RESUMO
Regulated transcriptional readthrough during stress maintains genome structure and ensures access to genes that are necessary for cellular recovery. A broad number of genes, including of the bacterial sensor Toll-like receptor 4 (TLR-4), are markedly transcribed on initiating the systemic inflammatory response. Here we study the transcriptional patterns of tlr4 and of its modulator grp78 during human sepsis, and establish their correlations with the outcome of patients. We measured the daily tlr4 and grp78 RNA expression levels in peripheral blood of septic patients, immediately after admission to intensive care, and modeled these RNA values with a sine damping function. We obtained negative correlations between the transcription of tlr4 and grp78 RNA in the survivor group. In contrast, such relation is lost in the deceased patients. Loss of transcriptional homeostasis predicted by our model within the initial 4 days of hospitalization was confirmed by death of those patients up to 28 days later.
Assuntos
Proteínas de Choque Térmico/imunologia , Modelos Biológicos , Sepse/imunologia , Receptor 4 Toll-Like/imunologia , Transcrição Gênica/imunologia , Adulto , Idoso , Intervalo Livre de Doença , Chaperona BiP do Retículo Endoplasmático , Feminino , Proteínas de Choque Térmico/sangue , Humanos , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/sangue , RNA Mensageiro/imunologia , Sepse/sangue , Sepse/mortalidade , Taxa de Sobrevida , Receptor 4 Toll-Like/sangueRESUMO
This study aimed to investigate the association of serum high-mobility group box-1 (HMGB1) and toll-like receptor 4 (TLR4) expressions with the risk of epilepsy as well as their correlations with disease severity and resistance to anti-epilepsy drugs. One hundred and five epilepsy patients and 100 healthy controls (HCs) were enrolled in this case-control study, and serum samples were collected from all participants to assess the HMGB1 and TLR4 expressions by enzyme-linked immunosorbent assay (ELISA). Both serum HMGB1 (P<0.001) and TLR4 (P<0.001) expressions were higher in epilepsy patients than in HCs, and they displayed good predictive values for risk of epilepsy. Moreover, HMGB1 was positively correlated with TLR4 level (r=0.735, P<0.001). HMGB1 and TLR4 levels were both elevated in patients with an average seizure duration >5 min compared to patients with a seizure duration ≤5 min (P=0.001 and P=0.014, respectively). Also, HMGB1 and TLR4 were increased in patients with seizure frequency >3 times per month compared to patients with seizure frequency ≤3 times per month (both P=0.001). In addition, HMGB1 and TLR4 expressions were higher in intractable cases compared to drug-responsive cases (P<0.001). In conclusion, both HMGB1 and TLR4 expressions were correlated with increased risk and severity of epilepsy and their level was higher in patients resistant to anti-epilepsy drugs.
Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsia/sangue , Proteína HMGB1/sangue , Receptor 4 Toll-Like/sangue , Adulto , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Epilepsia/tratamento farmacológico , Feminino , Humanos , Masculino , Valor Preditivo dos Testes , Fatores de Risco , Índice de Gravidade de DoençaRESUMO
This study aimed to explore the influence of gut microbiota alterations induced by Linderae radix ethanol extract (LREE) on alcoholic liver disease (ALD) in rats and to study the anti-inflammatory effect of LREE on ALD through the lipopolysaccharide (LPS) toll-like receptor 4 (TLR4)-nuclear factor kappa B (NF-κB) pathway. ALD rat models were established by intragastric liquor [50% (v/v) ethanol] administration at 10 mL/kg body weight for 20 days. Rats were divided into six groups: normal group (no treatment), model group (ALD rats), Essentiale group (ALD rats fed with Essentiale, 137 mg/kg), and LREE high/moderate/low dose groups (ALD rats fed with 4, 2, or 1 g LREE/kg). NF-κB and LPS levels were evaluated. Liver pathological changes and intestinal ultrastructure were examined by hematoxylin and eosin staining and transmission electron microscopy. The gut microbiota composition was evaluated by 16S rDNA sequencing. Expression levels of TLR4 and CD68 in liver tissue, and occludin and claudin-1 in intestinal tissue were measured. LREE treatment significantly reduced NF-κB and LPS levels, improved liver pathological changes, and ameliorated intestinal ultrastructure injury. Meanwhile, LREE-fed groups showed a higher abundance of Firmicutes and a lower abundance of Bacteroidetes than the rats in the model group. Administration of LREE suppressed TLR4 overexpression and promoted the expression of occludin and claudin-1 in intestine tissue. Thus, LREE could partly ameliorate microflora dysbiosis, suppress the inflammatory response, and attenuate liver injury in ALD rats. The protective effect of LREE might be related to the LPS-TLR4-NF-κB pathway.
Assuntos
Microbioma Gastrointestinal/efeitos dos fármacos , Inflamação/prevenção & controle , Lindera/química , Hepatopatias Alcoólicas/prevenção & controle , Fígado/ultraestrutura , Extratos Vegetais/farmacologia , Animais , Citocinas/sangue , Modelos Animais de Doenças , Lipopolissacarídeos/sangue , Hepatopatias Alcoólicas/diagnóstico por imagem , Masculino , Raízes de Plantas/química , Proteínas Serina-Treonina Quinases/sangue , Ratos , Ratos Sprague-Dawley , Receptor 4 Toll-Like/sangue , Quinase Induzida por NF-kappaBRESUMO
This study aimed to explore the influence of gut microbiota alterations induced by Linderae radix ethanol extract (LREE) on alcoholic liver disease (ALD) in rats and to study the anti-inflammatory effect of LREE on ALD through the lipopolysaccharide (LPS) toll-like receptor 4 (TLR4)-nuclear factor kappa B (NF-κB) pathway. ALD rat models were established by intragastric liquor [50% (v/v) ethanol] administration at 10 mL/kg body weight for 20 days. Rats were divided into six groups: normal group (no treatment), model group (ALD rats), Essentiale group (ALD rats fed with Essentiale, 137 mg/kg), and LREE high/moderate/low dose groups (ALD rats fed with 4, 2, or 1 g LREE/kg). NF-κB and LPS levels were evaluated. Liver pathological changes and intestinal ultrastructure were examined by hematoxylin and eosin staining and transmission electron microscopy. The gut microbiota composition was evaluated by 16S rDNA sequencing. Expression levels of TLR4 and CD68 in liver tissue, and occludin and claudin-1 in intestinal tissue were measured. LREE treatment significantly reduced NF-κB and LPS levels, improved liver pathological changes, and ameliorated intestinal ultrastructure injury. Meanwhile, LREE-fed groups showed a higher abundance of Firmicutes and a lower abundance of Bacteroidetes than the rats in the model group. Administration of LREE suppressed TLR4 overexpression and promoted the expression of occludin and claudin-1 in intestine tissue. Thus, LREE could partly ameliorate microflora dysbiosis, suppress the inflammatory response, and attenuate liver injury in ALD rats. The protective effect of LREE might be related to the LPS-TLR4-NF-κB pathway.
Assuntos
Animais , Masculino , Ratos , Extratos Vegetais/farmacologia , Lindera/química , Microbioma Gastrointestinal/efeitos dos fármacos , Inflamação/prevenção & controle , Fígado/ultraestrutura , Hepatopatias Alcoólicas/prevenção & controle , Lipopolissacarídeos/sangue , Citocinas/sangue , Ratos Sprague-Dawley , Proteínas Serina-Treonina Quinases/sangue , Raízes de Plantas/química , Modelos Animais de Doenças , Receptor 4 Toll-Like/sangue , Hepatopatias Alcoólicas/diagnóstico por imagemRESUMO
This study aimed to investigate the association of serum high-mobility group box-1 (HMGB1) and toll-like receptor 4 (TLR4) expressions with the risk of epilepsy as well as their correlations with disease severity and resistance to anti-epilepsy drugs. One hundred and five epilepsy patients and 100 healthy controls (HCs) were enrolled in this case-control study, and serum samples were collected from all participants to assess the HMGB1 and TLR4 expressions by enzyme-linked immunosorbent assay (ELISA). Both serum HMGB1 (P<0.001) and TLR4 (P<0.001) expressions were higher in epilepsy patients than in HCs, and they displayed good predictive values for risk of epilepsy. Moreover, HMGB1 was positively correlated with TLR4 level (r=0.735, P<0.001). HMGB1 and TLR4 levels were both elevated in patients with an average seizure duration >5 min compared to patients with a seizure duration ≤5 min (P=0.001 and P=0.014, respectively). Also, HMGB1 and TLR4 were increased in patients with seizure frequency >3 times per month compared to patients with seizure frequency ≤3 times per month (both P=0.001). In addition, HMGB1 and TLR4 expressions were higher in intractable cases compared to drug-responsive cases (P<0.001). In conclusion, both HMGB1 and TLR4 expressions were correlated with increased risk and severity of epilepsy and their level was higher in patients resistant to anti-epilepsy drugs.
Assuntos
Humanos , Masculino , Feminino , Adulto , Proteína HMGB1/sangue , Epilepsia/sangue , Receptor 4 Toll-Like/sangue , Anticonvulsivantes/uso terapêutico , Índice de Gravidade de Doença , Ensaio de Imunoadsorção Enzimática , Estudos de Casos e Controles , Valor Preditivo dos Testes , Fatores de Risco , Epilepsia/tratamento farmacológicoRESUMO
The present study was designed to investigate the protective effects and mechanism of inactivated lactobacillus (ILA) on cerebral ischemia reperfusion injury (CIRI) in rats. In this experiment, 30 male Sprague Dawley rats were randomly divided into control group, IRI groups, and ILA group. A middle cerebral artery occlusion and reperfusion model was prepared. The rats were killed after 24 hours of recovery of blood flow of cerebral ischemia resulting from 60-min occlusion. The cerebral infarction volume and neurological scores were assayed by staining and behavioral observation. Malondialdehyde (MDA) and superoxide dismutase (SOD) levels were assayed by biochemical kits. Cell apoptosis was assayed by Tunnel and the Toll-like receptor (TLR)-4, IkB, and A20 were assayed by western blot. The neurobehavioral scores in IRI rats were significantly lower compared to the control group while ILA improved the neurobehavioral scores of the ILA groups. The cerebral infarction volume and neural cell apoptosis of rats in the ILA groups decreased significantly compared with those in the IRI group. In addition, MDA level in the ILA groups decreased whereas SOD activity increased compared to the IRI group. Moreover, ILA also inhibited the expression of TLR-4 and promoted the expression of IkB and A20. ILA inhibited the apoptosis of neural cells, decreased cerebral infarction volume, and reduced oxidative stress through inhibition of TLR-4/NF-kappa B signaling, improving neurobehavioral scores. Thus from the present study it was concluded that ILA has protective effect on CIRI.
Assuntos
Apoptose , Isquemia Encefálica/prevenção & controle , Infarto da Artéria Cerebral Média/complicações , Lacticaseibacillus paracasei , Fármacos Neuroprotetores/administração & dosagem , Traumatismo por Reperfusão/prevenção & controle , Animais , Isquemia Encefálica/etiologia , Modelos Animais de Doenças , Regulação para Baixo , Masculino , NF-kappa B/sangue , Distribuição Aleatória , Ratos Sprague-Dawley , Traumatismo por Reperfusão/etiologia , Receptor 4 Toll-Like/sangueRESUMO
The present study was designed to investigate the protective effects and mechanism of inactivated lactobacillus (ILA) on cerebral ischemia reperfusion injury (CIRI) in rats. In this experiment, 30 male Sprague Dawley rats were randomly divided into control group, IRI groups, and ILA group. A middle cerebral artery occlusion and reperfusion model was prepared. The rats were killed after 24 hours of recovery of blood flow of cerebral ischemia resulting from 60-min occlusion. The cerebral infarction volume and neurological scores were assayed by staining and behavioral observation. Malondialdehyde (MDA) and superoxide dismutase (SOD) levels were assayed by biochemical kits. Cell apoptosis was assayed by Tunnel and the Toll-like receptor (TLR)-4, IkB, and A20 were assayed by western blot. The neurobehavioral scores in IRI rats were significantly lower compared to the control group while ILA improved the neurobehavioral scores of the ILA groups. The cerebral infarction volume and neural cell apoptosis of rats in the ILA groups decreased significantly compared with those in the IRI group. In addition, MDA level in the ILA groups decreased whereas SOD activity increased compared to the IRI group. Moreover, ILA also inhibited the expression of TLR-4 and promoted the expression of IkB and A20. ILA inhibited the apoptosis of neural cells, decreased cerebral infarction volume, and reduced oxidative stress through inhibition of TLR-4/NF-kappa B signaling, improving neurobehavioral scores. Thus from the present study it was concluded that ILA has protective effect on CIRI.
Assuntos
Animais , Masculino , Apoptose , Isquemia Encefálica/prevenção & controle , Infarto da Artéria Cerebral Média/complicações , Lacticaseibacillus paracasei , Fármacos Neuroprotetores/administração & dosagem , Traumatismo por Reperfusão/prevenção & controle , Isquemia Encefálica/etiologia , Modelos Animais de Doenças , Regulação para Baixo , NF-kappa B/sangue , Distribuição Aleatória , Ratos Sprague-Dawley , Traumatismo por Reperfusão/etiologia , Receptor 4 Toll-Like/sangueRESUMO
Abstract The present study was aimed to identify the underlying mechanisms of improper renal function in Leishmania donovani infection that causes VL. Mice (BALB/c) were infected with L. donovani and different parameters for proteinuria were assessed. The levels of superoxide anion (O2 -), hydrogen peroxide (H2O2), lipid peroxidation (MDA), inflammatory cytokines, and toll-like receptor (TLR) 2 and 4 expression were found significantly elevated at 60th day in these animals and declined at 90th day post infection. However, TGF-β and caspase 3 activities were higher at 90th day in comparison to 60th day post infection. These findings suggested that exacerbated inflammatory conditions correlate with abnormal renal functions in L. donovani infection, which is further augmented by activated TLRs expressions by circulating leishmanial antigens. Further, the increased levels of TGF-β and caspase 3 at 90th day suggested TGF-β mediated apoptotic cell death of renal and other cells during later stages of disease that may eventually result in release of host and parasitic factors in urine during visceral leishmaniasis.
Assuntos
Animais , Feminino , Ratos , Fator de Crescimento Transformador beta/sangue , Receptor 2 Toll-Like/sangue , Receptor 4 Toll-Like/sangue , Rim/parasitologia , Rim/patologia , Leishmaniose Visceral/patologia , Leishmania donovani , Apoptose , Modelos Animais de Doenças , Leishmaniose Visceral/sangue , Camundongos Endogâmicos BALB CRESUMO
The present study was aimed to identify the underlying mechanisms of improper renal function in Leishmania donovani infection that causes VL. Mice (BALB/c) were infected with L. donovani and different parameters for proteinuria were assessed. The levels of superoxide anion (O2-), hydrogen peroxide (H2O2), lipid peroxidation (MDA), inflammatory cytokines, and toll-like receptor (TLR) 2 and 4 expression were found significantly elevated at 60th day in these animals and declined at 90th day post infection. However, TGF-ß and caspase 3 activities were higher at 90th day in comparison to 60th day post infection. These findings suggested that exacerbated inflammatory conditions correlate with abnormal renal functions in L. donovani infection, which is further augmented by activated TLRs expressions by circulating leishmanial antigens. Further, the increased levels of TGF-ß and caspase 3 at 90th day suggested TGF-ß mediated apoptotic cell death of renal and other cells during later stages of disease that may eventually result in release of host and parasitic factors in urine during visceral leishmaniasis.
Assuntos
Rim/patologia , Rim/parasitologia , Leishmaniose Visceral/patologia , Receptor 2 Toll-Like/sangue , Receptor 4 Toll-Like/sangue , Fator de Crescimento Transformador beta/sangue , Animais , Apoptose , Modelos Animais de Doenças , Feminino , Leishmania donovani , Leishmaniose Visceral/sangue , Camundongos , Camundongos Endogâmicos BALB CRESUMO
Cancer is the second most common cause of death among children aged 1-14 years. Leukemia accounts for one-third of all childhood cancers, 78% of which is acute lymphoblastic leukemia (ALL). The development of cancer has been associated with malignant cells that express low levels of immunogenic molecules, which facilitates their escape from the antineoplastic immune response. It is thought that it may be possible to rescue the antineoplastic immune response through the activation of recognition receptors, such as Toll-like receptors (TLRs), which activate the innate immune system. TLRs are type I membrane glycoproteins expressed mainly in immune system cells such as monocytes, neutrophils, macrophages, dendritic cells, T, B and natural killer cells. The aim of the present study was to evaluate the expression of TLR1, TLR3, TLR4, TLR7 and TLR9 in peripheral blood mononuclear cells (PBMCs) in patients with ALL and prior to any treatment. PBMCs were obtained from 50 pediatric patients diagnosed with ALL and from 20 children attending the ophthalmology and orthopedics services. The mean fluorescence intensity was obtained by analysis of immunofluorescence. We found lower expression levels of TLR1, TLR3, TLR4, TLR7 and TLR9 in PBMCs from patients with ALL compared with those from control patients. We also observed that the PBMCs from patients with Pre-B and B ALL had lower TLR4 expression than controls and patients with Pro-B, Pre-B, B and T ALL had lower TLR7 expression than controls. The present study is the first to demonstrate reduced expression of TLRs in PBMCs from pediatric patients with ALL. This finding is of great relevance and may partly explain the reduction in the antineoplastic immune response in patients with ALL.