RESUMO
OBJECTIVE: To explore the effect of shikonin on the recovery of nerve function after acute spinal cord injury(SCI) in rats. METHODS: 96 male Sprague-Dawley(SD)rats were divided into 4 groups randomly:sham operation group (Group A), sham operation+shikonin group (Group B), SCI+ DMSO(Group C), SCI+shikonin group (Group D).The acute SCI model of rats was made by clamp method in groups C and D . After subdural catheterization, no drug was given in group A. rats in groups B and D were injected with 100 mg·kg-1 of shikonin through catheter 30 min after modeling, and rats in group C were given with the same amount of DMSO, once a day until the time point of collection tissue. Basso-Beattie-Bresnahan(BBB) scores were performed on 8 rats in each group at 6, 12, and 3 d after moneling, and oblique plate tests were performed on 1, 3, 7 and 14 d after modeling, and then spinal cord tissues were collected. Eight rats were intraperitoneally injected with propidine iodide(PI) 1 h before sacrificed to detection PI positive cells at 24 h in each group. Eight rats were sacrificed in each group at 24 h after modeling, the spinal cord injury was observed by HE staining.The Nissl staining was used to observe survivor number of nerve cells. Western-blot technique was used to detect the expression levels of Bcl-2 protein and apoptosis related protein RIPK1. RESULTS: After modeling, BBB scores were normal in group A and B, but in group C and D were significantly higher than those in group A and B. And the scores in group D were higher than those in group C in each time point (P<0.05). At 12 h after modeling, the PI red stained cells in group D were significantly reduced compared with that in group C, and the disintegration of neurons was alleviated(P<0.05). HE and Nissl staining showed nerve cells with normal morphology in group A and B at 24h after operation. The degree of SCI and the number of neuronal survival in group D were better than those in group C, the difference was statistically significant at 24h (P<0.05). The expression of Bcl-2 and RIPK1 proteins was very low in group A and B;The expression of RIPK1 was significantly increased in Group C and decreased in Group D, with a statistically significant difference (P<0.05);The expression of Bcl-2 protein in group D was significantly higher than that in group C (P<0.05). CONCLUSION: Shikonin can alleviate the pathological changes after acute SCI in rats, improve the behavioral score, and promote the recovery of spinal nerve function. The specific mechanism may be related to the inhibition of TNFR/RIPK1 signaling pathway mediated necrotic apoptosis.
Assuntos
Dimetil Sulfóxido , Naftoquinonas , Traumatismos da Medula Espinal , Animais , Masculino , Ratos , Dimetil Sulfóxido/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos Sprague-Dawley , Medula Espinal/metabolismo , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/metabolismo , Receptores do Fator de Necrose Tumoral/efeitos dos fármacos , Receptores do Fator de Necrose Tumoral/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/efeitos dos fármacos , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismoRESUMO
AIMS: Apoptosis of podocytes plays a crucial role in diabetic nephropathy (DN) development, and astragaloside (AS-IV) has a significant impact on podocyte apoptosis. This study aims to explore the effect of AS-IV on diabetic nephropathy progression. MATERIALS AND METHODS: The diabetic nephropathy model was established in rats with streptozotocin (STZ) injection. The albuminuria was examined by using the enzyme linked immunosorbent assay (ELISA). The expression of miR-378, tumor-necrosis factor (TNF) receptor (TNFR)-associated factor 5 (TRAF5) mRNA and protein was analyzed by qRT-PCR and western blot, respectively. Cell transfection was conducted for modulating endogenous expression of miR-378. Dual luciferase reporter assay was used to evaluate the interaction between miR-378 and TRAF5. The terminal deoxynucleotidy transferase dUTP nick end labeling (TUNEL) staining assay was performed for apoptosis detection. KEY FINDINGS: AS-IV protected diabetic rats from developing into diabetic nephropathy. The expression of miR-378 was down-regulated in diabetic nephropathy rats, which was reversed by AS-IV. AS-IV enhanced the expression of miR-378 in podocytes treated with high glucose. MiR-378 negatively regulated TRAF5. AS-IV inhibited the expression of TRAF5 through miR-378. AS-IV suppressed apoptosis of podocytes via targeting miR-378. SIGNIFICANCE: AS-IV suppresses apoptosis of the podocytes through the miR-378/TRAF5 signaling pathway, and thereby repressing diabetic nephropathy development.
Assuntos
Apoptose/efeitos dos fármacos , Nefropatias Diabéticas/patologia , MicroRNAs/efeitos dos fármacos , Podócitos/efeitos dos fármacos , Saponinas/farmacologia , Fator 5 Associado a Receptor de TNF/efeitos dos fármacos , Triterpenos/farmacologia , Albuminúria/induzido quimicamente , Animais , Células Cultivadas , Diabetes Mellitus Experimental/patologia , Marcação In Situ das Extremidades Cortadas , Masculino , Camundongos , Ratos , Ratos Sprague-Dawley , Receptores do Fator de Necrose Tumoral/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , TransfecçãoRESUMO
OBJECTIVE: Our study aimed to investigate the possible modifying effects of leptin and combined use of resveratrol on rat renal I/R injury and their relationship on signal pathways and apoptosis-related mechanisms. BACKGROUND: Renal ischemia-reperfusion (I/R) injury is an important cause of acute renal failure. METHODS: Male Sprague Dawley rats were divided into 5 groups: Control, I/R, I/R+leptin, I/R+resveratrol and I/R+leptin+resveratrol. Leptin (10 µg/kg BW) was administered (i.p.) 30 min prior to I/R. Resveratrol was administered by gavage at 20 mg/kg BW per d for 12 d prior to I/R. The left renal artery was exposed to 1 h of ischemia and 1 h of reperfusion. RESULTS: Resveratrol treatment alone increased TNF-α, TNF-α R1, NF-κB, SIRT-1, STAT1 and STAT3 mRNA levels and decreased caspase 3 protein levels. Leptin treatment alone significantly decreased the caspase 3 protein levels. The combined use of resveratrol and leptin significantly increased STAT3, and caspase 3 mRNA levels, and decreased the caspase 3 protein levels. Apoptosis was significantly decreased especially in the leptin and leptin+resveratrol groups. CONCLUSION: The present study suggest that a combined use of resveratrol and leptin has preventive and regulatory effects on renal I/R injury; the mechanism involves decreasing apoptosis, likely by altering the JAK/STAT pathway and SIRT1 expression (Fig. 8, Ref. 24).
Assuntos
Antioxidantes/farmacologia , Rim/efeitos dos fármacos , Leptina/farmacologia , Traumatismo por Reperfusão/genética , Sirtuína 1/efeitos dos fármacos , Estilbenos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Caspase 3/efeitos dos fármacos , Caspase 3/genética , Caspase 3/metabolismo , Expressão Gênica , Rim/metabolismo , Masculino , NF-kappa B/efeitos dos fármacos , NF-kappa B/genética , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores do Fator de Necrose Tumoral/efeitos dos fármacos , Receptores do Fator de Necrose Tumoral/genética , Traumatismo por Reperfusão/metabolismo , Resveratrol , Fator de Transcrição STAT1/efeitos dos fármacos , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT3/efeitos dos fármacos , Fator de Transcrição STAT3/genética , Transdução de Sinais , Sirtuína 1/genética , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Fator de Necrose Tumoral alfa/genéticaRESUMO
The tumor necrosis factor (TNF) superfamily (TNFSF) contains about thirty structurally related receptors (TNFSFRs) and about twenty protein ligands that bind to one or more of these receptors. Almost all of these cell surface protein-protein interactions (PPIs) represent high-value therapeutic targets for inflammatory or immune modulation in autoimmune diseases, transplant recipients, or cancers, and there are several biologics including antibodies and fusion proteins targeting them that are in various phases of clinical development. Small-molecule inhibitors or activators could represent possible alternatives if the difficulties related to the targeting of protein-protein interactions by small molecules can be addressed. Compounds proving the feasibility of such approaches have been identified through different drug discovery approaches for a number of these TNFSFR-TNFSF type PPIs including CD40-CD40L, BAFFR-BAFF, TRAIL-DR5, and OX40-OX40L. Corresponding structural, signaling, and medicinal chemistry aspects are briefly reviewed here. While none of these small-molecule modulators identified so far seems promising enough to be pursued for clinical development, they provide proof-of-principle evidence that these interactions are susceptible to small-molecule modulation and can serve as starting points toward the identification of more potent and selective candidates.
Assuntos
Descoberta de Drogas , Receptores do Fator de Necrose Tumoral/metabolismo , Fatores de Necrose Tumoral/metabolismo , Animais , Sítios de Ligação , Humanos , Ligantes , Modelos Moleculares , Terapia de Alvo Molecular , Ligação Proteica , Conformação Proteica , Domínios e Motivos de Interação entre Proteínas , Receptores do Fator de Necrose Tumoral/química , Receptores do Fator de Necrose Tumoral/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Fatores de Necrose Tumoral/químicaRESUMO
BACKGROUND AND OBJECTIVE: Smoking cigarettes increases the risk of oral tissue damage leading to periodontal disease. Gingival fibroblasts, the predominant cell type inhabiting gingival connective tissue, play a critical role in remodeling and maintaining gingival structure. The objective of this study was to investigate the effect of long-term exposure to cigarette smoke on human gingival fibroblast survival/apoptosis and the molecular pathways involved in these cell responses. MATERIAL AND METHODS: Human gingival fibroblasts were extracted from healthy non-smokers and cultured in the presence of cigarette smoke condensate (CSC). At the end of each time point, cell growth was evaluated by means of MTT assay. Apoptotic and necrotic gene's expression was investigated by polymerase chain reaction array and by annexin V/propidium iodide staining and cell cycle assays. Western blot was used to investigate Bax and p53 proteins. These tests were supported by caspase 3 activity analyses. RESULTS: High levels of CSC decreased cell growth and deregulated cell cycle progression by increasing the G(0)/G(1) and reducing the S and G(2)/M phases of the gingival fibroblasts. Polymerase chain reaction arrays revealed the activation of several apoptotic genes by CSC, including TNF receptors, caspases, Bax and p53. This was supported by increases in the Bax and p53 protein levels as well as by an elevated activity of caspase-3 in the CSC-exposed cells. Immunofluorescence staining demonstrated that both Bax and caspase-3 displayed a cytosolic and mitochondrial distribution in the CSC-exposed gingival fibroblasts, compared to controls. The damaging effect of CSC on gingival fibroblast growth was also supported by the decrease in interleukin 6 and 8 secretion by the gingival fibroblasts. CONCLUSION: These results suggest that CSC may contribute to deregulating fibroblast functions. This can compromise fibroblast-epithelial cell interactions, which ultimately increases the risk of gingival tissue damage and the onset of periodontitis.
Assuntos
Caspase 3/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Gengiva/efeitos dos fármacos , Fumaça/efeitos adversos , Produtos do Tabaco/efeitos adversos , Proteína Supressora de Tumor p53/efeitos dos fármacos , Proteína X Associada a bcl-2/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Contagem de Células , Técnicas de Cultura de Células , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Forma Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Citosol/efeitos dos fármacos , Gengiva/citologia , Humanos , Interleucina-6/análise , Interleucina-8/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Receptores do Fator de Necrose Tumoral/efeitos dos fármacos , Fatores de TempoRESUMO
Cadmium (Cd) is a human carcinogen that likely acts via epigenetic mechanisms. However, the precise role of Cd in melanoma remains to be defined. The goals of this study are to: (i) examine the effect of Cd on the proliferation rate of cutaneous and uveal melanoma cells; (ii) identify the genes affected by Cd exposure; (iii) understand whether epigenetic changes are involved in the response to Cd. The cell growth capacity increased at 48 h after Cd treatment at doses ranging from 0.5 to 10 µM. The research on the key genes regulating proliferation has shown that aberrant methylation is responsible for silencing of p16(INK4A) and caspase 8 in uveal and cutaneous melanoma cells, respectively. The methylation and expression patterns of p14(ARF), death receptors 4/5, and E-cadherin remained unmodified after Cd treatment in all the cell lines analyzed. Ectopic expression of p16(INK4A) abolished the overgrowth of uveal melanoma cells in response to Cd and the overexpression of caspase 8 drastically increased the apoptotic rate of Cd-treated cutaneous melanoma cells. In conclusion, our data suggest that hypermethylation of p16(INK4A) and caspase 8 represents the most common event linked to Cd-induced stimulation of cell growth and inhibition of cell death pathway in melanoma.
Assuntos
Cloreto de Cádmio/toxicidade , Epigênese Genética/efeitos dos fármacos , Melanoma/induzido quimicamente , Caspase 8/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidor p16 de Quinase Dependente de Ciclina/efeitos dos fármacos , Humanos , Metilação/efeitos dos fármacos , Reação em Cadeia da Polimerase em Tempo Real , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/efeitos dos fármacos , Receptores do Fator de Necrose Tumoral/efeitos dos fármacos , Neoplasias Cutâneas/induzido quimicamente , Proteína Supressora de Tumor p14ARF/efeitos dos fármacos , Neoplasias Uveais/induzido quimicamenteAssuntos
Colite Ulcerativa/tratamento farmacológico , Doença de Crohn/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Anticorpos Monoclonais/uso terapêutico , Gastroenterologia/história , Fármacos Gastrointestinais/história , História do Século XX , Humanos , Infliximab , Receptores do Fator de Necrose Tumoral/efeitos dos fármacos , Fator de Necrose Tumoral alfa/históriaRESUMO
Fibroblast growth factor-inducible 14 (Fn14) is a member of the tumour necrosis factor (TNF) receptor family that is induced in a variety of cell types in situations of tissue injury. Fn14 becomes activated by TNF-like weak inducer of apoptosis (TWEAK), a typical member of the TNF ligand family. TWEAK is constitutively expressed by monocytes and some tumour cell lines and also shows cytokine inducible expression in various other cell types. Fn14 activation results in stimulation of signalling pathways culminating in the activation of NFκB transcription factors and various MAPKs but might also trigger the PI3K/Akt pathway and GTPases of the Rho family. In accordance with its tissue damage-associated expression pattern and its pleiotropic proinflammatory signalling capabilities, the TWEAK-Fn14 system has been implicated in a huge number of pathologies. The use of TWEAK- and Fn14-knockout mice identified the TWEAK-Fn14 system as a crucial player in muscle atrophy, cerebral ischaemia, kidney injury, atherosclerosis and infarction as well as in various autoimmune scenarios including experimental autoimmune encephalitis, rheumatoid arthritis and inflammatory bowel disease. Moreover, there is increasing preclinical evidence that Fn14 targeting is a useful option in tumour therapy. Based on a discussion of the signalling capabilities of TWEAK and Fn14, this review is focused on two major issues. On the one hand, on the molecular and cellular basis of the TWEAK/Fn14-related pathological outcomes in the aforementioned diseases and on the other hand, on the preclinical experience that have been made so far with TWEAK and Fn14 targeting drugs.
Assuntos
Desenho de Fármacos , Receptores do Fator de Necrose Tumoral/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Fatores de Necrose Tumoral/metabolismo , Animais , Anticorpos/farmacologia , Citocina TWEAK , Humanos , Ligantes , Terapia de Alvo Molecular , Receptores do Fator de Necrose Tumoral/metabolismo , Proteínas Recombinantes/farmacologia , Receptor de TWEAK , Fatores de Necrose Tumoral/farmacologiaRESUMO
Receptor-based targeting of therapeutics may be a fascinating proposition to improve the therapeutic efficacy of encapsulated drugs. The development of safe and effective nanomedicines is a prerequisite in the current nanotechnological scenario. Currently, the surface engineering of nanocarriers has attracted great attention for targeted therapeutic delivery by selective binding of targeting ligand to the specific receptors present on the surface of cells. In this review, we have discussed the current status of various receptors such as transferrin, lectoferrin, lectin, folate, human EGF receptor, scavenger, nuclear and integrin, which are over-expressed on the surface of cancer cells; along with the relevance of targeted delivery systems such as nanoparticles, polymersomes, dendrimers, liposomes and carbon nanotubes. The review also focuses on the effective utilization of receptor-based targeted delivery systems for the management of cancer in effective ways by minimizing the drug-associated side effects and improving the therapeutic efficacy of developed nano-architectures.
Assuntos
Sistemas de Liberação de Medicamentos , Neoplasias/tratamento farmacológico , Receptores de Superfície Celular/efeitos dos fármacos , Animais , Receptores ErbB/efeitos dos fármacos , Humanos , Receptores de Hialuronatos/efeitos dos fármacos , Nanopartículas , Receptores para Leptina/efeitos dos fármacos , Receptores da Transferrina/efeitos dos fármacos , Receptores do Fator de Necrose Tumoral/efeitos dos fármacosRESUMO
PURPOSE OF REVIEW: Cancer patients undergoing treatment with cytotoxic chemotherapeutic agents (CCAs) often experience a cluster of treatment-related symptoms, which include fatigue, loss of appetite, disturbed sleep, depressed mood, cognitive difficulties, and changes in body composition. This symptom cluster collectively referred to herein as cancer treatment-related symptoms (CTRSs) decrease quality of life, and physical and social functioning. The preclinical and clinical studies described in this review represent important progress in understanding potential underlying mechanisms of CTRS. RECENT FINDINGS: Recent studies support a role for CCA-induced interleukin-1ß (IL-1ß) signaling in the cause of CTRS. CCAs may share a common ability to activate intracellular stress response pathways to trigger the synthesis, processing, and release of IL-1ß from immune cells. Fatigue, sleep disturbance, and cognitive difficulties in cancer patients exposed to CCAs correlate with plasma levels of IL-6, IL-1 receptor antagonist, and soluble tumor necrosis factor receptor-I/II, surrogate markers of IL-1ß-mediated central nervous system (CNS) inflammation. Additional preclinical work suggests IL-1ß-mediated CNS inflammation may cause CTRS by altering hypothalamic and hippocampal functioning. SUMMARY: Although additional research is necessary to further establish the link between CCA exposure, IL-1ß-mediated inflammatory processes and CTRS, these data provide hints for future studies and therapeutic approaches in ameliorating these symptoms in cancer patients.
Assuntos
Antineoplásicos/efeitos adversos , Comportamento de Doença/efeitos dos fármacos , Inflamação/induzido quimicamente , Interleucina-1beta/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Qualidade de Vida , Transdução de Sinais/efeitos dos fármacos , Antineoplásicos/uso terapêutico , Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/complicações , Fadiga/induzido quimicamente , Fadiga/complicações , Humanos , Hipotálamo/efeitos dos fármacos , Hipotálamo/fisiologia , Inflamação/sangue , Inflamação/complicações , Interleucina-1beta/sangue , Interleucina-1beta/fisiologia , Interleucina-6/sangue , Interleucina-6/fisiologia , Transtornos do Humor/induzido quimicamente , Neoplasias/complicações , Receptores de Interleucina/sangue , Receptores de Interleucina/efeitos dos fármacos , Receptores de Interleucina/fisiologia , Receptores do Fator de Necrose Tumoral/sangue , Receptores do Fator de Necrose Tumoral/efeitos dos fármacos , Receptores do Fator de Necrose Tumoral/fisiologia , Perfil de Impacto da Doença , SíndromeRESUMO
The overexpression of TNF has been implicated in a variety of disease conditions including rheumatoid arthritis, Crohn's disease, HIV and cancer. It is presently a therapeutic target for inflammatory diseases. Many of the therapeutics currently used are biologics designed to sequester TNF, preventing it from binding with its receptors. Recent research has been focused on finding small molecules that alter the production of TNF, modulate its signal transduction pathways, or directly inhibit the binding to its receptors. Modulation of a protein-protein interaction with small molecules is an interesting and nontrivial approach. The various strategies used in obtaining small-molecule, nonpeptide, inhibitors of the TNF-TNF receptor interaction through disruption of the TNF trimer or direct inhibition of the TNF-TNF receptor interaction are presented here.
Assuntos
Receptores do Fator de Necrose Tumoral/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Humanos , Modelos Moleculares , Ligação Proteica , Receptores do Fator de Necrose Tumoral/química , Receptores do Fator de Necrose Tumoral/metabolismo , Fator de Necrose Tumoral alfa/química , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Increased rates of tuberculosis (TB) reactivation have been reported in humans treated with TNF-α (TNF)-neutralizing drugs, and higher rates are observed with anti-TNF Abs (e.g., infliximab) as compared with TNF receptor fusion protein (etanercept). Mechanisms driving differential reactivation rates and differences in drug action are not known. We use a computational model of a TB granuloma formation that includes TNF/TNF receptor dynamics to elucidate these mechanisms. Our analyses yield three important insights. First, drug binding to membrane-bound TNF critically impairs granuloma function. Second, a higher risk of reactivation induced from Ab-type treatments is primarily due to differences in TNF/drug binding kinetics and permeability. Apoptotic and cytolytic activities of Abs and pharmacokinetic fluctuations in blood concentration of drug are not essential to inducing TB reactivation. Third, we predict specific host factors that, if augmented, would improve granuloma function during anti-TNF therapy. Our findings have implications for the development of safer anti-TNF drugs to treat inflammatory diseases.
Assuntos
Anticorpos Monoclonais/efeitos adversos , Antirreumáticos/efeitos adversos , Simulação por Computador , Tuberculose Latente/fisiopatologia , Modelos Biológicos , Mycobacterium tuberculosis/crescimento & desenvolvimento , Receptores do Fator de Necrose Tumoral/efeitos dos fármacos , Tuberculoma/fisiopatologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adalimumab , Anticorpos Monoclonais/sangue , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/sangue , Anticorpos Monoclonais Humanizados/farmacocinética , Antirreumáticos/sangue , Antirreumáticos/classificação , Antirreumáticos/farmacocinética , Apoptose/efeitos dos fármacos , Certolizumab Pegol , Citotoxicidade Imunológica , Etanercepte , Humanos , Fragmentos Fab das Imunoglobulinas/efeitos adversos , Fragmentos Fab das Imunoglobulinas/sangue , Imunoglobulina G/efeitos adversos , Imunoglobulina G/sangue , Infliximab , Tuberculose Latente/imunologia , Mycobacterium tuberculosis/imunologia , Permeabilidade , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/farmacocinética , Ligação Proteica , Receptores do Fator de Necrose Tumoral/sangue , Receptores do Fator de Necrose Tumoral/fisiologia , Risco , Tuberculoma/imunologia , Tuberculoma/microbiologia , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/fisiopatologia , Fator de Necrose Tumoral alfa/fisiologiaRESUMO
In this study, the protective effects of luteolin (1, a major component of Cirsium japonicum) were examined against d-galactosamine (GalN)/lipopolysaccharide (LPS)-induced fulminant hepatic failure. Mice received an intraperitoneal injection of 1 (25, 50, 100, and 200 mg·kg(-1)) 1 h before treatment with GalN (700 mg·kg(-1))/LPS (10 µg·kg(-1)). Treatment with GalN/LPS resulted in increased mortality and serum aminotransferase activity. These increases were attenuated by pretreatment with 1. Treatment with GalN/LPS induced an increase in the serum level of tumor necrosis factor-α (TNF-α) and protein expression of TNF-α receptor-associated death domain, and these increases were prevented by 1. In addition, 1 attenuated apoptosis induced by GalN/LPS treatment, which was analyzed using a caspase-3 and -8 activity assay, as well as by proapoptotic BH3-only protein and cytochrome c protein expression, and by a terminal deoxynuleotidyl transferase-mediated dUTP nick end-labeling method. After GalN/LPS injection, nuclear phosphorylated c-Jun levels showed a significant increase, which were attenuated by 1. The present findings suggest that luteolin ameliorates D-GalN/LPS-induced liver injury and that this protection is likely due to inhibition of the extrinsic and intrinsic apoptotic pathways.
Assuntos
Cirsium/química , Galactosamina/farmacologia , Luteolina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Injeções Intraperitoneais , Fígado/efeitos dos fármacos , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/tratamento farmacológico , Luteolina/química , Masculino , Camundongos , Camundongos Endogâmicos ICR , Estrutura Molecular , Receptores do Fator de Necrose Tumoral/efeitos dos fármacos , Transaminases/análise , Transaminases/sangue , Transaminases/metabolismo , Fator de Necrose Tumoral alfa/análise , Fator de Necrose Tumoral alfa/sangueRESUMO
Alcoholic liver disease (ALD) is a major cause of morbidity and mortality worldwide. The spectrum of disease ranges from fatty liver to hepatic inflammation, necrosis, progressive fibrosis and hepatocellular carcinoma. In developed countries, ALD is a major cause of end-stage liver disease that requires transplantation. The most effective therapy for ALD is alcohol abstinence. However, for patients with severe forms of ALD (that is, alcoholic hepatitis) and for those who do not achieve abstinence from alcohol, targeted therapies are urgently needed. The development of new drugs for ALD is hampered by the scarcity of studies and the drawbacks of existing animal models, which do not reflect all the features of the human disease. However, translational research using liver samples from patients with ALD has identified new potential therapeutic targets, such as CXC chemokines, osteopontin and tumor necrosis factor receptor superfamily member 12A. The pathogenetic roles of these targets, however, remain to be confirmed in animal models. This Review summarizes the epidemiology, natural history, risk factors and current knowledge of the pathogenetic mechanisms of ALD. In addition, this article provides a detailed description of the findings of these translational studies and of the animal models used to study ALD.
Assuntos
Hepatopatias Alcoólicas/tratamento farmacológico , Hepatopatias Alcoólicas/etiologia , Animais , Quimiocinas CXC/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Hepatopatias Alcoólicas/epidemiologia , Osteopontina/efeitos dos fármacos , Prevalência , Receptores do Fator de Necrose Tumoral/efeitos dos fármacosRESUMO
In the periphery, exercise induces interleukin (IL)-6 to downregulate tumor necrosis factor (TNF), elevate interleukin-1 receptor antagonist (IL-1RA), decreasing inflammation. Exercise also offers neuroprotection and facilitates brain repair. IL-6 production in the hippocampus following exercise suggests the potential of a similar protective role as in the periphery to down-regulate TNFα and inflammation. Using a chemical-induced model of hippocampal dentate granule cell death (trimethyltin, TMT 2.4 mg/kg, ip) dependent upon TNF receptor signaling, we demonstrate neuroprotection in mice with 2 weeks access to running wheel. Exercise attenuated neuronal death and diminished elevations in TNFα, TNF receptor 1, myeloid differentiation primary response gene (MyD) 88, transforming growth factor ß, chemokine (C-C motif) ligand 2 (CCL2), and CCL3. Elevated mRNA levels for IL-1α, IL-1RA, occurred with injury and protection. mRNA and protein levels of IL-6 and neuronal expression of IL-6 receptor α, were elevated with injury and protection. Microarray pathway analysis supported an up-regulation of TNFα cell death signaling pathways with TMT and inhibition by exercise. IL-6 pathway recruitment occurred in both conditions. IL-6 downstream signal events differed in the level of STAT3 activation. Exercise did not increase mRNA levels of brain derived neurotrophic factor, nerve growth factor, or glial derived neurotrophic factor. In IL-6 deficient mice, exercise did not attenuate TMT-induced tremor and a diminished level of neuroprotection was observed. These data suggest a contributory role for IL-6 induced by exercise for neuroprotection in the CNS similar to that seen in the periphery.
Assuntos
Hipocampo/efeitos dos fármacos , Interleucina-6/fisiologia , Neurônios/efeitos dos fármacos , Neurotoxinas/toxicidade , Condicionamento Físico Animal/fisiologia , Receptores do Fator de Necrose Tumoral/efeitos dos fármacos , Compostos de Trimetilestanho/toxicidade , Animais , Quimiocinas/biossíntese , Quimiocinas/genética , Epilepsia Tônico-Clônica/induzido quimicamente , Hipocampo/metabolismo , Hipocampo/patologia , Interleucina-6/biossíntese , Interleucina-6/deficiência , Interleucina-6/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Neurológicos , Fator 88 de Diferenciação Mieloide/biossíntese , Fator 88 de Diferenciação Mieloide/genética , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Neurônios/metabolismo , Neurônios/patologia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Quimera por Radiação , Distribuição Aleatória , Receptores do Fator de Necrose Tumoral/biossíntese , Receptores do Fator de Necrose Tumoral/fisiologia , Organismos Livres de Patógenos Específicos , Tremor/induzido quimicamente , Fator de Necrose Tumoral alfa/fisiologia , Regulação para CimaRESUMO
IMPORTANCE OF THE FIELD: The use of biologics as immune modulators in several autoimmune diseases has provided new tools to the physician's therapeutic armamentiarium and has led to improved patients' outcomes and quality of life. By producing autoantibodies, B cells in systemic lupus erythematosus (SLE) are key players in the pathogenesis of the disease and in its clinical manifestations. Therefore, biologics that target B cells in SLE aim at reducing the activity of these cells for the induction of remissions and/or amelioration of disease activity, reduction of organ involvement, and limitation of the complications and side effects caused by immunosuppressive therapies. AREAS COVERED IN THIS REVIEW: This review describes the past and current clinical trials with B-cell-targeted biologics in SLE, to provide a historical perspective and the state-of-the-art on the topic. WHAT THE READER WILL GAIN: We review how the disappointment in the field from promising agents has been instrumental in providing valuable lessons leading to an improved design of new trials that are now giving encouraging results. TAKE HOME MESSAGE: In systemic lupus erythematosus (SLE), the use of B-cell-based biologics in clinical trials has shown both disappointment and promise.
Assuntos
Linfócitos B/imunologia , Produtos Biológicos/uso terapêutico , Fatores Imunológicos/uso terapêutico , Lúpus Eritematoso Sistêmico/terapia , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Antígenos CD20/imunologia , Fator Ativador de Células B/imunologia , Fator Ativador de Células B/fisiologia , Linfócitos B/efeitos dos fármacos , Produtos Biológicos/farmacologia , Ensaios Clínicos como Assunto/estatística & dados numéricos , Humanos , Fatores Imunológicos/farmacologia , Terapia de Imunossupressão , Lúpus Eritematoso Sistêmico/imunologia , Estudos Multicêntricos como Assunto/estatística & dados numéricos , Receptores do Fator de Necrose Tumoral/efeitos dos fármacos , Receptores do Fator de Necrose Tumoral/imunologia , Proteínas Recombinantes de Fusão/farmacologia , Proteínas Recombinantes de Fusão/uso terapêutico , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/imunologiaRESUMO
The alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor (AMPAR) subunit GluR2, which regulates excitotoxicity and the inflammatory cytokine tumour necrosis factor alpha (TNFalpha) have both been implicated in motor neurone vulnerability in amyotrophic lateral sclerosis/motor neurone disease. TNFalpha has been reported to increase cell surface expression of AMPAR subunits to increase synaptic strength and enhance excitotoxicity, but whether this mechanism occurs in motor neurones is unknown. We used primary cultures of mouse motor neurones and cortical neurones to examine the interaction between TNFalpha receptor activation, GluR2 availability, AMPAR-mediated calcium entry and susceptibility to excitotoxicity. Short exposure to a physiologically relevant concentration of TNFalpha (10 ng/mL, 15 min) caused a marked redistribution of both GluR1 and GluR2 to the cell surface as determined by cell surface biotinylation and immunofluorescence. Using fura-2-acetoxymethyl ester microfluorimetry, we showed that exposure to TNFalpha caused a rapid reduction in the peak amplitude of AMPA-mediated calcium entry in a PI3-kinase and p38 kinase-dependent manner, consistent with increased insertion of GluR2-containing AMPAR into the plasma membrane. This resulted in a protection of motor neurones against kainate-induced cell death. Our data therefore, suggest that TNFalpha acts primarily as a physiological regulator of synaptic activity in motor neurones rather than a pathological drive in amyotrophic lateral sclerosis.
Assuntos
Sinalização do Cálcio/efeitos dos fármacos , Cálcio/metabolismo , Neurônios Motores/efeitos dos fármacos , Degeneração Neural/patologia , Fármacos Neuroprotetores , Receptores de AMPA/antagonistas & inibidores , Receptores de Superfície Celular/biossíntese , Fator de Necrose Tumoral alfa/farmacologia , Animais , Biotinilação , Western Blotting , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Agonistas de Aminoácidos Excitatórios/toxicidade , Feminino , Imunofluorescência , Ácido Caínico/antagonistas & inibidores , Ácido Caínico/toxicidade , Camundongos , Degeneração Neural/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Gravidez , Receptores de AMPA/biossíntese , Receptores de AMPA/genética , Receptores do Fator de Necrose Tumoral/efeitos dos fármacos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Espectrometria de Fluorescência , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Opioid receptor like-1 receptor (ORL(1)) is selective for orphaninFQ/nociceptin (OFQ/N), a peptide linked to stress. Since immunologic stimuli exert stressor-like effects, the neuroendocrine and behavioral effects of the T-cell superantigen staphylococcal enterotoxin A (SEA) were tested in ORL(1)(-/-) and ORL(1)(+/+) wildtype 129S6 mice. Within 2h of SEA challenge both genotypes showed elevated corticosterone, but only wildtypes were elevated after 4h, and had altered hypothalamic CRH mRNA. Although amygdaloid CRH and TNFalpha mRNA was increased by SEA, this did not vary with genotype. Interestingly, gustatory neophobia due to SEA challenge was augmented in ORL(1)(-/-) mice, although object neophobia tested 4days later was abrogated. These results suggest differential requirements for ORL(1) in the mediation of neuroimmune effects exerted at different times after an immune challenge.
Assuntos
Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Enterotoxinas/farmacologia , Neuroimunomodulação/efeitos dos fármacos , Receptores Opioides/fisiologia , Animais , Encéfalo/imunologia , Encéfalo/metabolismo , Corticosterona/sangue , Hormônio Liberador da Corticotropina/biossíntese , Hormônio Liberador da Corticotropina/efeitos dos fármacos , Citocinas/biossíntese , Citocinas/efeitos dos fármacos , Citocinas/imunologia , Ingestão de Alimentos/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/imunologia , Sistema Hipotálamo-Hipofisário/metabolismo , Masculino , Camundongos , Camundongos Knockout , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/imunologia , Sistema Hipófise-Suprarrenal/metabolismo , RNA Mensageiro/análise , Receptores do Fator de Necrose Tumoral/biossíntese , Receptores do Fator de Necrose Tumoral/efeitos dos fármacos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Baço/efeitos dos fármacos , Baço/imunologia , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Receptor de NociceptinaRESUMO
Extracellular adenosine-induced apoptosis of HepG2 cells, a human hepatoma cell line, in a concentration (0.1-20mM)- and treatment (24-72h)-dependent manner by activating caspase-3, -8, and -9. In the gene expression assay using a DNA microalley, adenosine upregulated mRNAs for tumor necrosis factor (TNF), TNF receptor 1-associated death domain protein (TRADD), TNF related apoptosis-inducing ligand receptor 2 (TRAIL-R2), TRADD/receptor-interacting protein kinase 1 (RIPK1), Fas-associated death domain protein (FADD), and caspase-9, involving activation of caspase-8 and -9 followed by the effector caspase-3. The results of the present study suggest that adenosine induces HepG2 cell apoptosis by activating those caspases as a result from tuning apoptosis-mediator gene transcription.