
Acetilglucosamina/metabolismo , Acetilglucosaminidasa/metabolismo , Ácido Hialurónico/biosíntesis , Queratinocitos/metabolismo , Glicosilación , Humanos
8.
Clin Exp Nephrol ; 23(5): 638-649, 2019 May.
Artículo en Inglés | MEDLINE | ID: mdl-30687875

RESUMEN

BACKGROUND: Thin basement membrane nephropathy (TBMN) is diagnosed by diffuse thinning of the glomerular basement membrane (GBM) without any clinical and pathologic findings of Alport syndrome and the other renal diseases. TBMN is characterized clinically by benign familial hematuria but rarely develops into end-stage renal disease. METHODS: In 27 cases of biopsy-proven TBMN, we evaluated the pathologic characteristics of TBMN, and examined the correlation between these pathologic characterizations and renal dysfunction. RESULTS: All patients had hematuria, and 21 patients (77.8%) had proteinuria. In six patients (28.6%) who were more than 50 years of age, the estimated glomerular filtration rate (eGFR) decreased from G3a to G4 in the chronic kidney disease stage. Pathologically, an irregular decrease in intensity of type IV collagen α5(IV) chain was seen in GBM, and irregular thinning with diffuse rough etched images was observed on the GBM surface with several sizes of holes by low-vacuum scanning electron microscopy. The glomerular morphology of TBMN was characterized by an increased number of small glomerular capillaries with an increased extracellular matrix (ECM). These characteristic morphologic alterations were evident from a young age in patients with TBMN, but were not correlated directly with the decrease of eGFR, the degree of hematuria, and proteinuria. The decrease of eGFR in patients with TBMN who were more than 50 years of age might be primarily mediated by arteriolosclerosis-associated glomerulosclerosis and interstitial fibrosis. CONCLUSION: Characteristic pathological glomerular findings and GBM alterations occurred from a young age but were not associated directly with renal impairment in biopsy-proven TBMN.


Asunto(s)
Membrana Basal Glomerular/ultraestructura , Hematuria/patología , Adolescente , Adulto , Biopsia , Niño , Preescolar , Femenino , Tasa de Filtración Glomerular , Hematuria/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto Joven
9.
Clin Exp Nephrol ; 22(4): 871-880, 2018 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-29372474

RESUMEN

BACKGROUND: Liquid chromatography-tandem mass spectrometry (LC-MS/MS) has recently been utilized to accurately detect the amyloid proteins of renal amyloidosis. The present study investigated the optimal procedures for analyzing samples by LCMS/MS, and the advantage of using this technique to diagnosis renal amyloidosis. METHODS: To detect amyloid proteins, laser microdissected glomeruli from AL (n = 13) or AA (n = 10) renal amyloidosis patients were digested and analyzed by LCMS/MS. To determine the best procedures for analyzing samples by LCMS/MS, we examined the suitability of tissue samples, frozen or formalin-fixed paraffin-embedded (FFPE), the number of dissected glomeruli required for analysis (2, 10, or 50 glomeruli), and the amount of trypsin with or without dithiothreitol (DTT). We additionally compared the detection of amyloid proteins between immunostaining and LCMS/MS. RESULTS: Examining 10 dissected glomeruli from FFPE sections digested with trypsin 3 µL (0.1 mg/mL) without DDT made it possible to detect amyloid protein in all 10 AA and in 10 out of 12 AL amyloidosis cases. All AA amyloidosis cases were diagnosed using immunohistochemistry for amyloid A. With immunostaining, however, there were several inconclusive immunoglobulin and/or their light chain staining noted in the AA or AL amyloidosis cases. Even so, LCMS/MS was able to accurately detect amyloid protein in renal amyloidosis. CONCLUSION: The use of 10 laser microdissected glomeruli (170,000-220,000 µm2) with amyloid deposition from FFPE sections digested with trypsin 3 µL (0.1 mg/mL) allowed the accurate detection of amyloid protein in AA and AL amyloidosis.


Asunto(s)
Amiloidosis/diagnóstico , Cromatografía Liquida , Enfermedades Renales/diagnóstico , Espectrometría de Masas en Tándem , Animales , Humanos , Japón , Glomérulos Renales/patología , Ratones , Microdisección , Conejos
11.
Chudoku Kenkyu ; 29(1): 16-20, 2016 Mar.
Artículo en Japonés | MEDLINE | ID: mdl-27255018

RESUMEN

INTRODUCTION: In cases of transport by rescue helicopter or ambulance of patients having ingested hazardous substances, medical personnel may be at a certain risk of inhaling the substances. However, few reports have addressed such risk of causing secondary casualties. PURPOSE: This simulation study aimed to assess the risk of inhalation of hydrogen sulfide and chlo-opicrin in the cabin of a helicopter or an ambulance transporting a patient who has ingested calcium polysulfide or chloropicrin, which were previously reported to cause secondary casualties. METHOD: Concentrations of hydrogen sulfide and chloropicrin were assessed on the following as-umptions :The patient ingested 100 mL of the causative or original chemical. All chemical substances reacted with the gastric juice or were thoroughly vomited and evaporated uniformly within the cabin space of the helicopter or ambulance. Environmental conditions were 20 *degrees at 1 atmosphere of pres-ure in a 5 m3 cabin volume in the helicopter and a 13.5 m3 cabin volume in the ambulance. RESULTS: In the case of calcium polysulfide ingestion which produced hydrogen sulfide, its concen-ration reached 774 ppm in the helicopter and 287 ppm in the ambulance. For chloropicrin ingestion, the concentrations were 4,824 ppm and 1,787 ppm, respectively. DISCUSSION: The simulated concentration of hydrogen sulfide was more than 500 ppm in the heli-opter, which may lead to respiratory paralysis and death. The simulated concentration of chloropicrin was more than 300 ppm, which has a risk of death within 10 minutes. Currently, as far as Japanese laws are concerned, there are no restrictions requiring pretransport assessment or setting criteria for transporting patients who might have ingested hazardous substances that could cause secondary casu-lties when vomited. CONCLUSION: When patients who might have ingested hazardous chemicals are transported, it is important to recognize the risk of causing secondary casualties by vomiting the chemicals.


Asunto(s)
Ambulancias Aéreas , Ambulancias , Exposición a Riesgos Ambientales/efectos adversos , Exposición a Riesgos Ambientales/análisis , Sustancias Peligrosas/efectos adversos , Exposición por Inhalación/análisis , Exposición por Inhalación/prevención & control , Medición de Riesgo , Transporte de Pacientes , Compuestos de Calcio/efectos adversos , Compuestos de Calcio/análisis , Ingestión de Alimentos , Humanos , Hidrocarburos Clorados/efectos adversos , Hidrocarburos Clorados/análisis , Sulfuro de Hidrógeno/efectos adversos , Sulfuro de Hidrógeno/análisis , Sulfuros/efectos adversos , Sulfuros/análisis , Volatilización
12.
Nat Med ; 13(4): 470-6, 2007 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-17401375

RESUMEN

Infection with Helicobacter pylori (H. pylori) is a risk factor for the development of gastric cancer. Here we show that infection of gastric epithelial cells with 'cag' pathogenicity island (cagPAI)-positive H. pylori induced aberrant expression of activation-induced cytidine deaminase (AID), a member of the cytidine-deaminase family that acts as a DNA- and RNA-editing enzyme, via the IkappaB kinase-dependent nuclear factor-kappaB activation pathway. H. pylori-mediated upregulation of AID resulted in the accumulation of nucleotide alterations in the TP53 tumor suppressor gene in gastric cells in vitro. Our findings provide evidence that aberrant AID expression caused by H. pylori infection might be a mechanism of mutation accumulation in the gastric mucosa during H. pylori-associated gastric carcinogenesis.


Asunto(s)
Citidina Desaminasa/metabolismo , Mucosa Gástrica/metabolismo , Regulación Neoplásica de la Expresión Génica , Genes p53/genética , Infecciones por Helicobacter/genética , Neoplasias Gástricas/genética , Antígenos Bacterianos/metabolismo , Proteínas Bacterianas/metabolismo , Cartilla de ADN , Infecciones por Helicobacter/metabolismo , Humanos , Inmunohistoquímica , Modelos Biológicos , Mutagénesis/genética , FN-kappa B/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/fisiología , Neoplasias Gástricas/microbiología
13.
Nihon Rinsho ; 72(2): 216-20, 2014 Feb.
Artículo en Japonés | MEDLINE | ID: mdl-24605518

RESUMEN

The number of the chemical compounds handled in current Japan is approximately 60,000, and approximately 1,500 of new chemicals are registered every year. Approximately 200 chemicals are regulated. The prescribed industrial disease occurs 200-320 cases in a recent year, and the half are caused by unregulated chemicals. In this report, recent cases, especially the chemicals of which uses are increasing or newly introduced, such as hydrofluoric acid and nitrogen-based organic solvent, are described about onset situations, symptoms and the preventive measures required in handling. In addition, national preventive measures against industrial diseases by the exposure to chemical compounds are described.


Asunto(s)
Enfermedades Profesionales/inducido químicamente , Humanos , Medición de Riesgo
14.
Cureus ; 16(3): e56028, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38606210

RESUMEN

Although immunoglobulin G4 (IgG4)-related kidney diseases are typically characterized by tubulointerstitial nephritis with abundant infiltration of IgG4-positive plasma cells and fibrosis, there have been relatively rare cases of IgG4-related glomerulonephritis. Several cases of IgG4-related disease (IgG4-RD) following coronavirus disease 2019 (COVID-19) mRNA vaccination have been reported. However, there are no reports of IgG4-related glomerulonephritis following COVID-19 vaccination. Herein, we present a case of IgG4-related membranous nephropathy (MN) occurring after COVID-19 vaccination. A 69-year-old Japanese male presented to our hospital with edema that started the day after his second COVID-19 vaccination. The patient exhibited nephrotic syndrome and was diagnosed with MN based on the results of a kidney biopsy. Although serum IgG4 levels were elevated to 946 mg/dL, no evidence of organ involvement suggestive of IgG4-RD was observed. Treatment with prednisolone and cyclosporine resulted in complete remission, and immunosuppressive agents were tapered. However, one month after discontinuing the immunosuppressive agents, the patient was readmitted with swelling around the submandibular glands and exertional dyspnea. Serum IgG4 level was markedly elevated at 2,320 mg/dL, and computed tomography revealed submandibular gland swelling and thickening of the interlobular septum and bronchovascular bundles in both lungs. The patient was diagnosed with IgG4-RD based on elevated serum IgG4 levels and infiltration of IgG4-positive plasma cells in the submandibular gland biopsy. Upon resuming treatment with prednisolone, the symptoms attributed to IgG4-RD improved within a few days. In cases of nephrotic syndrome following COVID-19 vaccination, it may be advisable to conduct detailed examinations to assess the possibility of the development of IgG4-RDs.

15.
Proc Natl Acad Sci U S A ; 107(51): 22237-42, 2010 Dec 21.
Artículo en Inglés | MEDLINE | ID: mdl-21135245

RESUMEN

Etiologic risk factors for hepatocellular carcinoma can be involved in the transformation process by directly targeting intracellular signaling pathways or by indirectly stimulating chronic cycles of hepatocyte destruction and regeneration. However, the contribution of these two routes to hepatocarcinogenesis has not been determined, partly because of the difficulty in distinguishing damaged and regenerated hepatocytes. Here we report that induced deletion of the damaged DNA binding protein 1 (DDB1) abrogates the self-renewing capacity of hepatocytes, resulting in compensatory proliferation of DDB1-expressing hepatocytes. Constitutive stimulation of this regeneration process leads to development of hepatocellular carcinoma, which surprisingly contains no disruption of the DDB1 gene, indicating a cell-nonautonomous role of DDB1 inactivation in tumor initiation. Our results suggest that viruses and hepatoxins may cause liver tumors by simply driving hepatocyte turnover without directly targeting cancer cells.


Asunto(s)
Carcinoma Hepatocelular/metabolismo , Transformación Celular Neoplásica/metabolismo , Proteínas de Unión al ADN/metabolismo , Eliminación de Gen , Neoplasias Hepáticas/metabolismo , Hígado/metabolismo , Proteínas de Neoplasias/metabolismo , Regeneración , Animales , Carcinoma Hepatocelular/genética , Proliferación Celular , Transformación Celular Neoplásica/genética , Proteínas de Unión al ADN/genética , Hepatocitos/metabolismo , Neoplasias Hepáticas/genética , Ratones , Ratones Mutantes , Proteínas de Neoplasias/genética
16.
J Med Invest ; 70(3.4): 457-463, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37940532

RESUMEN

Sarcopenia is widely believed to be linked to poorer outcomes in inpatient rehabilitation. This study aimed to assess the impact of sarcopenia on functional outcomes and dietary intake during hospitalization in adults undergoing convalescent rehabilitation. We conducted a retrospective cohort analysis at a single rehabilitation institution. The Asian Working Group Consensus Criteria for Sarcopenia was used to diagnose. The Functional Independence Measure (FIM) score was used at hospital discharge to measure the primary functional outcome. Energy and protein intakes during hospitalization were calculated as part of the nutritional assessment. There were 126 patients in the research (median age, 73 yr;54% women). Stroke (n = 73;53.4% sarcopenia) and musculoskeletal disorders (n = 53;56.6% sarcopenia) were among the admission diagnoses. Multiple linear regression analysis revealed that the FIM total score at discharge was modestly associated with sarcopenia only in stroke patients (? = 0.1872, P = 0.09), as well as significantly and independently associated with protein intake during admission only in stroke patients (? = 0.3217, P < 0.05). In hospitalized stroke patients undergoing convalescent therapy, sarcopenia is related to lower functional results. Early identification of sarcopenia and treatment with rehabilitation nutrition should be implemented in this population. J. Med. Invest. 70 : 457-463, August, 2023.


Asunto(s)
Sarcopenia , Rehabilitación de Accidente Cerebrovascular , Accidente Cerebrovascular , Adulto , Humanos , Femenino , Anciano , Masculino , Sarcopenia/complicaciones , Sarcopenia/diagnóstico , Actividades Cotidianas , Recuperación de la Función , Estudios Retrospectivos , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/diagnóstico , Resultado del Tratamiento
17.
Int J Cancer ; 130(6): 1294-301, 2012 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-21469143

RESUMEN

Apolipoprotein B mRNA editing enzyme catalytic polypeptide 2 (APOBEC2) was originally identified as a member of the cytidine deaminase family with putative nucleotide editing activity. To clarify the physiologic and pathologic roles, and the target nucleotide of APOBEC2, we established an APOBEC2 transgenic mouse model and investigated whether APOBEC2 expression causes nucleotide alterations in host DNA or RNA sequences. Sequence analyses revealed that constitutive expression of APOBEC2 in the liver resulted in significantly high frequencies of nucleotide alterations in the transcripts of eukaryotic translation initiation factor 4 gamma 2 (Eif4g2) and phosphatase and tensin homolog (PTEN) genes. Hepatocellular carcinoma developed in 2 of 20 APOBEC2 transgenic mice at 72 weeks of age. In addition, constitutive APOBEC2 expression caused lung tumors in 7 of 20 transgenic mice analyzed. Together with the fact that the proinflammatory cytokine tumor necrosis factor-α induces ectopic expression of APOBEC2 in hepatocytes, our findings indicate that aberrant APOBEC2 expression causes nucleotide alterations in the transcripts of the specific target gene and could be involved in the development of human hepatocellular carcinoma through hepatic inflammation.


Asunto(s)
Carcinoma Hepatocelular/patología , Transformación Celular Neoplásica/metabolismo , Citidina Desaminasa/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Pulmonares/patología , Proteínas Musculares/metabolismo , Desaminasas APOBEC , Animales , Secuencia de Bases , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Transformación Celular Neoplásica/genética , Citidina Desaminasa/genética , Factor 4G Eucariótico de Iniciación/genética , Factor 4G Eucariótico de Iniciación/metabolismo , Células Hep G2 , Hepatocitos/metabolismo , Hepatocitos/patología , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas Musculares/genética , Nucleótidos/genética , Nucleótidos/metabolismo , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Edición de ARN , Análisis de Secuencia/métodos , Factor de Necrosis Tumoral alfa/metabolismo
18.
Cancer Sci ; 103(7): 1201-6, 2012 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-22469133

RESUMEN

Chronic inflammation is a strong risk factor for the development of cancer. Many previous studies have demonstrated that a transcriptional factor, nuclear factor (NF)-κB, plays an important role in the association between inflammation and cancer development, particularly tumor promotion and tumor progression. Although it is well recognized that cancer develops via stepwise accumulation of genetic aberrations, the mechanisms underlying the generation of these genetic alterations in normal epithelial cells under inflammatory conditions are not known. We recently demonstrated that pathogenic bacterial or viral factors and the subsequent inflammatory reactions lead to the aberrant expression of a DNA mutator enzyme, activation-induced cytidine deaminase (AID), in various epithelial cells via NF-κB activation, which causes the accumulation of genetic alterations in tumor-related genes. AID activation is widely observed in gastrointestinal tissues with cancer-associated inflammation, such as chronic viral hepatitis, Helicobacter pylori-related gastritis, Barrett's esophagus and inflammatory bowel disease. Furthermore, a deficiency of endogenous AID expression reduces both accumulation of somatic mutations in tumor-related genes and tumor incidence in a mouse model of inflammation-associated cancer development. These findings strongly suggest that AID plays an integral role in inflammation-associated carcinogenesis and is therefore a potential target molecule for the prevention and treatment of cancers.


Asunto(s)
Transformación Celular Neoplásica , Citidina Desaminasa/genética , Inestabilidad Genómica , Inflamación/genética , Animales , Aberraciones Cromosómicas , Citidina Desaminasa/metabolismo , Daño del ADN , Humanos , Inflamación/enzimología , Modelos Genéticos , Mutación
19.
Epidemiology ; 23(3): 368-76, 2012 May.
Artículo en Inglés | MEDLINE | ID: mdl-22415110

RESUMEN

BACKGROUND: Cadmium, a ubiquitous environmental pollutant, is classified as a carcinogenic substance. Several laboratory and epidemiologic studies of workers and subjects in polluted areas have suggested a positive association between cadmium exposure and risk of several cancers. However, data from general populations are sparse. We prospectively examined the association between cadmium exposure and incidence of cancer in a Japanese population with a relatively high dietary intake of cadmium. METHODS: We conducted a population-based prospective study in 90,383 Japanese men and women 45-74 years of age. Participants responded to a validated questionnaire that included 138 food items. We estimated dietary cadmium intake from 6 food groups, based on the questionnaire data. During 9 years of follow-up, 5849 cancer cases were identified. Hazard ratios (HRs) and 95% confidence intervals (CIs) for cancer were calculated by Cox proportional hazards modeling. RESULTS: There was no evidence of an association of cadmium consumption and total cancer, with HRs in the highest versus lowest cadmium intake group of 0.94 (95% CI = 0.82 to 1.08; test for trend, P = 0.46) for men and 0.96 (0.81 to 1.15; 0.60) for women. No site-specific cancers were associated with cadmium intake in men or women. CONCLUSION: We found no associations of cancer with cadmium, at least at the exposure levels observed in a general population in Japan.


Asunto(s)
Cadmio/toxicidad , Contaminación de Alimentos , Neoplasias/inducido químicamente , Adulto , Anciano , Cadmio/análisis , Encuestas sobre Dietas , Femenino , Estudios de Seguimiento , Contaminación de Alimentos/análisis , Encuestas Epidemiológicas , Humanos , Incidencia , Japón/epidemiología , Masculino , Persona de Mediana Edad , Análisis Multivariante , Neoplasias/epidemiología , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Sistema de Registros , Encuestas y Cuestionarios
20.
Environ Health Prev Med ; 17(3): 235-45, 2012 May.
Artículo en Inglés | MEDLINE | ID: mdl-22048870

RESUMEN

OBJECTIVES: Chronic inorganic arsenic (iAs) exposure currently affects tens of millions of people worldwide. To accurately determine the proportion of urinary arsenic metabolites in residents continuously exposed to iAs, we performed arsenic speciation analysis of the urine of these individuals and determined whether a correlation exists between the concentration of iAs in drinking water and the urinary arsenic species content. METHODS: The subjects were 165 married couples who had lived in the Pabna District in Bangladesh for more than 5 years. Arsenic species were measured using high-performance liquid chromatography and inductively coupled plasma mass spectrometry. RESULTS: The median iAs concentration in drinking water was 55 µgAs/L (range <0.5-332 µgAs/L). Speciation analysis revealed the presence of arsenite, arsenate, monomethylarsonic acid (MMA), and dimethylarsinic acid in urine samples with medians (range) of 16.8 (7.7-32.3), 1.8 (<0.5-3.3), 13.7 (5.6-25.0), and 88.6 µgAs/L (47.9-153.4 µgAs/L), respectively. No arsenobetaine or arsenocholine was detected. The concentrations of the 4 urinary arsenic species were significantly and linearly related to each other. The urinary concentrations of total arsenic and each species were significantly correlated with the iAs concentration of drinking water. CONCLUSIONS: All urinary arsenic species are well correlated with each other and with iAs in drinking water. The most significant linear relationship existed between the iAs concentration in drinking water and urinary iAs + MMA concentration. From these results, combined with the effects of seafood ingestion, the best biomarker of iAs exposure is urinary iAs + MMA concentration.


Asunto(s)
Arsénico/análisis , Arsenicales/orina , Agua Potable/química , Monitoreo del Ambiente/métodos , Contaminantes Químicos del Agua/análisis , Adulto , Anciano , Arseniatos/orina , Arsénico/metabolismo , Arsenitos/orina , Bangladesh , Biomarcadores/orina , Ácido Cacodílico/orina , Cromatografía Líquida de Alta Presión , Femenino , Humanos , Modelos Lineales , Masculino , Espectrometría de Masas , Persona de Mediana Edad , Contaminantes Químicos del Agua/orina , Contaminación Química del Agua/análisis
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