RESUMO
Twelve phthalideisoquinoline hemiacetal alkaloids including eight new ones (1-8) and one natural alkaloid characterized by an aziridine moiety with unassigned NMR data (9), were isolated and identified from the bulbs of Corydalis decumbens. Their structures were established by comprehensive analyses of HRESIMS, NMR, X-ray crystallography, and ECD analyses. The unambiguously established structures of the phthalideisoquinoline hemiacetal alkaloids indicated that the absolute configurations of C-1, C-9, and C-7' were confusable only relied on coupling constants. A summary of their ECD spectra was concluded and provided an insight for C-1, C-9, and C-7' absolute configuration assignment. These new compounds were evaluated to induce autophagy flux through flow cytometry analysis. Moreover, compounds 2 and 6 could significantly induce autophagy and inhibit Tau pathology by AMPK-ULK1 pathway activation, which provided an avenue for anti-AD lead compounds discovery.
Assuntos
Alcaloides , Corydalis , Corydalis/química , Proteínas Quinases Ativadas por AMP/metabolismo , Alcaloides/química , Espectroscopia de Ressonância Magnética , AutofagiaRESUMO
Proprotein convertase subtilisin/kexin type 9 (PCSK9), also known as neural apoptosis regulated convertase (NARC1), is a key modulator of cholesterol metabolism. PCSK9 increases the serum concentration of low-density lipoprotein cholesterol by escorting low-density lipoprotein receptors (LDLRs) from the membrane of hepatic cells into lysosomes, where the LDLRs are degraded. Owing to the importance of PCSK9 in lipid metabolism, considerable effort has been made over the past decade in developing drugs targeting PCSK9 to lower serum lipid levels. Nevertheless, some problems and challenges remain. In this review we first describes the structure and function of PCSK9 and its gene polymorphisms. We then discuss the various designs of pharmacological targets of PCSK9, including those that block the binding of PCSK9 to hepatic LDLRs (mimetic peptides, adnectins, and monoclonal antibodies), inhibit PCSK9 expression (the clustered regularly interspaced short palindromic repeats/Cas9 platform, small molecules, antisense oligonucleotides, and small interfering RNAs), and interfere with PCSK9 secretion. Finally, this review highlights future challenges in this field, including safety concerns associated with PCSK9 monoclonal antibodies, the limited utility of PCSK9 inhibitors in the central nervous system, and the cost-effectiveness of PCSK9 inhibitors.
Assuntos
Hipolipemiantes/farmacologia , Inibidores de PCSK9 , Inibidores de Serina Proteinase/farmacologia , Animais , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados/farmacologia , Anticolesterolemiantes/farmacologia , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Endonucleases/genética , Humanos , Terapia de Alvo Molecular , Oligonucleotídeos Antissenso/farmacologia , Polimorfismo Genético , Pró-Proteína Convertase 9/química , Pró-Proteína Convertase 9/genética , Pró-Proteína Convertase 9/imunologia , RNA Interferente Pequeno/farmacologia , Receptores de LDL/genética , Receptores de LDL/metabolismoRESUMO
OBJECTIVE: To examine the expression of cysteinyl leukotriene receptor-1 (CysLTR-1) and cysteinyl leukotriene receptor-2 (CysLTR-2) in the adenoid tissues from children with adenoid hypertrophy (AH) and to explore the role of leukotrienes in the pathogenesis of AH. METHODS: Sixty children with AH who were treated by adenoidectomy and/or tonsillectomy were classified into two groups: simple AH and AH plus allergic rhinitis (n=30 each). Twenty children who underwent tonsillectomy due to recurrent purulent tonsillitis were selected as the control group. The expression of CysLTR-1 and CysLTR-2 in the excised tonsil and/or adenoid tissues was determined by immunofluorescence histochemical labeling and integrated optical density measurement. RESULTS: The expression of CysLTR-1 and CysLTR-2 in the adenoid and tonsil tissues increased significantly in both the simple AH group and AH plus allergic rhinitis group compared with the control group (P<0.01). The expression of CysLTR-1 and CysLTR-2 in the AH plus allergic rhinitis group increased more significantly compared with the simple AH group (P<0.01). CONCLUSIONS: CysLTR-1 and CysLTR-2 are highly expressed in the adenoid tissues from children with AH, suggesting that leukotrienes are involved in the pathogenesis of AH.
Assuntos
Tonsila Faríngea/patologia , Receptores de Leucotrienos/fisiologia , Tonsila Faríngea/química , Adolescente , Criança , Pré-Escolar , Feminino , Imunofluorescência , Humanos , Hipertrofia , Masculino , Receptores de Leucotrienos/análise , Rinite Alérgica/metabolismoRESUMO
A 58-year-old man exhibited polyarthritis, fever, thrombocytopenia and progressive anemia. Undifferentiated connective tissue diseases(UCTD) was diagnosed based on laboratory and radiographic findings. After diagnosis, the patient received glucocorticoid and blood-transfusion. The symptoms were improved notablely. However,the level of hemoglobin was lower than normal(between 57 g/L and 75 g/L). Thrombocytes were 19 000/microl to 32 000/microl. Bone marrow aspiration revealed highly abnormal cell morphology, indicating myelodysplastic syndrome(MDS). A diagnosis of UCTD with MDS was made. The patient was successfully treated by decitabine and thalidomide(an immunosuppressive regimen). It is necessary to promptly examine bone marrow cell morphology and chromosomal aberration in cases with connective tissue diseases complicated by sudden cytopenia and thrombocytopenia.
Assuntos
Doenças do Tecido Conjuntivo/complicações , Doenças do Tecido Conjuntivo/diagnóstico , Síndromes Mielodisplásicas/complicações , Azacitidina/análogos & derivados , Azacitidina/uso terapêutico , Doenças do Tecido Conjuntivo/tratamento farmacológico , Decitabina , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/tratamento farmacológico , Talidomida/uso terapêuticoRESUMO
OBJECTIVE: To study the value of antiviral therapy for infectious monocytosis (IM) in children by comparing the near-term therapeutic efficacies and long-term follow-up results in children with this disorder between receiving antiviral therapy or not. METHODS: The medical data of IM children between 1999 and 2009 were retrospectively reviewed. A total of 172 cases with a follow-up visit period of 1 year and more were eligible. The children were classified into three groups according to the treatment protocol: ganciclovir treatment (n=49), acyclovir treatment (n=72) and symptomatic treatment (control; n=51). The children in the ganciclovir group received an intravenous drip of 10 mg/kg per day of ganciclovir, administered in twice-daily doses; Seven days later the drip volume was changed to 5 mg/kg, administered once each day; the total course lasting 10-14 days. The children in the acyclovir group received acyclovir orally at 20 mg/kg per day, administered in three times daily doses; the total course lasting 10-14 days. The children in the control group received symptomatic treatment only. In the three groups, indicators including fever course, improvement of isthmitis symptoms, lymph node retraction, hepatic and splenic lymph node retraction time, atypical lymphocyte fallback time and alteration of granulocyte amount after drug use were observed. The long-term follow-up visits covered such indicators as blood routine reexamination, hepatic function, liver and spleen B-ultrasonography, recovery rate, recurrence rate and mortality rate. RESULTS: In the acute phase, there were no differences in terms of fever course, isthmitis improvement, hepatic and splenic lymph node retraction time and the time of atypical lymphocyte falling back to below 10% among the three groups (P>0.05). During the period of follow-up visits between 1 year and 8 years and 10 months, no significant differences were observed in the recovery rate, the recurrence rate and the mortality rate among the three groups (P>0.05). CONCLUSIONS: The efficacies of antiviral therapy for IM children appear to be similar to non-antiviral therapy, suggesting that antiviral therapy fails to be beneficial for IM children.
Assuntos
Antivirais/uso terapêutico , Mononucleose Infecciosa/tratamento farmacológico , Aciclovir/uso terapêutico , Adolescente , Criança , Pré-Escolar , Feminino , Seguimentos , Ganciclovir/uso terapêutico , Humanos , Lactente , Masculino , Estudos RetrospectivosRESUMO
Background: Patients with systemic sclerosis (SSc) have poor prognosis without cure methods. We began, 10 years ago, to relieve active SSc using short-term intravenous high-dose methylprednisolone pulse (MP-Pulse) and then maintain remission using long-term and low-dose oral glucocorticoids (LTLD-GC). Methods: Total 46 of SSc patients with interstitial lung disease (ILD) and induration of skin during January 2006 to December 2019 were analyzed retrospectively, who were followed up for 10 years or more. The patients were treated with MP-Pulse (15 mg/kg/day, 4 days/week, for 2 weeks) with (n=21) or without (n=25) LTLD-GC (prednisone 5-10 mg/day or methylprednisolone 4-8 mg/day). The biographic and clinical data, including occurrence of infection or any adverse reactions, were collected at baseline, 6 months, 1 year, and annually through 10 years after treatment. Results: From baseline to 10 years, compared with MP-Pulse alone, MP-Pulse/LTLD-GC significantly reduced skin and lung fibrosis and improved lung function: Rodnan skin score (mRSS: 22.1±12.4 to 8.16±2.5, P<0.001), forced vital capacity (FVC: 71.7% to 89.83%, P<0.001), forced expiratory volume in the first second (FEV1: 75.7% to 87.88%, P<0.001), diffusing capacity of the lung for carbon monoxide (DLCO: 63.4% to 87.73%, P<0.001), and high-resolution chest computerized tomography scan (HRCT score: 3.96±2.81 to 1.42±0.83, P<0.001). None of the 46 patients had femoral head necrosis, compression fracture, death, or life-threatening adverse events. Conclusion: These outcomes indicate that intravenous MP-Pulse combined with oral LTLD-GC could achieve significant remission and better long-term (10 years) efficacy without severe adverse effects in SSc patients with ILD and induration of skin.
RESUMO
Objective: T cells represent a predominant cell type in autoimmune disease. However, their exact roles are not fully clear in systemic sclerosis (SSc). This study aimed to mainly investigate the alteration in the absolute numbers of T-lymphocyte subsets and the serum levels of cytokines in SSc patients. Methods: A total of 76 patients with SSc and 76 age- and sex-matched healthy controls (HCs) were enrolled. The levels of circulating T cell subsets and serum cytokines were measured by flow cytometry. T cell subsets or serum cytokines correlations with disease activity and organ involvement were analyzed. Results: The absolute numbers of Th2 and Treg cells in SSc patients were lower than those in HCs (p < 0.05), resulting in the ratios of Th1/Th2 [25.01 (12.24, 38.61) vs. 11.64 (6.38, 20.34)] and Th17/Treg [0.42 (0.17, 0.66) vs. 0.17 (0.13, 0.29)] were increased significantly (p < 0.001). The absolute numbers of total T, Th, and Treg cells were negatively correlated with CRP (r = -0.406, p = 0.002; r = -0.263, p < 0.05; r = -0.367 p < 0.01). The serum levels of IL-2, SIL-2R, IL-6, IL-10, INF-γ, and TNF-α were significantly higher than those in HCs (p < 0.001). Increasing IL-2 in the wake of the augment of ESR (r = 0.671, p = 0.004), so did IL-6 (r = 0.378, p < 0.05). The ratio of Th17/Treg in SSc-ILD patients had lower levels than that in other patients [0.35 (0.14, 0.53) vs. 0.64 (0.26, 0.93) p = 0.028]; Treg cells were lessened in patients with Raynaud's phenomenon relative to controls [3.00 (2.41, 4.28) vs. 3.55 (2.86, 4.53) p < 0.05]. The levels of IL-2, IL-10 and INF-γ [3.32 (1.05,11.73) vs. 2.32 (0.44,6.45), p = 0.045], [8.08 (3.63, 355,77) vs. 4.89 (0.78, 21.44), p = 0.02], [6.31 (2.66, 44.03) vs. 4.03 (0.22, 16.96), p = 0.009] were elevated in patients with arthralgia, while the level of Th17 was decreased [0.62 (0.20,2.16) vs. 1.26 (0.22,10.93), p = 0.026]. ROC curve analysis yielded an optimal cut-off IL-2, IL-10, and INF-γ levels of 2.67, 5.93, and 5.32 pg/ml for the presence of arthralgia. Conclusion: We exhibited abnormalities in T subsets and the production of their cytokines in SSc, as compared with those in HCs. This may allow the pathogenesis of SSc and the development of novel therapeutic interventions aimed at targeting these cells and the cytokines they produce.
RESUMO
Objectives: We have reported previously that Belimumab, a human monoclonal antibody that inhibits B-cell activating factor(BAFF) could be an effective and safe option to treat Neuropsychiatric manifestations of SLE (NPSLE). To avoid inadequate efficacy of Belimumab and significant adverse events of often-used dose of cyclophosphamide (CYC) for SLE, we evaluated the efficacy, safety, and possible immune mechanisms of Belimumab treatment in combination with intermittent low-dose intravenous CYC for moderate-to-severe SLE. Methods: In this non blinded and parallel-group trial, we collected 82 cases of moderate-to-severe SLE patients, 40 received Belimumab treatment and 42 received conventional treatments as historical controls for 24 weeks. The demographic features, clinical manifestations, and laboratory indicators including peripheral blood lymphocyte subgroups or subsets were compared before and after the treatments. Results: Compared with the baseline, 6 months post Belimumab group treatment, disease activity score SLEDAI (13.78 to 3.82, P<0.05) and BILAG scores (16.40 to 5.48, P<0.05) were reduced; C3 (0.19 to 1.14, P<0.05) and C4 (0.04 to 0.22, P<0.05) increased; the absolute numbers of B and T cells were the first decreased and then significantly increased, tended to balance. Moreover, Belimumab group treatment significantly reduced the serum levels of IL-6, the ratio of B and T cells, and the proportion of infections and menstrual disorders. Conclusion: Compared with conventional treatment, Belimumab with low-dose intravenous CYC significantly reduced disease activity scores and maintained the B/T cell balance for SLE patients at 24 weeks. It was more efficacy and safe (adverse events such as infection were significantly lower). It should be the mechanism that Belimumab combined with low-dose intravenous CYC therapy restores the balance of T and B cells, which proposes a potential treatment strategyfor SLE.
Assuntos
Lúpus Eritematoso Sistêmico , Anticorpos Monoclonais Humanizados/efeitos adversos , Ciclofosfamida/efeitos adversos , Humanos , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Resultado do TratamentoRESUMO
Intracerebral hemorrhage (ICH) is a catastrophic stroke with high mortality, and the mechanism underlying ICH is largely unknown. Previous studies have shown that high serum uric acid (SUA) levels are an independent risk factor for hypertension, cardiovascular disease (CVD), and ischemic stroke. However, our metabolomics data showed that SUA levels were lower in recurrent intracerebral hemorrhage (R-ICH) patients than in ICH patients, indicating that lower SUA might contribute to ICH. In this study, we confirmed the association between low SUA levels and the risk for recurrence of ICH and for cardiac-cerebral vascular mortality in hypertensive patients. To determine the mechanism by which low SUA effects ICH pathogenesis, we developed the first low SUA mouse model and conducted transcriptome profiling of the cerebrovasculature of ICH mice. When combining these assessments with pathological morphology, we found that low SUA levels led to ICH in mice with angiotensin II (Ang II)-induced hypertension and aggravated the pathological progression of ICH. In vitro, our results showed that p-Erk1/2-MMP axis were involved in the low UA-induce degradation of elastin, and that physiological concentrations of UA and p-Erk1/2-specific inhibitor exerted a protective role. This is the first report describing to the disruption of the smooth muscle cell (SMC)-elastin contractile units in ICH. Most importantly, we revealed that the upregulation of the p-Erk1/2-MMP axis, which promotes the degradation of elastin, plays a vital role in mediating low SUA levels to exacerbate cerebrovascular rupture during the ICH process.
Assuntos
Hemorragia Cerebral/sangue , Hemorragia Intracraniana Hipertensiva/sangue , Miócitos de Músculo Liso/metabolismo , Acidente Vascular Cerebral/sangue , Ácido Úrico/sangue , Animais , Hemorragia Cerebral/patologia , Humanos , Hipertensão/sangue , Sistema de Sinalização das MAP Quinases/fisiologia , Metaloproteinases da Matriz/metabolismo , Camundongos , Fatores de Risco , Acidente Vascular Cerebral/patologia , Regulação para CimaRESUMO
To study the effects of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) on the differentiation of T cells and the levels of cytokines in patients with early rheumatoid arthritis (eRA). The levels of Th1, Th2, Th17, and Treg cells were detected with BDFACS Calibur flow cytometer. The expression of IFN-ɤ, TNF-α, IL-2, IL-4, IL-6, IL-10, IL-17, and IL-22 was examined in 54 patients with eRA using a cytometric bead array (CBA). After 72 h of incubation of PBMCs from eRA patients with 1,25(OH)2D3, the levels of IFN-ɤ, TNF-α, IL-2, IL-6, and IL-17 significantly decreased compared to those of the control. 1,25(OH)2D3 had no significantly impact on the levels of IL-4, IL-10, and IL-22. The proportion of Th17 and the ratio of Th17/Treg significantly decreased in 1,25(OH)2D3-treated groups compared to those of the control. 1,25(OH)2D3 had no significantly impact on the proportion of Th1, Th2, Treg, and the ratio of Th1/Th2. Although no statistically significant difference was observed, proportion of Th1 was decreased after 1,25(OH)2D3 treatment compared with anti-CD3/CD28 only. The present study demonstrated that 1,25(OH)2D3 inhibited the synthesis of specific cytokines: Th1 (IFN-ɤ) and Th17 (IL-17, IL-22, IL-6, TNF-α) might upregulated Th2 cytokine (IL-4), which indicated the possible immunoregulatory roles and bone-sparing effects of 1,25(OH)2D3 in eRA through modulation of the Th1 and Th17 cytokine balance.
Assuntos
Artrite Reumatoide/metabolismo , Calcitriol/metabolismo , Subpopulações de Linfócitos T/imunologia , Células Th17/imunologia , Adulto , Diferenciação Celular , China , Citocinas/genética , Citocinas/metabolismo , Feminino , Regulação da Expressão Gênica , Humanos , Imunomodulação , Ativação Linfocitária , Masculino , Pessoa de Meia-IdadeRESUMO
Hydrogen sulfide (H2S) is an endogenous gaseous signaling molecule that plays important roles in the cardiovascular system. In our previous studies, we demonstrated that H2S regulates lipid metabolism. In the present study, we aimed to explore the mechanisms through which H2S regulates lipid metabolism in HepG2 cells in vitro. Treatment of the HepG2 cells with H2S inhibited the expression of proprotein convertase subtilisin/kexin type 9 (PCSK9) and increased the level of lowdensity lipoprotein receptor (LDLR) in a time and dosedependent manner. The knockdown of PCSK9 by siRNA effectively increased the levels of LDLR and 1,1'dioctadecyl3,3,3',3'tetramethylindocarbocyanine perchloratelabeled LDL (DiILDL) uptake in the H2Streated HepG2 cells. Furthermore, the phosphoinositide 3kinase (PI3K)/protein kinase B (Akt)sterol regulatory element binding proteins 2 (SREBP2) signaling pathway was confirmed to be involved in H2Sregulated PCSK9 expression. Notably, the HepG2 cells were incubated with 30% serum and DiILDL for 24 h, and the results revealed that H2S increased lipid uptake, but caused no increase in lipid accumulation. On the whole, the findings of this study demonstrate that H2S is involved in the regulation of lipid metabolism in HepG2 cells through the regulation of the expression of PCSK9 via the PI3K/AktSREBP2 signaling pathway. To the very best of our knowledge, this study is the first to report that H2S can regulate the expression of PCSK9.
Assuntos
Sulfeto de Hidrogênio/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Inibidores de PCSK9 , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo , Células Hep G2 , Humanos , Modelos Biológicos , Pró-Proteína Convertase 9/metabolismo , Receptores de LDL/metabolismo , Regulação para Cima/efeitos dos fármacosRESUMO
BACKGROUND: We have reported previously the insufficient absolute number or functional defects of regulatory T cells (Tregs) in patients with rheumatoid arthritis (RA), challenging conventional unspecific immunosuppressive therapy. Sirolimus, a mTOR inhibitor, is reported to allow growth of functional Tregs; here, we investigated the efficacy of low-dose sirolimus combined with conventional immunosuppressants (sirolimus immunoregulation therapy) for RA treatment with lower side effects and better tolerance. METHODS: In this nonblinded and parallel-group trial, we randomly assigned 62 patients to receive conventional glucocorticoids and immunosuppressants with or without sirolimus at a dosage of 0.5 mg on alternate days for 24 weeks in a 2 : 1 ratio. The demographic features, clinical manifestations, and laboratory indicators including peripheral blood lymphocyte subgroups and CD4+T subsets were compared before and after the treatment. RESULTS: Finally, 37 patients in the sirolimus group and 18 in the conventional treated group completed the 6-month study. By 24 weeks, the patients with sirolimus experienced significant reduction in disease activity indicators including DAS28, ESR, and the number of tender joints and swollen joints (p < 0.001). Notably, they had a higher level of Tregs as compared with those with conventional therapy alone (p < 0.05), indicating that sirolimus could partly restore the reduced Tregs. Concomitantly, their usage of immunosuppressants for controlling disease activity was decreased as compared with the conventional group with no difference in blood routine, and liver and renal functions both before and after the treatment of sirolimus and between the two groups (p > 0.05). CONCLUSIONS: Low-dose sirolimus immunoregulatory therapy selectively upregulated Tregs and partly replaced the usage of immunosuppressants to control disease activity without overtreatment and evaluable side effect. Further study is required using a large sample of RA patients treated with sirolimus for a longer period. This trial is registered at the Chinese Clinical Trial Registry (http://www.chictr.org.cn/showproj.aspx?proj=17245).
Assuntos
Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Imunomodulação/efeitos dos fármacos , Imunossupressores/administração & dosagem , Sirolimo/administração & dosagem , Adulto , Artrite Reumatoide/diagnóstico , Biomarcadores , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Resultado do TratamentoRESUMO
Atherosclerosis is characterized by chronic inflammation and lipid accumulation in arterial walls, resulting in several vascular events. Proprotein convertase subtilisin kexin 9 (PCSK9), a serine protease, has a pivotal role in the degradation of hepatic low-density lipoprotein receptor (LDLR). It can increase plasma concentrations of low-density lipoprotein cholesterol and affect lipid metabolism. Recently, PCSK9 has been found to accelerate atherosclerosis via mechanisms apart from that involving the degradation of LDLR, with an emerging role in regulating the inflammatory response in atherosclerosis. Apolipoprotein E receptor 2 (apoER2), one of the LDLR family members expressed in macrophages, can bind to its ligand apolipoprotein E (apoE), exhibiting an anti-inflammatory role in atherosclerosis. Evidence suggests that apoER2 is a target of PCSK9. This review aims to discuss PCSK9 as a potential regulator of apoE/apoER2 against inflammation in atherosclerosis.
Assuntos
Apolipoproteínas E/metabolismo , Aterosclerose/patologia , Proteínas Relacionadas a Receptor de LDL/metabolismo , Pró-Proteína Convertase 9/fisiologia , Humanos , InflamaçãoRESUMO
INTRODUCTION: The co-existence of focal segmental glomerulosclerosis (FSGS) and rheumatoid arthritis (RA), presenting either together or in succession, is very rare. A variety of histopathological features in the clinical renal disease may occur in RA. Only 8 studies have previously reported this poorly understood connection. CLINICAL FINDINGS/DIAGNOSES: A case of a 54-year-old male with RA lasting for more than 7 years developed cheirarthritis as the first signs. Symmetric polyarthralgia and multiple swollen joints throughout the body were followed, accompanied with morning stiffness. Gradually, he suffered from albuminuria, hypoalbuminemia, edema, and hyperlipidemia in 2014. The patient had the history of administering loxoprofen, celecoxib, leflunomide, and methotrexate. He was diagnosed as RA, nephrotic syndrome. Renal biopsy confirmed FSGS. CONCLUSION: Our case and the review of the literature indicate that FSGS is one of the causes of nephrotic syndrome in RA. It strongly suggested that RA patients with the abnormal kidney functions should be routinely screened for FSGS to guide the therapy, achieve both RA and FSGS remission, determine a prognosis, and avoid end-stage renal lesion.
Assuntos
Artrite Reumatoide , Glomerulosclerose Segmentar e Focal , Rim/patologia , Síndrome Nefrótica , Artrite Reumatoide/complicações , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/fisiopatologia , Artrite Reumatoide/terapia , Biópsia/métodos , Diagnóstico Diferencial , Gerenciamento Clínico , Glomerulosclerose Segmentar e Focal/complicações , Glomerulosclerose Segmentar e Focal/diagnóstico , Glomerulosclerose Segmentar e Focal/fisiopatologia , Glomerulosclerose Segmentar e Focal/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Síndrome Nefrótica/diagnóstico , Síndrome Nefrótica/etiologiaAssuntos
Anticorpos Monoclonais Humanizados , Imunossupressores , Lúpus Eritematoso Sistêmico , Adulto , Anticorpos Monoclonais Humanizados/uso terapêutico , Sistema Nervoso Central/fisiopatologia , Feminino , Humanos , Imunossupressores/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto JovemRESUMO
AIM: To determine the prevalence of symptomatic osteoarthritis (OA) in rural regions of Shanxi Province, China, and to identify factors increasing the prevalence of OA. METHOD: Residents over 16 years of age of targeted towns and villages in rural regions of Shanxi Province were sampled using a stratified multi-stage cluster method. Those exhibiting symptoms of rheumatism were referred to rheumatologists and those in whom rheumatism was suspected were X-rayed within 10 days of interview. OA was diagnosed by consensus (two or three rheumatologists). Factors associated with the presence of OA were identified. RESULTS: A total of 7126 permanent residents were surveyed and 1734 (24.3%) had OA. Knee OA was the most prevalent form of OA (13.8%), followed by lumbar (7.4%), cervical (3.4%), hand (3.3%), shoulder (3.0%), elbow (2.9%), ankle (0.7%), hip (0.6%), wrist (0.5%), thoracic (0.5%) and foot OA (0.5%). All of knee, ankle, shoulder and hand OA exhibited a gender bias. Advanced age, a sweet tooth, poor home ventilation, poor home heating, separation, divorce, or death of a partner, low-grade occupation, low educational level, high body mass index and the presence of concomitant cardiovascular disease, were associated with the presence of OA. CONCLUSION: Symptomatic OA is very prevalent in rural regions of Shanxi Province. Many factors increase the prevalence of the condition. Primary and secondary prevention programs seeking to improve living conditions, to reduce obesity, and to effectively treat concomitant cardiovascular disease, are required.
Assuntos
Articulações/fisiopatologia , Osteoartrite do Quadril/epidemiologia , Saúde da População Rural , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Fenômenos Biomecânicos , Distribuição de Qui-Quadrado , China/epidemiologia , Análise por Conglomerados , Comorbidade , Estudos Transversais , Feminino , Inquéritos Epidemiológicos , Humanos , Articulações/diagnóstico por imagem , Estilo de Vida , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Osteoartrite do Quadril/diagnóstico , Osteoartrite do Quadril/fisiopatologia , Valor Preditivo dos Testes , Prevalência , Fatores de Risco , Fatores Socioeconômicos , Adulto JovemRESUMO
MicroRNAs are a group of endogenously small non-coding RNA molecules that downregulate gene expression at the post-transcriptional level through binding to the 3'UTR of target mRNAs. Recent findings have revealed a key role for microRNAs in the pathophysiological processes of atherosclerosis. As a complex disease, atherosclerosis is influenced by a combination of multiple genes and environmental factors. Both of them play a role in atherogenesis by affecting different types of cells (such as endothelial cell, vascular smooth muscle cell and monocyte/macrophage) function. MicroRNAs control the senescence and dysfunction of endothelial cells, proliferation and migration of vascular smooth muscle cells, and macrophage-driven cytokine production and polarization. By these effects, microRNAs can influence the processes of atherosclerosis and may represent new molecular targets for therapy.
Assuntos
Aterosclerose/genética , MicroRNAs/fisiologia , Células Endoteliais/patologia , Humanos , Macrófagos/patologia , Terapia de Alvo Molecular/métodos , Músculo Liso Vascular/patologiaRESUMO
Focal adhesion kinase (FAK) is known to promote the proliferation, migration and survival of synovial cells and plays an important role in the occurrence, development and pathological process of rheumatoid arthritis (RA). The aim of the present study was to observe FAK changes in synovial cells of rats with collagen-induced arthritis (CIA) and after intervention with disease modifying anti-rheumatic drugs (DMARDs) alone or in combination in a CIA female SD rat model induced by collagen type II. The rats were randomized to 8 groups: normal control group, CIA model control group, methotrexate (MTX, 0.9 mg/kg/w) group, cyclophosphamide (CTX, 24 mg/kg/3 w) group, leflunomide (LEF, 1.2 mg/kg/d) group, MTX + CTX group, LEF + CTX group, and MTX + LEF group. They were intervened with DMARDs alone or in combination for six weeks. The experiment lasted a total of 9 weeks in vivo. Articular inflammation was measured during the process of drug intervention in terms of the degree of swelling degree in the right hind foot using a venire caliper. All animals were sacrificed by breaking the neck after 9 weeks. Then, the ankle was fixed, decalcified, embedded, and HE stained, and prepared into slices to observe pathological changes in the synovial tissue. FAK expression in synovial cells was assayed by immunohistochemistry and the mean optical density (OD) value was measured using the HPIAS-2000 image analysis system. It was found that FAK expression was negative in normal control group, positive in CIA model control group, and decreased in the three DMARD combination treatment groups significantly as compared with that in the three single-drug groups (P < 0.05). FAK expression in LEF + CTX group or MTX + CTX group decreased more significantly than that in MTX + LEF group (P < 0.05), and there was no statistically significant difference between LEF + CTX and MTX + CTX groups. The arthritis index and pathological change in the synovial tissue in LEF + CTX group or MTX + CTX group were improved more significantly than those in MTX + LEF group or single-drug groups. Our results showed that FAK expression was positive in CIA rats, indicating that it played an important role in the pathogenesis of RA, and that intervention with DMARDs could reduce the FAK expression in synovial cells of CIA rats. We hope these findings would contribute to the treatment of RA and other rheumatic diseases by reducing adhesion, proliferation and migration of synovial cells and inhibiting the over-expression of FAK.
Assuntos
Antirreumáticos/farmacologia , Artrite Experimental/tratamento farmacológico , Colágeno Tipo II , Quinase 1 de Adesão Focal/metabolismo , Articulações/efeitos dos fármacos , Membrana Sinovial/efeitos dos fármacos , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/enzimologia , Artrite Experimental/patologia , Ciclofosfamida/farmacologia , Quimioterapia Combinada , Feminino , Isoxazóis/farmacologia , Articulações/enzimologia , Articulações/patologia , Leflunomida , Metotrexato/farmacologia , Ratos Sprague-Dawley , Membrana Sinovial/enzimologia , Membrana Sinovial/patologia , Fatores de TempoRESUMO
OBJECTIVE: Recent studies have shown that circulating microRNAs might be useful, novel biomarkers for the diagnosis of acute myocardial infarction. The aims of this study were to evaluate the expression of cardiac-specific miRNAs (miR-1, -133a, -208b, and -499) in patients with acute myocardial infarction and to compare the diagnostic values of these miRNAs with that of cardiac troponin T. METHODS: Sixty-seven plasma samples obtained from patients with acute myocardial infarction and 32 plasma specimens collected from healthy volunteers were analyzed in this study. The levels of cardiac-specific miRNAs (miR-1, -133a, -208b, and -499) were measured by quantitative reverse transcription-polymerase chain reaction, and the concentrations of plasma cardiac troponin T were measured using electrochemiluminescence-based methods and an Elecsys 2010 Immunoassay Analyzer. RESULTS: The levels of plasma miR-1, -133a, -208b, and -499 were significantly higher in acute myocardial infarction patients (all p<0.001) than in healthy volunteers. The expression of the cardiac-specific miRNAs in acute myocardial infarction patients decreased to close to the baseline levels at the time of hospital discharge (all p>0.05). There were no correlations between the levels of the four circulating miRNAs and the clinical characteristics of the study population (all p>0.05). Furthermore, receiver operating characteristic curve analyses showed that the four plasma miRNAs were not superior to cardiac troponin T for the diagnosis of acute myocardial infarction (all p>0.05). CONCLUSION: Our results demonstrate that circulating miR-1, -133a, -208b, and -499 may be useful biomarkers in acute myocardial infarction patients but that these miRNAs are not superior to cardiac troponin T for the diagnosis of acute myocardial infarction.