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1.
Cells ; 9(4)2020 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-32290250

RESUMO

Interleukin 26 (IL-26) is a new member of the IL-10 family that is highly expressed in rheumatoid arthritis (RA). However, the functions of IL-26 produced by macrophages in RA have not been elucidated. In the present work, we evaluated the effects and the mechanisms of IL-26 on M1 and M2 macrophage differentiation. Human or mouse macrophage cells were treated with lipopolysaccharides (LPS), interferon gamma (IFNγ), or IL-4 alone or concurrently treated with IL-26 to monitor M1 or M2 macrophage subtypes. The expression level of M1 or M2 macrophage genes was evaluated by reverse transcription polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). The molecular mechanisms of downstream signaling activation during differentiation were investigated by immunoblotting assay. Our results found that IL-26 promoted macrophage cells from CD80+ M1 macrophage differentiation, not from the CD206+ M2 phenotype. The messenger RNA of M1-type macrophage markers tumor necrosis factor alpha (TNFα) and inducible nitric oxide synthase (iNOS) was up-regulated in the IL-26-treated group. Also, the M1-related proinflammatory cytokines TNFα and IL-6 were induced after IL-26 stimulation. Interestingly, IL-10, a cytokine marker of M2 macrophage, was also elevated after IL-26 stimulation. Moreover, the M1-like macrophage stimulated by IL-26 underwent cJUN, nuclear factor kappa B (NF-κB), and signal transducer and activator of transcription 1 (STAT1) activation. Our findings suggested the role of IL-26 in synovial macrophages of active rheumatoid arthritis and provided a new insight into IL-26 as a candidate therapeutic target in rheumatoid arthritis.

2.
J Immunol ; 204(6): 1448-1461, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-32060137

RESUMO

Tris (dibenzylideneacetone) dipalladium (Tris DBA), a small-molecule palladium complex, has been shown to inhibit cell growth and proliferation in pancreatic cancer, lymphocytic leukemia, and multiple myeloma. In the current study, we examined the therapeutic effects of Tris DBA on glomerular cell proliferation, renal inflammation, and immune cells. Treatment of accelerated and severe lupus nephritis (ASLN) mice with Tris DBA resulted in improved renal function, albuminuria, and pathology, including measurements of glomerular cell proliferation, cellular crescents, neutrophils, fibrinoid necrosis, and tubulointerstitial inflammation in the kidneys as well as scoring for glomerulonephritis activity. The treated ASLN mice also showed significantly decreased glomerular IgG, IgM, and C3 deposits. Furthermore, the compound was able to 1) inhibit bone marrow-derived dendritic cell-mediated T cell functions and reduce serum anti-dsDNA autoantibody levels; 2) differentially regulate autophagy and both the priming and activation signals of the NLRP3 inflammasome; and 3) suppress the phosphorylation of JNK, ERK, and p38 MAPK signaling pathways. Tris DBA improved ASLN in mice through immunoregulation by blunting the MAPK (ERK, JNK)-mediated priming signal of the NLRP3 inflammasome and by regulating the autophagy/NLRP3 inflammasome axis. These results suggest that the pure compound may be a drug candidate for treating the accelerated and deteriorated type of lupus nephritis.

3.
Kaohsiung J Med Sci ; 36(6): 441-449, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31961055

RESUMO

Although human leucocyte antigen (HLA)-B27 is strongly associated with ankylosing spondylitis (AS), the association of unfolded protein response (UPR) induced by HLA-B27 misfolding in AS remains controversial. Since dendritic cells (DCs) are crucial in induction of AS in HLA-B27-transgenic rats, and plasmacytoid DCs (pDCs) belong to one type of DCs, we here aim to study the relevance of pDCs and UPR in AS. Peripheral pDCs were isolated from 27 HLA-B27(+) AS patients and 37 controls. The bone marrow (BM) and synovium of inflamed hips from AS patients and controls were obtained. We found a significantly higher frequency of pDCs in the peripheral blood, BM, or inflamed synovium of hips, which is associated with the enhanced expression of pDC trafficking molecules, CCR6 and CCL20 in the synovium of AS patients. Functional analysis further revealed that several inflammatory cytokines, including TNFα, IL-6, and IL-23, secreted by pDCs were significantly increased in AS patients as compared with those in controls. Remarkably, protein kinase RNA-like endoplasmic reticulum kinase (PERK) pathway in UPR was up-regulated in pDCs of AS patients. Notably, PERK inhibitor treatment significantly inhibited the enhanced cytokine production by pDCs of AS patients. Further, the extent of PERK activation was significantly associated with the increased disease severity of AS patients. Our data uncover the aberrant distribution and function of pDCs in AS patients. The up-regulated PERK pathway in UPR of pDCs not only contributes to enhanced cytokine production of pDCs, but also is associated with increased disease activity of AS patients.

4.
J Formos Med Assoc ; 119(1 Pt 3): 480-487, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31303456

RESUMO

BACKGROUND: Patients who have symptoms of sicca, such as dry eyes and mouth, may have Sjögren's syndrome (SS). However, the conservative culture makes patients hesitate to undergo an invasive biopsy, which contributes to the difficulty of confirming a diagnosis. We aimed to identify the characteristics of patients with sicca symptoms to develop a better predictive value for each item included in the three different diagnostic criteria for SS and clarify the best diagnostic tools for the local population. METHODS: This is a single-center retrospective case-control study from January 2016 to December 2017. Patients who underwent sialoscintigraphy because of clinical symptoms of xerostomia and xerophthalmia at one medical center were reviewed via the patients' electronic medical records. RESULTS: Of 515 patients enrolled, the severity of results for sialoscintigraphy and Schirmer's test was correlated with a diagnosis of SS and generated receiver operator characteristic curve. The area under curve (AUC) was 0.603 for positive Schirmer's test, 0.687 for positive anti-Ro/La results, 0.893 for a positive salivary gland biopsy. The AUC was 0.626 and 0.602 for Schirmer's test which is redefined as <10 mm/5 minutes in either eye and according to 2016 the American College of Rheumatology/ European League Against Rheumatism criteria, respectively. CONCLUSION: Our results indicate the cut-off point for defining a positive test result in the Schirmer's test is worth modified to <10 mm/5 minutes in either eye.

5.
Front Immunol ; 10: 1951, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31475012

RESUMO

Chinese herbal medicines used in combination have long-term been shown to be mild remedies with "integrated effects." However, our study provides the first demonstration that M1, an active metabolite of ginsenoside, exerted its dramatic therapeutic effects on accelerated and severe lupus nephritis (ASLN) mice, featuring acute renal function impairment, heavy proteinuria, high serum levels of anti-dsDNA, and high-grade, diffuse proliferative renal lesions. In the present study, NZB/WF1 mice were given injections of lipopolysaccharide to induce the ASLN model. M1 (30 mg/kg) was then administered to the mice by gavage daily, and the mice were sacrificed on week 3 and week 5 after the induction of disease. To identify the potential mechanism of action for the pure compound, levels of NLRP3 inflammasome activation in bone marrow-derived dendritic cells (BMDCs), podocytes and macrophages, and antigen-specific T cell activation in BMDCs were determined in addition to mechanistic experiments in vivo. Treatment with M1 dramatically improved renal function, albuminuria and renal lesions and reduced serum levels of anti-dsDNA in the ASLN mice. These beneficial effects with M1 treatment involved the following cellular and molecular mechanistic events: [1] inhibition of NLRP3 inflammasome associated with autophagy induction, [2] modulation of T help cell activation, and [3] induction of regulatory T cell differentiation. M1 improved the ASLN mice by blunting NLRP3 inflammasome activation and differentially regulating T cell functions, and the results support M1 as a new therapeutic candidate for LN patients with a status of abrupt transformation of lower-grade (mesangial) to higher-grade (diffuse proliferative) nephritis.

6.
Biochem Biophys Res Commun ; 517(1): 155-163, 2019 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-31353084

RESUMO

Osteoarthritis (OA) is a common degenerative joint disease characterized by progressive deterioration of articular cartilage. There have been reports that small molecule inhibitors have anti-osteoarthritis effects; however, the effects of 3-(4-chloro-2-fluorophenyl)-6-(2,4-difluorophenyl)-2H-benzo[e] [1,3]oxazine-2,4(3H)-dione (Cm-02) and 6-(2,4-difluorophenyl)-3-(3,4-difluorophenyl)-2H-benzo[e] [1,3]oxazine-2,4(3H)-dione (Ck-02), small molecule inhibitors which share many structural similarities with quercetin (a potent anti-inflammatory flavonoid), remain unclear. In this study, TNF-α-stimulated porcine and human chondrocyte models were used to investigate the inhibitory effects of Cm-02 and Ck-02 on the molecular mechanisms underlying the anti-OA effects. TNF-α was used to stimulate porcine and human chondrocytes to mimic immunomodulatory potency in-vitro. Anti-osteoarthritic effects were characterized in terms of protein and mRNA levels associated with the pathogenesis of OA. We also examined (1) the inducible nitric oxide synthase (iNOS)-nitric oxide (NO) system in cultured chondrocytes, (2) matrix metalloproteinases (MMPs) in cultured chondrocytes, and (3) aggrecan degradation in cartilage explants. Finally, we tested the activation of nuclear factor-kappaB (NF-κB), interferon regulatory factor-1 (IRF-1), and activate the protein-1 (AP-1), and we tested the signal transduction and activation of transcription-3 (STAT-3). Our results indicate that, in chondrocytes, Cm-02 and Ck-02 inhibit TNF-α induced NO production, iNOS, MMP, the expression of disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS), and the enzyme activity of MMP-13. Furthermore, both Cm-02 and Ck-02 were found to stimulate TNF-α, which has been shown to suppress the activation of several transcription factors, including NF-κB, STAT-3, and IRF-1 in porcine and human chondrocytes. Cm-02 and Ck-02 were also found to help prevent the release of proteoglycans from cartilage explants. Our findings demonstrate that both Cm-02 and Ck-02 have potent anti-inflammatory activities and the ability to protect cartilage in an OA cell model. These findings indicate that Cm-02 and Ck-02 have the potential to be further developed for the therapeutic treatment of OA.

7.
Nutrients ; 11(5)2019 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-31137797

RESUMO

Genistein is an isoflavone extracted from soybean (Glycine max). This compound has anti-inflammatory, anti-oxidative, and anti-cancer effects; however, the mechanism underlying the effects of genistein on IL-1ß-stimulated human osteoarthritis (OA) chondrocytes remains unknown. Our objectives in this study were to explore the anti-inflammatory effects of genistein on IL-1ß-stimulated human OA chondrocytes and to investigate the potential mechanisms which underlie them. Our results from an in-vitro model of osteoarthritis indicate that genistein inhibits the IL-1ß-induced expression of the catabolic factors nitric oxide synthase 2 (NOS2), cyclooxygenase 2 (COX-2), and matrix metalloproteinases (MMPs). Genistein was shown to stimulate Ho-1 expression, which has been associated with Nrf-2 pathway activation in human chondrocytes. In a rat model, genistein was also shown to attenuate the progression of traumatic osteoarthritis. Taken together, these results demonstrate the effectiveness of genistein in mediating the inflammation associated with joint disorders. Our results also indicate that genistein could potentially serve as an alternative therapeutic treatment for OA.


Assuntos
Anti-Inflamatórios/farmacologia , Condrócitos/efeitos dos fármacos , Genisteína/farmacologia , Articulações/efeitos dos fármacos , Osteoartrite/tratamento farmacológico , Animais , Células Cultivadas , Condrócitos/metabolismo , Condrócitos/patologia , Ciclo-Oxigenase 2/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Heme Oxigenase-1/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Interleucina-1beta/farmacologia , Articulações/metabolismo , Articulações/patologia , Metaloproteinases da Matriz/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Osteoartrite/metabolismo , Osteoartrite/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Transdução de Sinais
8.
Acta Histochem ; 121(5): 628-637, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31133374

RESUMO

The identification of prognostic markers for colorectal cancer (CRC) has important clinical implications. However, the association between meningioma 1 (MN1) expression and clinical outcomes of CRC has not been fully investigated. The aim of this study was to investigate the expression of MN1 in the clinical context of CRC. We first used immunohistochemistry (IHC) staining to examine and compare MN1 expression between multiple human cancer tissues and normal tissues. Initial screening revealed that the expression of MN1 proteins was significantly higher in tumor tissues of the breast, colon, and liver than in normal tissues. In further testing conducted on 59 paired CRC samples, we observed that the expression of MN1 in CRC tissue samples was significantly higher than in adjacent normal tissues. Moreover, high MN1 expression was not significantly associated with clinicopathological characteristics. Kaplan-Meier survival analysis revealed that high expression of MN1 mRNA or MN1 protein was significantly associated with poor CRC prognosis. Furthermore, univariate Cox analysis revealed that a high MN1 score was significantly associated with prognostic factors. Multivariate Cox analysis further indicated that gender, histologic grade, tumor-node-metastasis (TNM) stage, and a high MN1 score were independent factors of overall CRC survival rates. Finally, MN1 and PCNA protein levels were positively correlated, which suggests that MN1 may be involved in the cell proliferation process during CRC formation. Our results, which confirm those of other studies, indicate that (1) high levels of MN1 expression contribute to poor CRC prognosis and (2) MN1 can serve as a novel potential biomarker in predicting the prognosis of CRC patients.


Assuntos
Neoplasias Colorretais/mortalidade , Proteínas Supressoras de Tumor/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida , Proteínas Supressoras de Tumor/genética
9.
Medicine (Baltimore) ; 98(14): e14984, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30946325

RESUMO

To determine the incidence and risk of Parkinson disease (PD) in patients with Sjögren syndrome (SS) according to a nationwide population-based database.In total, 12,640 patients in the SS cohort and 50,560 in the non-SS cohort were enrolled from Taiwan's National Health Insurance Research Database from 2000 to 2010. We used the Cox multivariable proportional hazards model to determine the risk factors for PD in the SS cohort.We observed an increased incidence of PD in patients with SS, with a crude hazard ratio (HR) of 1.40 and an adjusted HR (aHR) of 1.23. The cumulative incidence of PD was 1.95% higher in the SS cohort than in the non-SS cohort. The SS cohort had an elevated HR under medication use, namely cevimeline and pilocarpine (crude HR, 1.28), hydroxychloroquine (crude HR, 1.43; aHR, 1.46), and methylprednisolone (crude HR, 2.21; aHR, 1.49). Patients receiving other non-hydroxychloroquine immunosuppressant therapies had a lower risk (aHR, 0.86) of PD. Furthermore, patients with SS aged 20 to 49 years had a 1.93-fold higher risk of PD than did those without SS (aHR, 1.93). The risk of PD was higher (aHR, 2.20) in patients with SS without comorbidities than in those with comorbidities. The aHR of PD significantly increased when the follow-up period exceeded 9 years (aHR, 1.93).We determined an increased risk of PD in patients with SS. Further investigation is warranted to determine the possible underlying mechanisms and the potential role of non-hydroxychloroquine immunosuppressants in ameliorating PD.


Assuntos
Imunossupressão/efeitos adversos , Doença de Parkinson/etiologia , Síndrome de Sjogren/tratamento farmacológico , Adulto , Idoso , Anti-Inflamatórios/efeitos adversos , Anti-Inflamatórios/uso terapêutico , Antirreumáticos/efeitos adversos , Antirreumáticos/uso terapêutico , Comorbidade , Feminino , Humanos , Hidroxicloroquina/efeitos adversos , Hidroxicloroquina/uso terapêutico , Imunossupressão/estatística & dados numéricos , Incidência , Masculino , Metilprednisolona/efeitos adversos , Metilprednisolona/uso terapêutico , Pessoa de Meia-Idade , Agonistas Muscarínicos/efeitos adversos , Agonistas Muscarínicos/uso terapêutico , Programas Nacionais de Saúde/estatística & dados numéricos , Doença de Parkinson/epidemiologia , Pilocarpina/efeitos adversos , Pilocarpina/uso terapêutico , Quinuclidinas/efeitos adversos , Quinuclidinas/uso terapêutico , Estudos Retrospectivos , Fatores de Risco , Síndrome de Sjogren/complicações , Síndrome de Sjogren/diagnóstico , Síndrome de Sjogren/epidemiologia , Taiwan/epidemiologia , Tiofenos/efeitos adversos , Tiofenos/uso terapêutico
10.
Antiviral Res ; 159: 134-142, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30300716

RESUMO

The chikungunya virus (CHIKV) is a mosquito-borne virus that belongs to the genus Alphavirus, family Togaviridae. It is the cause of chikungunya fever in humans, which presents a serious global threat due to its high rate of contagion. The clinical symptoms of CHIKV include fever and persistent, severe arthritis. Micafungin has broad-spectrum fungicidal activity against Candida spp. is a promising echinocandin that was recently approved by the U.S. Food and Drug Administration (FDA) and has demonstrated activity against Candida and Aspergillus. Recent studies have demonstrated the antiviral activity of micafungin; however, the inhibitory effects against CHIKV have yet to be investigated. Our objectives in this study were to explore the antiviral effects of micafungin on CHIKV infection and to elucidate the potential molecular mechanisms of inhibition. We determined that micafungin has the ability to counter CHIKV-induced cytopathic effects. We further discovered that micafungin limits virus replication, release, cell-to-cell transmission, and also slightly affected virus stability during high doses treatment. The efficacy of micafungin was further confirmed against two clinical isolates of CHIKV and two alphaviruses: Sindbis virus (SINV) and Semliki Forest virus (SFV). Our findings suggest that micafungin has considerable potential as a novel inhibitor against the viral replication, and intracellular and extracellular transmission of CHIKV, and has a little effect on virus stability. Our findings also suggest that micafungin could have curative effects on other alphavirus infections.


Assuntos
Alphavirus/efeitos dos fármacos , Antivirais/farmacologia , Vírus Chikungunya/efeitos dos fármacos , Micafungina/farmacologia , Infecções por Alphavirus/tratamento farmacológico , Febre de Chikungunya/tratamento farmacológico , Febre de Chikungunya/virologia , Vírus da Floresta de Semliki/efeitos dos fármacos , Vírus Sindbis/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
11.
BMJ Open ; 8(7): e020821, 2018 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-29982207

RESUMO

OBJECTIVES: Previous research has shown that patients with nephrotic syndrome (NS) have a higher risk of cognitive impairment, dementia or neurodegenerative disorder. The present study aimed to examine a relationship, if any exists between NS and Parkinson's disease (PD), a neurodegenerative disorder and secondary parkinsonism (sPS). METHODS: A nationwide retrospective observational study conducted using data from the 2000-2010 Taiwan National Health Insurance Research Database. This study included 3663 patients with NS and 14 652 randomly selected, age-matched and sex-matched patients without NS. A Cox multivariable proportional hazards model was used to evaluate the risk of PD and sPS (PDsPS) in the NS cohort. RESULTS: This study identified a positive association between NS and the risk of PDsPS in both men and women and in all age groups (adjusted HR 1.51; 95% CI 1.37 to 1.66). Compared with patients without NS and comorbidities, those with NS with two or more comorbidities exhibited an 8.23-fold higher risk of PDsPS (95% CI 6.22 to 10.9) and patients with NS and one comorbidity exhibited a 2.93-fold higher risk of PDsPS (95% CI 2.37 to 3.63). CONCLUSIONS: Patients with NS have an increased risk of PDsPS. This increased risk may be related to brain vascular damage or blood-brain barrier impairment. Further research is necessary to explore the underlying relationship between NS and PDsPS.


Assuntos
Síndrome Nefrótica/epidemiologia , Doença de Parkinson Secundária/epidemiologia , Doença de Parkinson/epidemiologia , Adulto , Idoso , Estudos de Casos e Controles , Comorbidade , Bases de Dados Factuais , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Taiwan/epidemiologia , Adulto Jovem
12.
Int J Mol Sci ; 19(5)2018 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-29757957

RESUMO

In this study, we synthesized hundreds of analogues based on the structure of small-molecule inhibitors (SMIs) that were previously identified in our laboratory with the aim of identifying potent yet safe compounds for arthritis therapeutics. One of the analogues was shown to share structural similarity with quercetin, a potent anti-inflammatory flavonoid present in many different fruits and vegetables. We investigated the immunomodulatory effects of this compound, namely 6-(2,4-difluorophenyl)-3-(3-(trifluoromethyl)phenyl)-2H-benzo[e][1,3]oxazine-2,4(3H)-dione (Cf-02), in a side-by-side comparison with quercetin. Chondrocytes were isolated from pig joints or the joints of patients with osteoarthritis that had undergone total knee replacement surgery. Several measures were used to assess the immunomodulatory potency of these compounds in tumor necrosis factor (TNF-α)-stimulated chondrocytes. Characterization included the protein and mRNA levels of molecules associated with arthritis pathogenesis as well as the inducible nitric oxide synthase (iNOS)⁻nitric oxide (NO) system and matrix metalloproteinases (MMPs) in cultured chondrocytes and proteoglycan, and aggrecan degradation in cartilage explants. We also examined the activation of several important transcription factors, including nuclear factor-kappaB (NF-κB), interferon regulatory factor-1 (IRF-1), signal transducer and activator of transcription-3 (STAT-3), and activator protein-1 (AP-1). Our overall results indicate that the immunomodulatory potency of Cf-02 is fifty-fold more efficient than that of quercetin without any indication of cytotoxicity. When tested in vivo using the induced edema method, Cf-02 was shown to suppress inflammation and cartilage damage. The proposed method shows considerable promise for the identification of candidate disease-modifying immunomodulatory drugs and leads compounds for arthritis therapeutics.


Assuntos
Substâncias Protetoras/química , Substâncias Protetoras/farmacologia , Quercetina/química , Quercetina/farmacologia , Animais , Artrite/tratamento farmacológico , Artrite/etiologia , Artrite/metabolismo , Artrite/patologia , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Colágeno/metabolismo , Imunomodulação/efeitos dos fármacos , Metaloproteinase 13 da Matriz/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Proteoglicanas/metabolismo , Relação Estrutura-Atividade , Suínos , Fatores de Transcrição/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
13.
Int J Mol Sci ; 19(3)2018 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-29534535

RESUMO

Osteoarthritis (OA) is the most common joint disorder and primarily affects older people. The ideal anti-OA drug should have a modest anti-inflammatory effect and only limited or no toxicity for long-term use. Because the antitussive medication dextromethorphan (DXM) is protective in atherosclerosis and neurological diseases, two common disorders in aged people, we examined whether DXM can be protective in pro-inflammatory cytokine-stimulated chondrocytes and in a collagen-induced arthritis (CIA) animal model in this study. Chondrocytes were prepared from cartilage specimens taken from pigs or OA patients. Western blotting, quantitative PCR, and immunohistochemistry were adopted to measure the expression of collagen II (Col II) and matrix metalloproteinases (MMP). DXM significantly restored tumor necrosis factor-alpha (TNF-α)-mediated reduction of collagen II and decreased TNF-α-induced MMP-13 production. To inhibit the synthesis of MMP-13, DXM blocked TNF-α downstream signaling, including I kappa B kinase (IKK)α/ß-IκBα-nuclear factor-kappaB (NF-κB) and c-Jun N-terminal kinase (JNK)-activator protein-1 (AP-1) activation. Besides this, DXM protected the CIA mice from severe inflammation and cartilage destruction. DXM seemed to protect cartilage from inflammation-mediated matrix degradation, which is an irreversible status in the disease progression of osteoarthritis. The results suggested that testing DXM as an osteoarthritis therapeutic should be a focus in further research.


Assuntos
Antitussígenos/farmacologia , Condrócitos/efeitos dos fármacos , Dextrometorfano/farmacologia , Osteoartrite/tratamento farmacológico , Animais , Antitussígenos/uso terapêutico , Células Cultivadas , Condrócitos/metabolismo , Colágeno Tipo II/genética , Colágeno Tipo II/metabolismo , Dextrometorfano/uso terapêutico , Humanos , Quinase I-kappa B/genética , Quinase I-kappa B/metabolismo , Masculino , Metaloproteinases da Matriz/genética , Metaloproteinases da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos DBA , Suínos , Fator de Transcrição AP-1/genética , Fator de Transcrição AP-1/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
14.
Am J Med Sci ; 355(2): 153-161, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29406043

RESUMO

BACKGROUND: Fibromyalgia is a syndrome of chronic pain and other symptoms and is associated with patient discomfort and other diseases. This nationwide matched-cohort population-based study aimed to investigate the association between fibromyalgia and the risk of developing dementia, and to clarify the association between fibromyalgia and dementia. MATERIALS AND METHODS: A total of 41,612 patients of age ≥50 years with newly diagnosed fibromyalgia between January 1, and December 31, 2000 were selected from the National Health Insurance Research Database of Taiwan, along with 124,836 controls matched for sex and age. After adjusting for any confounding factors, Fine and Gray competing risk analysis was used to compare the risk of developing dementia during the 10 years of follow-up. RESULTS: Of the study subjects, 1,704 from 41,612 fibromyalgia patients (21.23 per 1,000 person-years) developed dementia when compared to 4,419 from 124,836 controls (18.94 per 1,000 person-years). Fine and Gray competing risk analysis revealed that the study subjects were more likely to develop dementia (hazard ratio: 2.29, 95% CI: 2.16-2.42; P < 0.001). After adjusting for sex, age, monthly income, urbanization level, geographic region of residence and comorbidities the hazard ratio was 2.77 (95% CI: 2.61-2.95, P < 0.001). Fibromyalgia was associated with increased risk of all types of dementia in this study. CONCLUSIONS: The study subjects with fibromyalgia had a 2.77-fold risk of dementia in comparison to the control group. Therefore, further studies are needed to elucidate the underlying mechanisms of the association between fibromyalgia and the risk of dementia.


Assuntos
Bases de Dados Factuais , Demência/epidemiologia , Demência/etiologia , Fibromialgia/complicações , Fibromialgia/epidemiologia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Demência/fisiopatologia , Feminino , Fibromialgia/fisiopatologia , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Fatores Sexuais , Fatores Socioeconômicos , Taiwan/epidemiologia
15.
Neurologist ; 23(1): 7-11, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29266037

RESUMO

OBJECTIVE: We investigated the efficacy of plasma exchange (PE) in antiphospholipid antibody (aPL)-positive patients with a spontaneous intracerebral hemorrhage (ICH) and high D-dimer levels. MATERIALS AND METHODS: From May 2013 to May 2016, we evaluated 32 patients who were below the age of 50 and presented with spontaneous ICH. Five patients were positive for aPL antibody and 3 had a higher level of D-dimer. These 3 patients underwent 5 sessions of PE using fresh frozen plasma as replacement fluid. We analyzed the days postadmission until PE-start, the days of intensive care unit (ICU) hospitalization, D-dimer series, Glasgow Coma Scale (GCS) scores, and modified Rankin scale (mRS) scores. D-dimer levels and GCS scores were recorded at both pre-PE and post-PE stages. The mRS scores were recorded at pre-PE stage and 3 months post-PE. RESULTS: The mean postadmission period until PE-start was 8.33 days. The mean ICU hospitalization was 17.33 days. The D-dimer level pre-PE ranged from 2.34 to 5.44 mg/L fibrinogen equivalent unit (FEU). The D-dimer level post-PE ranged from 1.05 to 3.30 mg/L FEU. The amount of decline of the D-dimer level between pre-PE and post-PE ranged from 0.65 to 2.14 mg/L FEU. The GCS score pre-PE was between 7 and 8. The highest post-PE GCS score was 14. The improved GCS scores post-PE ranged from 3 to 6. The improved mRS scores of 3 months post-PE ranged from 3 to 4. CONCLUSIONS: The concurrent presence of positive aPL and a higher D-dimer level may worsen the neurological outcome of patients with a spontaneous ICH. Aggressive PE is effective for the treatment of such patients, decreasing the extent of the ICU hospitalization.


Assuntos
Síndrome Antifosfolipídica/complicações , Síndrome Antifosfolipídica/terapia , Hemorragia Cerebral/complicações , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Troca Plasmática , Adulto , Anticorpos Antifosfolipídeos/imunologia , Feminino , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento
16.
Medicine (Baltimore) ; 96(27): e7350, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28682883

RESUMO

RATIONALE: Nivolumab (Nivo) is an immune checkpoint inhibitor that has been used to treat advanced melanoma, nonsmall cell lung carcinoma, and renal cell carcinoma since 2015. Nivo is associated with several side effects, including hepatitis, pneumonitis, acute renal failure, endocrine disorder, and other immune-related adverse events. Here, we describe the case of a 65-year-old man with squamous cell lung carcinoma who developed myasthenia gravis (MG) after a third Nivo infusion. PATIENT CONCERNS: A 65-year-old man with advanced squamous cell lung carcinoma developed ptosis, diplopia, drop head, and general weakness 5 days after a third Nivo infusion. DIAGNOSES, INTERVENTIONS, AND OUTCOMES: We diagnosed him with Nivo-related MG and myositis based on clinical symptoms, elevation of muscle enzymes, negativity for autoantibodies and exclusion of other diagnoses. Steroid treatment with methylprednisolone 1 mg/kg/d and pyridostigmine 60 mg twice a day was administered beginning at admission; however, the patient's condition progressively worsened, despite treatment. Respiratory failure developed 2 weeks after admission, and his family declined the use of a mechanical ventilator. The patient died on day 27 after the third Nivo infusion. LESSONS: Nivo-related MG should be highly suspected in patients who develop ptosis, diplopia, and general weakness. The corresponding treatments include discontinuation of Nivo and steroid treatment with plasmapheresis. The disease course may be rapid and fatal. This report stresses the importance of awareness of this rare and lethal adverse effect while using nivolomab immunotherapy.


Assuntos
Anticorpos Monoclonais/efeitos adversos , Antineoplásicos/efeitos adversos , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Miastenia Gravis/induzido quimicamente , Idoso , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma de Células Escamosas/complicações , Diagnóstico Diferencial , Evolução Fatal , Humanos , Neoplasias Pulmonares/complicações , Masculino , Miastenia Gravis/diagnóstico , Miastenia Gravis/terapia , Nivolumabe
17.
Sci Rep ; 7(1): 2359, 2017 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-28539647

RESUMO

High uric acid levels are a risk factor for cardiovascular disorders and gout; however, the role of physiological concentrations of soluble uric acid (sUA) is poorly understood. This study aimed to clarify the effects of sUA in joint inflammation. Both cell cultures of primary porcine chondrocytes and mice with collagen-induced arthritis (CIA) were examined. We showed that sUA inhibited TNF-α- and interleukin (IL)-1ß-induced inducible nitric oxide synthase, cyclooxygenase-2 and matrix metalloproteinase (MMP)-13 expression. Examination of the mRNA expression of several MMPs and aggrecanases confirmed that sUA exerts chondroprotective effects by inhibiting the activity of many chondro-destructive enzymes. These effects attenuated collagen II loss in chondrocytes and reduced proteoglycan degradation in cartilage explants. These results were reproduced in chondrocytes cultured in three-dimensional (3-D) alginate beads. Molecular studies revealed that sUA inhibited the ERK/AP-1 signalling pathway, but not the IκBα-NF-κB signalling pathway. Increases in plasma uric acid levels facilitated by the provision of oxonic acid, a uricase inhibitor, to CIA mice exerted both anti-inflammatory and arthroprotective effects in these animals, as demonstrated by their arthritis severity scores and immunohistochemical analysis results. Our study demonstrated that physiological concentrations of sUA displayed anti-inflammatory and chondroprotective effects both in vitro and in vivo.


Assuntos
Artrite Experimental/prevenção & controle , Condrócitos/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Ácido Úrico/farmacologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacologia , Artrite Experimental/genética , Artrite Experimental/metabolismo , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/metabolismo , Células Cultivadas , Condrócitos/metabolismo , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Interleucina-1beta/farmacologia , Masculino , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 13 da Matriz/metabolismo , Camundongos Endogâmicos DBA , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Substâncias Protetoras/química , Substâncias Protetoras/metabolismo , Substâncias Protetoras/farmacologia , Transdução de Sinais/efeitos dos fármacos , Solubilidade , Suínos , Fator de Necrose Tumoral alfa/farmacologia , Ácido Úrico/química , Ácido Úrico/metabolismo
18.
Oncotarget ; 8(30): 50098-50108, 2017 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-28177920

RESUMO

Sjögren syndrome (SS) is commonly known to be correlated with lymphoma. This study included 16,396 individuals in the SS cohort and 65,584 individuals in the non-SS cohort, all of whom were enrolled in the Taiwan National Health Insurance database between 2000 and 2010. We evaluated the risk factors of non-Hodgkin's lymphoma (NHL) in the primary SS cohort by applying a Cox multivariable proportional-hazards model. We increased the correlation of patients with SS and NHL, with an adjusted HR of 4.314 (95% CI 2.784 - 6.685). Of the 16,396 SS patients, 66 individuals had salivary gland slices without NHL development, while the other 16,330 individuals that did not have salivary gland slices revealed 30 individuals that developed NHL. Of the 16,396 SS patients, 128 individuals underwent immunomodulator agent therapy (including hydroxychloroquine, azathioprine, cyclosporine, methotrexate, and rituximab) without NHL development. None of the 30 individuals that developed NHL from SS received immunomodulator agents. We found that patients with SS were at an increased risk of developing NHL, with the most common NHL subgroup being diffused large B-cell lymphoma. SS patients who were candidates for salivary gland slices or immunomodulator agents were associated with a lower risk of developing lymphoma over time. We recommend that patients at a higher risk upon diagnosis of SS receive close follow-up and aggressive treatment.


Assuntos
Biomarcadores/metabolismo , Linfoma/etiologia , Síndrome de Sjogren/complicações , Estudos de Coortes , Feminino , Humanos , Linfoma/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Síndrome de Sjogren/patologia
19.
J Am Soc Nephrol ; 28(7): 2022-2037, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28179433

RESUMO

IL-36 cytokines are proinflammatory and have an important role in innate and adaptive immunity, but the role of IL-36 signaling in renal tubulointerstitial lesions (TILs), a major prognostic feature of renal inflammation and fibrosis, remains undetermined. In this study, increased IL-36α expression detected in renal biopsy specimens and urine samples from patients with renal TILs correlated with renal function impairment. We confirmed the increased expression of IL-36α in the renal tubular epithelial cells of a mouse model of unilateral ureteral obstruction (UUO) and related cell models using mechanically induced pressure, oxidative stress, or high mobility group box 1. In contrast, the kidneys of IL-36 receptor (IL-36R) knockout mice exhibit attenuated TILs after UUO. Compared with UUO-treated wild-type mice, UUO-treated IL-36 knockout mice exhibited markedly reduced NLRP3 inflammasome activation and macrophage/T cell infiltration in the kidney and T cell activation in the renal draining lymph nodes. In vitro, recombinant IL-36α facilitated NLRP3 inflammasome activation in renal tubular epithelial cells, macrophages, and dendritic cells and enhanced dendritic cell-induced T cell proliferation and Th17 differentiation. Furthermore, deficiency of IL-23, which was diminished in IL-36R knockout UUO mice, also reduced renal TIL formation in UUO mice. In wild-type mice, administration of an IL-36R antagonist after UUO reproduced the results obtained in UUO-treated IL-36R knockout mice. We propose that IL-36 signaling contributes to the pathogenesis of renal TILs through the activation of the NLRP3 inflammasome and IL-23/IL-17 axis.


Assuntos
Inflamassomos/fisiologia , Interleucina-17/fisiologia , Interleucina-1/fisiologia , Interleucina-23/fisiologia , Rim/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/fisiologia , Nefrite/etiologia , Transdução de Sinais , Animais , Fibrose/etiologia , Humanos , Camundongos , Obstrução Ureteral/etiologia
20.
Acta Neurol Taiwan ; 25(3): 83-87, 2016 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-27854085

RESUMO

PURPOSE: Co-occurrence of Guillain-Barré syndrome (GBS) and other autoimmune diseases is rare. We present the case of a patient with co-occurrence of GBS and primary Sjögren syndrome (pSS). CASE REPORT: An 82-year-old woman presented with acute ascending flaccid paralysis and acute respiratory failure. Nerve conduction studies and cerebrospinal fluid analysis confirmed the diagnosis of GBS of acute inflammatory demyelinating polyradiculoneuropathy subtype. The initial unresponsiveness to plasma exchange therapy raised the suspicion of other potential diseases. She was later proved to have underlying pSS. Her neurological deficits and respiratory failure improved dramatically with combination therapy of intravenous immunoglobulin (IVIg) and immunosuppressive agent. CONCLUSION: pSS should be considered as a possible cause of refractory GBS, particularly in elderly women. Combination therapy with IVIg and immunosuppressive agent may be beneficial.


Assuntos
Síndrome de Guillain-Barré/diagnóstico , Síndrome de Sjogren/diagnóstico , Idoso de 80 Anos ou mais , Feminino , Síndrome de Guillain-Barré/tratamento farmacológico , Síndrome de Guillain-Barré/etiologia , Humanos , Fatores Imunológicos/uso terapêutico , Síndrome de Sjogren/complicações , Síndrome de Sjogren/tratamento farmacológico
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