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1.
Int J Mol Sci ; 25(19)2024 Oct 03.
Artículo en Inglés | MEDLINE | ID: mdl-39409006

RESUMEN

Vitamin D plays an important role in psoriasis, but its involvement in pathogenesis remains unclear. This study aimed to evaluate vitamin D receptor (VDR) expression on peripheral blood mononuclear cells (PBMCs) in patients with psoriasis and healthy controls and to study the effects of the Etanercept treatment on VDR expression on PBMCs in patients with psoriasis. Twenty patients with moderate to severe psoriasis received treatment with Etanercept for 24 weeks. The age- and sex-matched controls did not receive any intervention. VDR expression on CD3+ lymphocytes and CD14+ monocytes, and serum levels of total and free 25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxy vitamin D (1,25(OH)2D) were analyzed at baseline, after 10-12 weeks, and after 24 weeks in both groups. VDR expression was analyzed using flow cytometry. We observed higher expression of the VDR on CD14+ monocytes in psoriasis patients compared to healthy controls at baseline. This difference was no longer significant after 24 weeks of the Etanercept treatment. The patients with psoriasis improved clinically. However, VDR expression was unaltered during the Etanercept treatment, and there was no correlation between VDR expression and disease severity.


Asunto(s)
Etanercept , Leucocitos Mononucleares , Psoriasis , Receptores de Calcitriol , Vitamina D , Humanos , Psoriasis/sangre , Psoriasis/tratamiento farmacológico , Psoriasis/metabolismo , Receptores de Calcitriol/metabolismo , Receptores de Calcitriol/genética , Masculino , Femenino , Leucocitos Mononucleares/metabolismo , Adulto , Persona de Mediana Edad , Etanercept/uso terapéutico , Etanercept/farmacología , Vitamina D/análogos & derivados , Vitamina D/sangre , Monocitos/metabolismo , Receptores de Lipopolisacáridos/metabolismo , Estudios de Casos y Controles
2.
Sci Rep ; 14(1): 18377, 2024 08 08.
Artículo en Inglés | MEDLINE | ID: mdl-39112593

RESUMEN

The effects of calcitonin gene-related peptide (CGRP) on atherosclerosis remain unclear. We used apolipoprotein E-deficient (ApoE-/-) mice to generate double-knockout ApoE-/-:CGRP-/- mice lacking alpha CGRP. ApoE-/-:CGRP-/- mice exhibited larger atherosclerotic plaque areas, peritoneal macrophages with enhanced migration functions, and elevated levels of the inflammatory cytokine tumor necrosis factor (TNF)-⍺. Thus, we also explored whether inhibiting TNF-⍺ could improve atherosclerosis in ApoE-/-:CGRP-/- mice by administering etanercept intraperitoneally once a week (5 mg/kg) alongside a high-fat diet for 2 weeks. This treatment led to significant reductions in aortic root lesion size, atherosclerotic plaque area and macrophage migration in ApoE-/-:CGRP-/- mice compared with mice treated with human IgG (5 mg/kg). We further examined whether results observed in ApoE-/-:CGRP-/- mice could similarly be obtained by administering a humanized monoclonal CGRP antibody, galcanezumab, to ApoE-/- mice. ApoE-/- mice were subcutaneously administered galcanezumab at an initial dose of 50 mg/kg, followed by a dose of 30 mg/kg in the second week. Galcanezumab administration did not affect systolic blood pressure, serum lipid levels, or macrophage migration but led to a significant increase in lipid deposition at the aortic root. These findings suggest that alpha CGRP plays a critical role in inhibiting the progression of atherosclerosis.


Asunto(s)
Apolipoproteínas E , Aterosclerosis , Péptido Relacionado con Gen de Calcitonina , Ratones Noqueados , Placa Aterosclerótica , Animales , Aterosclerosis/metabolismo , Aterosclerosis/genética , Aterosclerosis/patología , Péptido Relacionado con Gen de Calcitonina/metabolismo , Ratones , Apolipoproteínas E/deficiencia , Apolipoproteínas E/genética , Placa Aterosclerótica/patología , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/genética , Dieta Alta en Grasa/efectos adversos , Factor de Necrosis Tumoral alfa/metabolismo , Masculino , Ratones Noqueados para ApoE , Modelos Animales de Enfermedad , Humanos , Anticuerpos Monoclonales Humanizados/farmacología , Etanercept/farmacología , Ratones Endogámicos C57BL , Movimiento Celular/efectos de los fármacos , Aorta/metabolismo , Aorta/patología , Aorta/efectos de los fármacos
3.
Clin Exp Pharmacol Physiol ; 51(8): e13906, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38965677

RESUMEN

In this study, we wanted to investigate the effectiveness of combining disease-modifying anti-rheumatic drugs (DMARD) with hyperbaric oxygen therapy (HBOT) in reducing inflammation in a rheumatoid arthritis (RA) model using rats. We divided 56 male Sprague-Dawley rats into seven groups and induced RA using complete Freund's adjuvant. Some groups received HBOT, whereas others were given etanercept or leflunomide. We started the treatment on the 10th day after inducing RA and continued it for 18 days. To evaluate the effectiveness of the treatments, we measured paw swelling and used X-rays to examine the joints before and after the treatment. We also analysed the levels of two inflammatory markers, tumour necrosis factor (TNF)-α and interleukin (IL)-1ß, using an enzyme-linked immunosorbent assay. Additionally, we conducted histological analysis and assessed the expressions of anti-IL-1ß and anti-TNF-α antibodies. All the treatment groups showed a significant decrease in arthritis scores, paw swelling and levels of TNF-α and IL-1ß. The X-ray images revealed improvements in joint structure, and the histopathological analysis showed reduced inflammation and collagen abnormalities. Combining DMARD with HBOT had similar effects to individual therapies, suggesting a cost-effective and potentially safer approach for improving outcomes in rats with RA.


Asunto(s)
Antirreumáticos , Artritis Reumatoide , Oxigenoterapia Hiperbárica , Interleucina-1beta , Ratas Sprague-Dawley , Factor de Necrosis Tumoral alfa , Animales , Oxigenoterapia Hiperbárica/métodos , Masculino , Antirreumáticos/uso terapéutico , Antirreumáticos/farmacología , Artritis Reumatoide/terapia , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/patología , Artritis Reumatoide/metabolismo , Ratas , Interleucina-1beta/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Modelos Animales de Enfermedad , Etanercept/uso terapéutico , Etanercept/farmacología , Artritis Experimental/terapia , Artritis Experimental/patología , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/metabolismo , Leflunamida/uso terapéutico , Leflunamida/farmacología
4.
Eur J Pharmacol ; 978: 176801, 2024 Sep 05.
Artículo en Inglés | MEDLINE | ID: mdl-38945285

RESUMEN

Depression is a serious medical illness characterized by persistent feelings of sadness, hopelessness, and lack of interest in daily activities. It can interfere with daily functioning and quality of life. Despite decades of research, the pathophysiology of depression remains incompletely understood. The correlation between depression and inflammation has recently attracted considerable attention. This study investigated the potential antidepressant effect of etanercept, a tumor necrosis factor-alpha (TNF-α) inhibitor, utilizing a chronic mild stress (CMS) model in rats. Male Wistar rats were divided into two groups; one following a non-stressed protocol and the other a stressed protocol for 5 weeks. From the beginning of the third week, rats were treated either with saline daily or with etanercept twice a week (0.3 mg/kg, i.p.) or with fluoxetine daily (10 mg/kg, i.p) as a reference. Etanercept exhibited comparable effects to those of fluoxetine in counteracting CMS-induced behavioral manifestation in the forced swimming and splash tests. Etanercept also restored serotonin and norepinephrine levels to control values in the prefrontal cortex (PFC). Moreover, the current study verified the antioxidant and anti-inflammatory effects of etanercept. Interestingly, etanercept halted the expression of both norepinephrine and serotonin transporters in stressed rats. This could be attributed to abrogation of the p38 mitogen-activated protein kinase (p38 MAPK) and signal transducer and activator of transcription 3 (STAT-3) pathways in the PFC. The findings of the present study contribute to the understanding of the potential of etanercept as an antidepressant and provide insights into the neurobiological mechanisms underlying its therapeutic effects.


Asunto(s)
Antidepresivos , Conducta Animal , Depresión , Etanercept , Ratas Wistar , Factor de Transcripción STAT3 , Proteínas de Transporte de Serotonina en la Membrana Plasmática , Estrés Psicológico , Animales , Etanercept/farmacología , Etanercept/uso terapéutico , Masculino , Depresión/tratamiento farmacológico , Depresión/metabolismo , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/metabolismo , Estrés Psicológico/psicología , Ratas , Factor de Transcripción STAT3/metabolismo , Conducta Animal/efectos de los fármacos , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/metabolismo , Norepinefrina/metabolismo , Corteza Prefrontal/metabolismo , Corteza Prefrontal/efectos de los fármacos , Fluoxetina/farmacología , Fluoxetina/uso terapéutico , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Serotonina/metabolismo , Enfermedad Crónica , Transducción de Señal/efectos de los fármacos
5.
Histol Histopathol ; 39(11): 1443-1455, 2024 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-38572731

RESUMEN

PURPOSE: We investigated the effect of tumor necrosis factor (TNF)-α antagonist on the structure and function of the streptozotocin-nicotinamide (STZ-NA)-induced diabetic rat colon. METHODS: Thirty rats were divided into normal control (NC), diabetic control (DC), and diabetic etanercept (DE) groups. The DE group was injected with etanercept twice a week. Blood glucose, body weight, fecal pellet, colonic transit time, and plasma TNF-α were measured. The colon was dissected out, followed by weight and length measurements. Toluidine blue and Verhoeff's staining, immunohistochemistry for TNF-α, RAGE, iNOS, arginase, and western blot for RAGE were performed on the colonic tissue. RESULTS: Administration of TNF-α antagonist had no significant effect on the body weight and blood glucose level of the diabetic groups. However, the DE group had a shorter and lighter colon and less coarse and less dense collagen fibers in the submucosal layer than the DC group. Weaker immunoreactivity of TNF-α, RAGE, iNOS, and arginase I was observed in colon tissue sections of the DE groups compared with the DC group. Although the etanercept effect on colonic function was not significantly different, the preventive effect size of etanercept on colon remodeling was considerably large, as shown by calculated-Cohen's d>0.8. CONCLUSIONS: TNF-α signaling in the colonic tissue of diabetic rats has a strong effect on tissue remodeling, leading to colon enlargement. TNF-α antagonists may be beneficial in preventing diabetic-related pathology in the colon in combination with anti-diabetic drugs.


Asunto(s)
Colon , Diabetes Mellitus Experimental , Etanercept , Factor de Necrosis Tumoral alfa , Animales , Diabetes Mellitus Experimental/tratamiento farmacológico , Colon/patología , Colon/efectos de los fármacos , Colon/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Masculino , Etanercept/farmacología , Etanercept/uso terapéutico , Ratas , Estreptozocina , Ratas Sprague-Dawley , Glucemia/metabolismo , Receptor para Productos Finales de Glicación Avanzada/metabolismo
6.
Front Immunol ; 15: 1354593, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38500874

RESUMEN

Background: There is no consensus on the effect of tumor necrosis factor-alpha (TNF-alpha) inhibitors on lipid profiles in patients with psoriasis. This study aimed to investigate the effects of TNF-alpha inhibitors on lipid profiles (triglycerides, total cholesterol, low-density lipoprotein, or high-density lipoprotein) in patients with psoriasis. Methods: We searched PubMed, Embase, and Cochrane Library databases for articles published before October 17, 2023. Four TNF-alpha inhibitors (infliximab, etanercept, adalimumab, and certolizumab) were included in our study. (PROSPERO ID: CRD42023469703). Results: A total of twenty trials were included. Overall results revealed that TNF-alpha inhibitors elevated high-density lipoprotein levels in patients with psoriasis (WMD = 2.31; 95% CI: 0.96, 3.67; P = 0.001), which was supported by the results of sensitivity analyses excluding the effect of lipid-lowering drugs. Subgroup analyses indicated that high-density lipoprotein levels were significantly increased in the less than or equal to 3 months group (WMD = 2.88; 95% CI: 1.37, 4.4; P < 0.001), the etanercept group (WMD = 3.4; 95% CI = 1.71, 5.09, P < 0.001), and the psoriasis group (WMD = 2.52; 95% CI = 0.57, 4.48, P = 0.011). Triglyceride levels were significantly increased in the 3 to 6-month group (WMD = 4.98; 95% CI = 1.97, 7.99, P = 0.001) and significantly decreased in the 6-month and older group (WMD = -19.84; 95% CI = -23.97, -15.7, P < 0.001). Additionally, Triglyceride levels were significantly increased in the psoriasis group (WMD = 5.22; 95% CI = 2.23, 8.21, P = 0.001). Conclusion: Our results revealed that TNF-alpha inhibitors might temporarily increase high-density lipoprotein levels in patients with psoriasis. However, changes in triglycerides were not consistent among the different durations of treatment, with significant increases after 3 to 6 months of treatment. Future prospective trials with long-term follow-up contribute to confirming and extending our findings. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023469703.


Asunto(s)
Psoriasis , Factor de Necrosis Tumoral alfa , Humanos , Etanercept/farmacología , Etanercept/uso terapéutico , Factor de Necrosis Tumoral alfa/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Psoriasis/tratamiento farmacológico , Factores Inmunológicos/uso terapéutico , Triglicéridos , Lipoproteínas HDL
7.
Eur J Pharmacol ; 970: 176507, 2024 May 05.
Artículo en Inglés | MEDLINE | ID: mdl-38492877

RESUMEN

BACKGROUND AND AIMS: Acute kidney injury (AKI) due to renal ischemia-reperfusion injury (RIRI) is associated with high morbidity and mortality, with no renoprotective drug available. Previous research focused on single drug targets, yet this approach has not reached translational success. Given the complexity of this condition, we aimed to identify a disease module and apply a multitarget network pharmacology approach. METHODS: Identification of a disease module with potential drug targets was performed utilizing Disease Module Detection algorithm using NADPH oxidases (NOXs) as seeds. We then assessed the protective effect of a multitarget network pharmacology targeting the identified module in a rat model of RIRI. Rats were divided into five groups; sham, RIRI, and RIRI treated with setanaxib (NOX inhibitor, 10 mg/kg), etanercept (TNF-α inhibitor, 10 mg/kg), and setanaxib and etanercept (5 mg/kg each). Kidney functions, histopathological changes and oxidative stress markers (MDA and reduced GSH) were assessed. Immunohistochemistry of inflammatory (TNF-α, NF-κB) apoptotic (cCasp-3, Bax/Bcl 2), fibrotic (α-SMA) and proteolysis (MMP-9) markers was performed. RESULTS: Our in-silico analysis yielded a disease module with TNF receptor 1 (TNFR1A) as the closest target to both NOX1 and NOX2. Targeting this module by a low-dose combination of setanaxib, and etanercept, resulted in a synergistic effect and ameliorated ischemic AKI in rats. This was evidenced by improved kidney function and reduced expression of inflammatory, apoptotic, proteolytic and fibrotic markers. CONCLUSIONS: Our findings show that applying a multitarget network pharmacology approach allows synergistic renoprotective effect in ischemic AKI and might pave the way towards translational success.


Asunto(s)
Lesión Renal Aguda , Daño por Reperfusión , Ratas , Animales , Factor de Necrosis Tumoral alfa/farmacología , Etanercept/farmacología , Riñón , Daño por Reperfusión/complicaciones , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/prevención & control , Isquemia/patología , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/prevención & control
8.
Br J Pharmacol ; 181(8): 1165-1181, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-37859583

RESUMEN

BACKGROUND AND PURPOSE: Millions of patients with inflammatory diseases are treated with tumour necrosis factor (TNF) inhibitors (TNFi). Individual treatment response varies, in part related to variable drug clearance. The role of TNF-TNFi complexes in clearance of the different TNFi is controversial. Moreover, mechanistic insight into the structural aspects and biological significance of TNF-TNFi complexes is lacking. We hypothesized a role for Fc-mediated clearance of TNF-TNFi immune complexes. Therefore, we investigated circulating TNF-TNFi complexes upon treatment with certolizumab-lacking Fc tails-in comparison with adalimumab, golimumab, infliximab and etanercept. EXPERIMENTAL APPROACH: Drug-tolerant ELISAs were developed and used to quantify TNF during adalimumab, golimumab, etanercept, certolizumab and infliximab treatment in patients with inflammatory arthritis or ulcerative colitis for a maximum follow-up of 1 year. Effects on in vitro TNF production and Fc-mediated uptake of TNF-TNFi complexes were investigated for all five TNFi. KEY RESULTS: Circulating TNF concentrations were >20-fold higher during certolizumab treatment compared with adalimumab, reaching up to 23.1 ng·ml-1 . Internalization of TNF-TNFi complexes by macrophages depended on Fc valency, with efficient uptake for the full antibody TNFi (three Fc tails), but little or no uptake for etanercept and certolizumab (one and zero Fc tail, respectively). TNF production was not affected by TNFi. Total TNF load did not affect clearance rate of total TNFi. CONCLUSIONS AND IMPLICATIONS: Differences in TNFi structure profoundly affect clearance of TNF, while it is unlikely that TNF itself significantly contributes to target-mediated drug disposition of TNFi.


Asunto(s)
Antirreumáticos , Artritis Reumatoide , Humanos , Adalimumab/farmacología , Adalimumab/uso terapéutico , Infliximab/farmacología , Infliximab/uso terapéutico , Etanercept/farmacología , Etanercept/uso terapéutico , Inhibidores del Factor de Necrosis Tumoral/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Factor de Necrosis Tumoral alfa
9.
Tissue Cell ; 85: 102249, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37865039

RESUMEN

Hepatic encephalopathy (HE) is one of the most debilitating cerebral complications of liver cirrhosis. The one-year survival of patients with liver cirrhosis and severe encephalopathy is less than 50%. Recent studies have indicated that neuroinflammation is a new player in the pathogenesis of HE, which seems to be involved in the development of cognitive impairment. In this study, we demonstrated neurobehavioral and neuropathological consequences of liver cirrhosis and tested the therapeutic potential of the tumor necrosis factor-α (TNF-α) inhibitor, etanercept. Sixty male adult Wistar albino rats (120-190 g) were allocated into four groups, where groups I and IV served as controls. Thioacetamide (TAA; 300 mg/kg) was intraperitoneally injected twice a week for five months to induce liver cirrhosis in group II (n = 20). Both TAA and etanercept (2 mg/kg) were administered to group III (n = 20). At the end of the experiment, spatial learning was assessed using Morris water maze. TNF-α was detected in both serum and hippocampus. The excised brains were also immunohistochemically stained with glial fibrillary acidic protein (GFAP) to estimate both the number and integrity of hippocampal astrocytes. Ultrastructural changes in the hippocampus were characterized by transmission electron microscopy. The results showed that blocking TNF-α by etanercept was accompanied by a lower TNF-α expression and a higher number of GFAP-positive astrocytes in the hippocampus. Etanercept intervention alleviated the neuronal and glial degenerative changes and impeded the deterioration of spatial learning ability. In conclusion, TNF-α is strongly involved in the development of liver cirrhosis and the associated encephalopathy. TNF-α blockers may be a promising approach for management of hepatic cirrhosis and its cerebral complications.


Asunto(s)
Encefalopatías , Encefalopatía Hepática , Ratas , Animales , Humanos , Masculino , Factor de Necrosis Tumoral alfa/metabolismo , Etanercept/farmacología , Etanercept/metabolismo , Aprendizaje Espacial , Modelos Animales de Enfermedad , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/tratamiento farmacológico , Ratas Wistar , Hipocampo/metabolismo , Encefalopatías/metabolismo , Encefalopatías/patología , Encefalopatía Hepática/tratamiento farmacológico , Encefalopatía Hepática/metabolismo , Encefalopatía Hepática/patología , Tioacetamida/toxicidad
10.
Pharmacol Res Perspect ; 11(5): e01136, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37750203

RESUMEN

Over a decade's experience of post-stroke rehabilitation by administering the specific anti-TNF biological, etanercept, by the novel perispinal route, is consistent with a wide range of chronically diminished neurological function having been caused by persistent excessive cerebral levels of TNF. We propose that this TNF persistence, and cerebral disease chronicity, largely arises from a positive autocrine feedback loop of this cytokine, allowing the persistence of microglial activation caused by the excess TNF that these cells produce. It appears that many of these observations have never been exploited to construct a broad understanding and treatment of certain chronic, yet reversible, neurological illnesses. We propose that this treatment allows these chronically activated microglia to revert to their normal quiescent state, rather than simply neutralizing the direct harmful effects of this cytokine after its release from microglia. Logically, this also applies to the chronic cerebral aspects of various other neurological conditions characterized by activated microglia. These include long COVID, Lyme disease, post-stroke syndromes, traumatic brain injury, chronic traumatic encephalopathy, post-chemotherapy, post-irradiation cerebral dysfunction, cerebral palsy, fetal alcohol syndrome, hepatic encephalopathy, the antinociceptive state of morphine tolerance, and neurogenic pain. In addition, certain psychiatric states, in isolation or as sequelae of infectious diseases such as Lyme disease and long COVID, are candidates for being understood through this approach and treated accordingly. Perispinal etanercept provides the prospect of being able to treat various chronic central nervous system illnesses, whether they are of infectious or non-infectious origin, through reversing excess TNF generation by microglia.


Asunto(s)
Enfermedades del Sistema Nervioso , Factor de Necrosis Tumoral alfa , Humanos , Enfermedad Crónica , Citocinas , Etanercept/farmacología , Etanercept/uso terapéutico , Microglía , Enfermedades del Sistema Nervioso/tratamiento farmacológico , Inhibidores del Factor de Necrosis Tumoral , Factor de Necrosis Tumoral alfa/fisiología , Retroalimentación Fisiológica
11.
Clin Exp Immunol ; 213(2): 209-220, 2023 07 21.
Artículo en Inglés | MEDLINE | ID: mdl-37279559

RESUMEN

Endogenous DNA is released into the bloodstream as cell-free DNA (cfDNA) following cell death and is associated with various pathological conditions. However, their association with therapeutic drugs against rheumatoid arthritis (RA) remains unknown. Therefore, we investigated the significance of cfDNA in RA treated with tocilizumab and tumour necrosis factor inhibitor (TNF-I). Biological DMARDs (bDMARDs), including tocilizumab and TNF-I, were administered to 77 and 59 RA patients, respectively. Plasma cfDNA levels were measured at weeks 0, 4, and 12 by quantitative polymerase chain reaction. Disease activity was evaluated at the same time point using DAS28ESR. cfDNA levels from RA synovial cells treated with tocilizumab or etanercept for 24 h were measured. Human toll-like receptor 9 (hTLR9)-expressing HEK293 cells, which release secreted embryonic alkaline phosphatase (SEAP) upon NF-κB activation, were stimulated by cfDNA from RA patients, and subsequently, SEAP levels were determined. NF-κB translocation was evaluated by immunofluorescence staining with or without tocilizumab. The DAS28ESR significantly improved in both bDMARD groups at week 12. However, plasma cfDNA levels significantly decreased in the tocilizumab group at week 12 compared to that in week 0. cfDNA levels correlated with DAS28ESR in biological treatment-naïve patients administered tocilizumab. cfDNA levels in synovial cells were significantly suppressed by tocilizumab treatment and unaltered with etanercept. HEK293 cells released SEAP upon cfDNA stimulation, and the observed NF-κB nuclear translocation was suppressed by tocilizumab. Tocilizumab suppressed inflammation via the TLR9 pathway by decreasing cfDNA levels. Regulation of cfDNA may be a therapeutic target for RA.


Asunto(s)
Artritis Reumatoide , FN-kappa B , Humanos , FN-kappa B/metabolismo , Receptor Toll-Like 9 , Etanercept/farmacología , Etanercept/uso terapéutico , Células HEK293 , Artritis Reumatoide/patología , Factor de Necrosis Tumoral alfa
12.
Life Sci ; 327: 121826, 2023 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-37270172

RESUMEN

AIMS: Rheumatoid arthritis is an autoimmune disease which induces chronic inflammation and increases the risk for sarcopenia and metabolic abnormalities. Nutritional strategies using omega 3 polyunsaturated fatty acids could be proposed to alleviate inflammation and improve the maintenance of lean mass. Independently, pharmacological agents targeting key molecular regulators of the pathology such as TNF alpha could be proposed, but multiple therapies are frequently necessary increasing the risk for toxicity and adverse effects. The aim of the present study was to explore if the combination of an anti-TNF therapy (Etanercept) with dietary supplementation with omega 3 PUFA could prevent pain and metabolic effects of RA. MATERIALS AND METHODS: RA was induced using collagen-induced arthritis (CIA) in rats to explore of supplementation with docosahexaenoic acid, treatment with etanercept or their association could alleviate symptoms of RA (pain, dysmobility), sarcopenia and metabolic alterations. KEY FINDINGS: We observed that Etanercept had major benefits on pain and RA scoring index. However, DHA could reduce the impact on body composition and metabolic alterations. SIGNIFICANCE: This study revealed for the first time that nutritional supplementation with omega 3 fatty acid could reduce some symptoms of rheumatoid arthritis and be an effective preventive treatment in patients who do not need pharmacological therapy, but no sign of synergy with an anti-TNF agent was observed.


Asunto(s)
Artritis Experimental , Artritis Reumatoide , Ácidos Grasos Omega-3 , Sarcopenia , Ratas , Animales , Etanercept/farmacología , Etanercept/uso terapéutico , Ácidos Docosahexaenoicos/farmacología , Ácidos Docosahexaenoicos/uso terapéutico , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/patología , Inhibidores del Factor de Necrosis Tumoral , Artritis Reumatoide/tratamiento farmacológico , Ácidos Grasos Omega-3/uso terapéutico , Inflamación , Dolor/tratamiento farmacológico
13.
J Dermatol ; 50(9): 1129-1139, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-37269158

RESUMEN

Decreased epidermal high-mobility group box 1 (HMGB1) expression is an early marker of epidermal injury in Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). Etanercept, an anti-tumor necrosis factor therapeutic, is effective in the treatment of SJS/TEN. The objective was to characterize antitumor necrosis factor-alpha (TNF-α)-mediated HMGB1 keratinocyte/epidermal release and etanercept modulation. HMGB1 release from TNF-α treated (± etanercept), or doxycycline-inducible RIPK3 or Bak-expressing human keratinocyte cells (HaCaTs) was determined by western blot/ELISA. Healthy skin explants were treated with TNF-α or serum (1:10 dilution) from immune checkpoint inhibitor-tolerant, lichenoid dermatitis or SJS/TEN patients ± etanercept. Histological and immunohistochemical analysis of HMGB1 was undertaken. TNF-α induced HMGB1 release in vitro via both necroptosis and apoptosis. Exposure of skin explants to TNF-α or SJS/TEN serum resulted in significant epidermal toxicity/detachment with substantial HMGB1 release which was attenuated by etanercept. Whole-slide image analysis of biopsies demonstrated significantly lower epidermal HMGB1 in pre-blistered SJS/TEN versus control (P < 0.05). Keratinocyte HMGB1 release, predominantly caused by necroptosis, can be attenuated by etanercept. Although TNF-α is a key mediator of epidermal HMGB1 release, other cytokines/cytotoxic proteins also contribute. Skin explant models represent a potential model of SJS/TEN that could be utilized for further mechanistic studies and targeted therapy screening.


Asunto(s)
Proteína HMGB1 , Síndrome de Stevens-Johnson , Humanos , Síndrome de Stevens-Johnson/diagnóstico , Factor de Necrosis Tumoral alfa , Etanercept/farmacología , Etanercept/uso terapéutico , Queratinocitos/metabolismo , Necrosis , Biomarcadores/metabolismo
14.
Exp Dermatol ; 32(8): 1299-1305, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37194367

RESUMEN

Generalized pustular psoriasis (GPP) is a rare but severe form of psoriasis. An early onset of the diseases is correlated with mutations among IL36RN, CARD14, AP1S3, MPO and SERPINA3 genes. Systemic biological agents including anti-TNF-α, anti-IL-17, anti-IL-12/IL-23, anti-IL1R, anti-IL1ß and anti-IL-36R act as novel treatment methods for GPP. Herein we report a female infant clinically diagnosed with GPP since she was 10-month-old. Results of whole-exome sequencing (WES) and Sanger sequencing revealed a reported heterozygous IL36RN (c.115+6T>C) and another reported heterozygous SERPINA3 frame-shifting variant (c.1247_1248del). Initial cyclosporin treatment for the patient led to a partial remission of the symptoms. However, the patient reached nearly total remission of pustules and erythema after anti-TNF-α inhibitor etanercept treatment. Results of further RNA sequencing (RNA-seq) done on peripheral blood mononuclear cells correlated with the clinical responses, showing that cyclosporin suppressed a portion of the neutrophil-related genes, while most genes associated with neutrophil activation, neutrophil-mediated immunity and degranulation were downregulated by the subsequent etanercept treatment. We report this case to demonstrate WES and RNA-seq in combination could come in handy in reaching a precise diagnosis and in evaluating or even predicting the molecular alterations underlying clinical treatment effectiveness.


Asunto(s)
Ciclosporina , Psoriasis , Humanos , Femenino , Lactante , Etanercept/farmacología , Etanercept/uso terapéutico , Ciclosporina/uso terapéutico , Transcriptoma , Interleucinas/genética , Leucocitos Mononucleares , Inhibidores del Factor de Necrosis Tumoral/uso terapéutico , Psoriasis/tratamiento farmacológico , Psoriasis/genética , Enfermedad Aguda , Enfermedad Crónica , Guanilato Ciclasa/genética , Proteínas de la Membrana/genética , Proteínas Adaptadoras de Señalización CARD/genética
15.
Adv Rheumatol ; 63(1): 14, 2023 03 22.
Artículo en Inglés | MEDLINE | ID: mdl-36949513

RESUMEN

BACKGROUND: Rheumatoid arthritis is an autoimmune inflammatory disease that often leads patients to muscle impairment and physical disability. This study aimed to evaluate changes in the activity of proteasome system in skeletal muscles of mice with collagen-induced arthritis (CIA) and treated with etanercept or methotrexate. METHODS: Male DBA1/J mice were divided into four groups (n = 8 each): CIA-Vehicle (treated with saline), CIA-ETN (treated with etanercept, 5.5 mg/kg), CIA-MTX (treated with methotrexate, 35 mg/kg) and CO (healthy control group). Mice were treated two times a week for 6 weeks. Clinical score and hind paw edema were measured. Muscles were weighted after euthanasia and used to quantify proteasome activity, gene (MuRF-1, PMSα4, PSMß5, PMSß6, PSMß7, PSMß8, PSMß9, and PSMß10), and protein (PSMß1, PSMß5, PSMß1i, PSMß5i) expression of proteasome subunits. RESULTS: Both treatments slowed disease development, but only CIA-ETN maintained muscle weight compared to CIA-MTX and CIA-Vehicle groups. Etanercept treatment showed caspase-like activity of 26S proteasome similar to CO group, while CIA-Vehicle and CIA-MTX had higher activity compared to CO group (p: 0.0057). MuRF-1 mRNA expression was decreased after etanercept administration compared to CIA-Vehicle and CO groups (p: 0.002, p: 0.007, respectively). PSMß8 and PSMß9 mRNA levels were increased in CIA-Vehicle and CIA-MTX compared to CO group, while CIA-ETN presented no difference from CO. PMSß6 mRNA expression was higher in CIA-Vehicle and CIA-MTX groups than in CO group. Protein levels of the PSMß5 subunit were increased in CO group compared to CIA-Vehicle; after both etanercept and methotrexate treatments, PSMß5 expression was higher than in CIA-Vehicle group and did not differ from CO group expression (p: 0.0025, p: 0.001, respectively). The inflammation-induced subunit ß1 (LMP2) was enhanced after methotrexate treatment compared to CO group (p: 0.043). CONCLUSIONS: The results of CIA-Vehicle show that arthritis increases muscle proteasome activation by enhanced caspase-like activity of 26S proteasome and increased PSMß8 and PSMß9 mRNA levels. Etanercept treatment was able to maintain the muscle weight and to modulate proteasome so that its activity and gene expression were compared to CO after TNF inhibition. The protein expression of inflammation-induced proteasome subunit was increased in muscle of CIA-MTX group but not following etanercept treatment. Thus, anti-TNF treatment may be an interesting approach to attenuate the arthritis-related muscle wasting.


Asunto(s)
Antirreumáticos , Artritis Experimental , Masculino , Humanos , Ratones , Animales , Etanercept/farmacología , Etanercept/uso terapéutico , Metotrexato/uso terapéutico , Antirreumáticos/uso terapéutico , Artritis Experimental/tratamiento farmacológico , Complejo de la Endopetidasa Proteasomal , Inhibidores del Factor de Necrosis Tumoral/uso terapéutico , Quimioterapia Combinada , Resultado del Tratamiento , Músculo Esquelético , Inflamación/tratamiento farmacológico
16.
Clin Exp Immunol ; 211(3): 233-238, 2023 03 24.
Artículo en Inglés | MEDLINE | ID: mdl-36571199

RESUMEN

We aimed to compare a transient receptor potential vanilloid 2 (TRPV2) agonist with a TNF inhibitor, and to test the potential of their combination in collagen-induced arthritis (CIA) as a potential future strategy for rheumatoid arthritis (RA). Following the onset of CIA DBA1/j mice were started on treatment with either vehicle, etanercept (8 mg/kg three times a week), the TRPV2 agonist O1821 (20-30 mg/kg/day), or a combination of both. Mice were scored over a 61-day period. Synovial tissues were obtained for RNA sequencing. Mice on monotherapy with either O1821 or etanercept developed milder clinical disease. The O1821 protection was observed at an earlier time-point than in the etanercept group. The combination therapy group achieved a more robust and sustained reduction in disease severity than either monotherapy group. All treatment groups had reduced scores for synovial inflammation, synovial hyperplasia, and erosive changes, compared with controls, with the combination group achieving the most significant protection. RNA sequencing and pathway analyses of synovial tissues identified pathways and processes regulated by the TRPV2 agonist, such as chemotaxis and cytokine receptor signaling, including IL6R. The combination therapy affected additional pathways not seen in the monotherapy groups. In conclusion, the TRPV2 agonist achieved an overall similar reduction in arthritis severity and histology scores as etanercept, but the combination therapy achieved a more sustained disease control and more pronounced reduction in joint damage, suggesting a potential future option for improving disease control in RA. RNA sequencing analyses identified new pathways regulated by TRPV2, and also by the combination treatment.


Asunto(s)
Artritis Experimental , Artritis Reumatoide , Ratones , Animales , Etanercept/farmacología , Etanercept/uso terapéutico , Etanercept/metabolismo , Inhibidores del Factor de Necrosis Tumoral , Artritis Reumatoide/patología , Membrana Sinovial/metabolismo , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/metabolismo , Gravedad del Paciente , Canales de Calcio/metabolismo , Canales de Calcio/uso terapéutico , Canales Catiónicos TRPV/genética , Canales Catiónicos TRPV/metabolismo , Canales Catiónicos TRPV/uso terapéutico
17.
J Invest Dermatol ; 143(6): 1023-1030.e7, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-36581093

RESUMEN

Stevens‒Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are severe cutaneous adverse drug reactions characterized by widespread keratinocyte cell death and epidermal detachment. At present, there is little understanding of how the detachment occurs or how it is abrogated by the TNF-α inhibitor etanercept, an effective SJS/TEN treatment. RNA sequencing was used to identify upregulated transcripts in formalin-fixed paraffin-embedded SJS/TEN skin biopsies. Epidermal matrix metalloproteinase 9 (MMP9) expression was assessed by immunohistochemistry in skin biopsies and cultured human skin explants exposed to serum from patients with cutaneous adverse drug reactions. TNF-α‒induced MMP9 expression and activity and its abrogation by etanercept were determined using the HaCaT immortalized keratinocyte cell line. Epidermal MMP9 expression was significantly higher in SJS/TEN skin (70.6%) than in healthy control skin (0%) (P = 0.0098) and nonbullous skin reactions (10.7%) (P = 0.0002). SJS/TEN serum induced significant MMP9 expression and collagenase activity in healthy skin explants, which was reduced by etanercept. Etanercept was also able to negate the TNF-α‒induced MMP9 expression in the HaCaT cell line. Data suggest that elevated epidermal MMP9 expression and collagenase activity are a putative pathogenic mechanism in SJS/TEN, which is limited by etanercept. Modulation of MMP9 expression and activity represents, to our knowledge, a previously unreported therapeutic target for the treatment of SJS/TEN.


Asunto(s)
Síndrome de Stevens-Johnson , Humanos , Síndrome de Stevens-Johnson/etiología , Factor de Necrosis Tumoral alfa/uso terapéutico , Metaloproteinasa 9 de la Matriz , Etanercept/farmacología , Etanercept/uso terapéutico , Queratinocitos/patología
18.
Mod Rheumatol ; 33(1): 111-121, 2023 Jan 03.
Artículo en Inglés | MEDLINE | ID: mdl-35141748

RESUMEN

OBJECTIVE: This study aimed to investigate the linkage of long non-coding RNA (lncRNA) expression profile with etanercept response in rheumatoid arthritis (RA) patients. METHODS: Peripheral blood mononuclear cell (PBMC) samples were collected from 80 RA patients prior to etanercept treatment. Samples from eight responders and eight non-responders at week 24 (W24) were proposed to RNA-sequencing, then 10 candidate lncRNAs were sorted and their PBMC expressions were validated by reverse transcription quantitative chain reaction (RT-qPCR) in 80 RA patients. Subsequently, clinical response by lncRNA (CRLnc) prediction model was established. RESULTS: RNA-sequencing identified 254 up-regulated and 265 down-regulated lncRNAs in W24 responders compared with non-responders, which were enriched in immune or joint related pathways such as B-cell receptor signaling, osteoclast differentiation and T-cell receptor signaling pathways, etc. By reverse transcription quantitative chain reaction (RT-qPCR) validation: Two lncRNAs were correlated with W4 response, three lncRNAs were correlated with W12 response, seven lncRNAs were correlated with W24 response. Subsequently, to construct and validate CRLnc prediction model, 80 RA patients were randomly divided into test set (n = 40) and validation set (n = 40). In the test set, lncRNA RP3-466P17.2 (OR = 9.743, P = .028), RP11-20D14.6 (OR = 10.935, P = .007), RP11-844P9.2 (OR = 0.075, P = .022), and TAS2R64P (OR = 0.044, P = .016) independently related to W24 etanercept response; then CRLnc prediction model integrating these four lncRNAs presented a good value in predicting W24 etanercept response (Area Under Curve (AUC): 0.956, 95%CI: 0.896-1.000). However, in the validation set, the CRLnc prediction model only exhibited a certain value in predicting W24 etanercept response (AUC: 0.753, 95%CI: 0.536-0.969). CONCLUSIONS: CRLnc prediction model is potentially a useful tool to instruct etanercept treatment in RA patients.


Asunto(s)
Artritis Reumatoide , ARN Largo no Codificante , Humanos , Etanercept/farmacología , Etanercept/uso terapéutico , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , ARN Largo no Codificante/uso terapéutico , Inhibidores del Factor de Necrosis Tumoral/uso terapéutico , Leucocitos Mononucleares/metabolismo , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/genética
19.
Brain ; 146(4): 1453-1466, 2023 04 19.
Artículo en Inglés | MEDLINE | ID: mdl-36087304

RESUMEN

Cystic white matter injury is highly associated with severe neurodevelopmental disability and cerebral palsy in preterm infants, yet its pathogenesis remains poorly understood and there is no established treatment. In the present study, we tested the hypothesis that slowly evolving cystic white matter injury after hypoxia-ischaemia is mediated by programmed necrosis initiated by tumour necrosis factor. Tumour necrosis factor blockade was begun 3 days after hypoxia-ischaemia to target the tertiary phase of injury, when most secondary cell death is thought to be complete. Chronically instrumented preterm foetal sheep (0.7 gestation) received 25 min of hypoxia-ischaemia induced by complete umbilical cord occlusion or sham-umbilical cord occlusion (controls, n = 10), followed by intracerebroventricular infusion of the soluble TNF inhibitor, Etanercept, at 3, 8 and 13 days after umbilical cord occlusion (n = 9) or vehicle (n = 9). Foetal brains were processed for histology at 21 days after umbilical cord occlusion. Umbilical cord occlusion with vehicle was associated with a spectrum of macroscopic white matter degeneration, including white matter atrophy, ventriculomegaly and overt temporal lobe cystic white matter injury. Oligodendrocyte maturational arrest and impaired labelling of myelin proteins, characteristic of diffuse white matter injury, was observed in the parietal lobe and surrounding the cystic lesions in the temporal lobe. Etanercept markedly attenuated cystic white matter injury on the side of the intracerebroventricular infusion, with partial contralateral protection. Further, Etanercept improved oligodendrocyte maturation and labelling of myelin proteins in the temporal and parietal lobes. The present study shows that cystic white matter injury reflects late-onset tertiary cell death mediated by delayed neuroinflammation through the tumour necrosis factor pathway. Delayed tumour necrosis factor blockade markedly attenuated cystic white matter injury and restored oligodendrocyte maturation and deficits in myelin protein expression. These data suggest that delayed tumour necrosis factor blockade may represent a viable therapeutic strategy to reduce the risk of cystic and diffuse white matter injury and potentially cerebral palsy after preterm birth, with a surprisingly wide therapeutic window.


Asunto(s)
Lesiones Encefálicas , Parálisis Cerebral , Hipoxia-Isquemia Encefálica , Nacimiento Prematuro , Sustancia Blanca , Recién Nacido , Humanos , Femenino , Ovinos , Animales , Sustancia Blanca/patología , Asfixia/complicaciones , Etanercept/farmacología , Etanercept/uso terapéutico , Etanercept/metabolismo , Recien Nacido Prematuro , Hipoxia-Isquemia Encefálica/patología , Lesiones Encefálicas/patología , Factores de Necrosis Tumoral/metabolismo
20.
Nephrol Dial Transplant ; 38(5): 1139-1150, 2023 05 04.
Artículo en Inglés | MEDLINE | ID: mdl-36269313

RESUMEN

BACKGROUND: Inflammation is a key driver of the transition of acute kidney injury to progressive fibrosis and chronic kidney disease (AKI-to-CKD transition). Blocking a-disintegrin-and-metalloprotease-17 (ADAM17)-dependent ectodomain shedding, in particular of epidermal growth factor receptor (EGFR) ligands and of the type 1 inflammatory cytokine tumor necrosis factor (TNF), reduces pro-inflammatory and pro-fibrotic responses after ischemic AKI or unilateral ureteral obstruction (UUO), a classical fibrosis model. Metalloprotease or EGFR inhibition show significant undesirable side effects in humans. In retrospective studies anti-TNF biologics reduce the incidence and progression of CKD in humans. Whether TNF has a role in AKI-to-CKD transition and how TNF inhibition compares to EGFR inhibition is largely unknown. METHODS: Mice were subjected to bilateral renal ischemia-reperfusion injury or unilateral ureteral obstruction. Kidneys were analyzed by histology, immunohistochemistry, qPCR, western blot, mass cytometry, scRNA sequencing, and cytokine profiling. RESULTS: Here we show that TNF or EGFR inhibition reduce AKI-to-CKD transition and fibrosis equally by about 25%, while combination has no additional effect. EGFR inhibition reduced kidney TNF expression by about 50% largely by reducing accumulation of TNF expressing immune cells in the kidney early after AKI, while TNF inhibition did not affect EGFR activation or immune cell accumulation. Using scRNAseq data we show that TNF is predominantly expressed by immune cells in AKI but not in proximal tubule cells (PTC), and PTC-TNF knockout did not affect AKI-to-CKD transition in UUO. Thus, the anti-inflammatory and anti-fibrotic effects of the anti-TNF biologic etanercept in AKI-to-CKD transition rely on blocking TNF that is released from immune cells recruited or accumulating in response to PTC-EGFR signals. CONCLUSION: Short-term anti-TNF biologics during or after AKI could be helpful in the prevention of AKI-to-CKD transition.


Asunto(s)
Lesión Renal Aguda , Productos Biológicos , Insuficiencia Renal Crónica , Obstrucción Ureteral , Humanos , Ratones , Animales , Etanercept/farmacología , Etanercept/uso terapéutico , Etanercept/metabolismo , Obstrucción Ureteral/metabolismo , Estudios Retrospectivos , Inhibidores del Factor de Necrosis Tumoral/metabolismo , Inhibidores del Factor de Necrosis Tumoral/farmacología , Insuficiencia Renal Crónica/patología , Riñón/patología , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/etiología , Lesión Renal Aguda/prevención & control , Receptores ErbB , Factor de Necrosis Tumoral alfa/metabolismo , Fibrosis , Productos Biológicos/metabolismo , Productos Biológicos/farmacología
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