RESUMO
OBJECTIVE: Cisplatin, a widely used anticancer agent, induces hepatotoxicity alongside organ damage. Understanding Cisplatin's toxicity mechanism and developing preventive measures are crucial. Our study explores Myricetin, a flavonoid, for its protective effects against Cisplatin-induced hepatotoxicity. METHODS: In our study, a total of 32 Wistar albino male rats were utilized, which were categorized into four distinct groups: Control, Myricetin, Cisplatin, and Myricetin+Cisplatin. For the histological assessment of hepatic tissues, hematoxylin-eosin and periodic acid Schiff staining were employed, alongside immunohistochemical measurements of TNF-α, interleukin-17, and interleukin-6 immunoreactivity. Additionally, aspartate transaminase and alanine transaminase values were examined by biochemical analysis. RESULTS: In the histological evaluation of the tissues, a normal healthy cell structure and a strong periodic acid Schiff (+) reaction were observed in the hepatocyte cells in the tissues of the Control and Myricetin groups, while intense eosinophilia, minimal vacuolization, congestion, and sinusoidal expansions were observed in the hematoxylin-eosin stainings, and a decrease in the positive reaction in the periodic acid Schiff staining was observed in the Cisplatin group. Consistent with these histological findings, an increase in TNF-α, interleukin-17, and interleukin-6 expressions (p<0.0001) and a concomitant increase in aspartate transaminase and alanine transaminase values were observed in the Cisplatin group. In the group protected by Myricetin, a significant improvement was observed in all these histological and biochemical values. CONCLUSION: Cisplatin induces notable histopathological alterations in the liver. In this context, Myricetin exhibits the potential to alleviate Cisplatin-induced damage by modulating histological parameters and biochemical processes.
Assuntos
Alanina Transaminase , Antineoplásicos , Aspartato Aminotransferases , Doença Hepática Induzida por Substâncias e Drogas , Cisplatino , Flavonoides , Interleucina-6 , Ratos Wistar , Fator de Necrose Tumoral alfa , Animais , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Cisplatino/toxicidade , Masculino , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Doença Hepática Induzida por Substâncias e Drogas/patologia , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Antineoplásicos/efeitos adversos , Antineoplásicos/toxicidade , Interleucina-6/análise , Interleucina-6/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Ratos , Interleucina-17/metabolismo , Imuno-HistoquímicaRESUMO
Tuberculosis (TB) is an infectious, chronic, and progressive disease occurring globally. Human TB is caused mainly by Mycobacterium tuberculosis (M. tuberculosis), while the main causative agent of bovine TB is Mycobacterium bovis (M. bovis). The latter is one of the most important cattle pathogens and is considered the main cause of zoonotic TB worldwide. The mechanisms responsible for tissue damage (necrosis) during post-primary TB remain elusive. Recently, IL-17A was reported to be important for protection against M. tuberculosis infection, but it is also related to the production of an intense inflammatory response associated with necrosis. We used two M. bovis isolates with different levels of virulence and high IL-17A production to study this important cytokine's contrasting functions in a BALB/c mouse model of pulmonary TB. In the first part of the study, the gene expression kinetics and cellular sources of IL-17A were determined by real time PCR and immunohistochemistry respectively. Non-infected lungs showed low production of IL-17A, particularly by the bronchial epithelium, while lungs infected with the low-virulence 534 strain showed high IL-17A expression on Day 3 post-infection, followed by a decrease in expression in the early stage of the infection and another increase during late infection, on Day 60, when very low bacillary burdens were found. In contrast, infection with the highly virulent strain 04-303 induced a peak of IL-17A expression on Day 14 of infection, 1 week before extensive pulmonary necrosis was seen, being lymphocytes and macrophages the most important sources. In the second part of the study, the contribution of IL-17A to immune protection and pulmonary necrosis was evaluated by suppressing IL-17A via the administration of specific blocking antibodies. Infection with M. bovis strain 534 and treatment with IL-17A neutralizing antibodies did not affect mouse survival but produced a significant increase in bacillary load and a non-significant decrease in inflammatory infiltrate and granuloma area. In contrast, mice infected with the highly virulent 04-303 strain and treated with IL-17A blocking antibodies showed a significant decrease in survival, an increase in bacillary loads on Day 24 post-infection, and significantly more and earlier necrosis. Our results suggest that high expression of IL-17A is more related to protection than necrosis in a mouse model of pulmonary TB induced by M. bovis strains.
Assuntos
Interleucina-17 , Camundongos Endogâmicos BALB C , Mycobacterium bovis , Tuberculose Pulmonar , Interleucina-17/metabolismo , Interleucina-17/imunologia , Animais , Mycobacterium bovis/patogenicidade , Mycobacterium bovis/imunologia , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/microbiologia , Tuberculose Pulmonar/patologia , Camundongos , Virulência , Pulmão/microbiologia , Pulmão/patologia , Pulmão/imunologia , Feminino , BovinosRESUMO
Kidney disease represents a major medical and economic burden for which improved treatments are urgently needed. Emerging data have implicated Th17 cells and IL-17 signaling in the underlying pathogenesis of autoantibody-induced glomerulonephritis (AGN). However, the downstream transduction pathways mediated by IL-17 in autoimmunity are not well defined. In this article, we show that CCAAT/enhancer-binding protein (C/EBP) δ is elevated in kidney biopsies from multiple manifestations of human AGN. C/EBPδ is similarly upregulated in a mouse model of anti-glomerular basement membrane protein-mediated kidney disease, and Cebpd-/- mice were fully refractory to disease. Although C/EBPδ is expressed in a variety of cell types, C/EBPδ was required only in the radioresistant compartment to drive GN pathology. C/EBPδ induced expression of several IL-17-induced kidney injury markers and cytokines implicated in disease, including Il6 and Lcn2. Because mouse AGN models do not progress to fibrosis, we employed a nephrotoxic injury model using aristolochic acid I to assess the contribution of the IL-17-C/EBPδ pathway to renal fibrotic events. Surprisingly, deficiency of either C/EBPδ or the IL-17 receptor caused kidney fibrosis to be enhanced. Thus, C/EBPδ and IL-17 play divergent and apparently stage-specific roles in the pathogenesis of kidney disease.
Assuntos
Proteína delta de Ligação ao Facilitador CCAAT , Glomerulonefrite , Animais , Humanos , Camundongos , Ácidos Aristolóquicos/toxicidade , Autoanticorpos/imunologia , Proteína delta de Ligação ao Facilitador CCAAT/genética , Modelos Animais de Doenças , Glomerulonefrite/imunologia , Glomerulonefrite/patologia , Interleucina-17/imunologia , Interleucina-17/metabolismo , Rim/imunologia , Rim/patologia , Lipocalina-2/genética , Lipocalina-2/metabolismo , Lipocalina-2/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais , Células Th17/imunologiaRESUMO
This work aimed to study the effect of repeated exposure to low doses of ozone on alpha-synuclein and the inflammatory response in the substantia nigra, jejunum, and colon. Seventy-two male Wistar rats were divided into six groups. Each group received one of the following treatments: The control group was exposed to air. The ozone groups were exposed for 7, 15, 30, 60, and 90 days for 0.25 ppm for four hours daily. Afterward, they were anesthetized, and their tissues were extracted and processed using Western blotting, immunohistochemistry, and qPCR. The results indicated a significant increase in alpha-synuclein in the substantia nigra and jejunum from 7 to 60 days of exposure and an increase in NFκB from 7 to 90 days in the substantia nigra, while in the jejunum, a significant increase was observed at 7 and 15 days and a decrease at 60 and 90 days for the colon. Interleukin IL-17 showed an increase at 90 days in the substantia nigra in the jejunum and increases at 30 days and in the colon at 15 and 90 days. Exposure to ozone increases the presence of alpha-synuclein and induces the loss of regulation of the inflammatory response, which contributes significantly to degenerative processes.
Assuntos
Colo , Jejuno , Ozônio , Substância Negra , alfa-Sinucleína , Animais , Masculino , Ratos , alfa-Sinucleína/metabolismo , Colo/metabolismo , Colo/efeitos dos fármacos , Colo/patologia , Inflamação/metabolismo , Inflamação/induzido quimicamente , Inflamação/patologia , Interleucina-17/metabolismo , Jejuno/metabolismo , Jejuno/efeitos dos fármacos , Jejuno/patologia , NF-kappa B/metabolismo , Ozônio/toxicidade , Ratos Wistar , Substância Negra/metabolismo , Substância Negra/efeitos dos fármacos , Substância Negra/patologiaRESUMO
BACKGROUND: Acute myocardial infarction (AMI) is one of the principal causes of death in Mexico and worldwide. AMI triggers an acute inflammatory process that induces the activation of different populations of the innate immune system. Innate lymphoid cells (ILCs) are an innate immunity, highly pleiotropic population, which have been observed to participate in tissue repair and polarization of the adaptive immune response. OBJECTIVE: We aimed to analyze the levels of subsets of ILCs in patients with ST-segment elevation myocardial infarction (STEMI), immediately 3 and 6 months post-AMI, and analyze their correlation with clinical parameters. RESULTS: We evaluated 29 STEMI patients and 15 healthy controls and analyzed the different subsets of circulating ILCs, immediately 3 and 6 months post-AMI. We observed higher levels of circulating ILCs in STEMI patients compared to control subjects and a significant correlation between ILC levels and cardiac function. We also found increased production of the cytokines interleukin 5 (IL-5) and interleukin 17A (IL-17A), produced by ILC2 cells and by ILC3 cells, respectively, in the STEMI patients. CONCLUSION: This study shows new evidence of the role of ILCs in the pathophysiology of AMI and their possible involvement in the maintenance of cardiac function.
Assuntos
Imunidade Inata , Linfócitos , Infarto do Miocárdio com Supradesnível do Segmento ST , Humanos , Infarto do Miocárdio com Supradesnível do Segmento ST/imunologia , Masculino , Feminino , Pessoa de Meia-Idade , Linfócitos/imunologia , Idoso , Interleucina-17/metabolismo , Interleucina-5 , Citocinas/metabolismo , Estudos de Casos e ControlesRESUMO
BACKGROUND: Patients with liver cirrhosis may show minimal hepatic encephalopathy (MHE) with mild cognitive impairment and motor incoordination. Rats with chronic hyperammonemia reproduce these alterations. Motor incoordination in hyperammonemic rats is due to increased GABAergic neurotransmission in cerebellum, induced by neuroinflammation, which enhances TNFα-TNFR1-S1PR2-CCL2-BDNF-TrkB pathway activation. The initial events by which hyperammonemia triggers activation of this pathway remain unclear. MHE in cirrhotic patients is triggered by a shift in inflammation with increased IL-17. The aims of this work were: (1) assess if hyperammonemia increases IL-17 content and membrane expression of its receptor in cerebellum of hyperammonemic rats; (2) identify the cell types in which IL-17 receptor is expressed and IL-17 increases in hyperammonemia; (3) assess if blocking IL-17 signaling with anti-IL-17 ex-vivo reverses activation of glia and of the TNFα-TNFR1-S1PR2-CCL2-BDNF-TrkB pathway. RESULTS: IL-17 levels and membrane expression of the IL-17 receptor are increased in cerebellum of rats with hyperammonemia and MHE, leading to increased activation of IL-17 receptor in microglia, which triggers activation of STAT3 and NF-kB, increasing IL-17 and TNFα levels, respectively. TNFα released from microglia activates TNFR1 in Purkinje neurons, leading to activation of NF-kB and increased IL-17 and TNFα also in these cells. Enhanced TNFR1 activation also enhances activation of the TNFR1-S1PR2-CCL2-BDNF-TrkB pathway which mediates microglia and astrocytes activation. CONCLUSIONS: All these steps are triggered by enhanced activation of IL-17 receptor in microglia and are prevented by ex-vivo treatment with anti-IL-17. IL-17 and IL-17 receptor in microglia would be therapeutic targets to treat neurological impairment in patients with MHE.
Assuntos
Cerebelo , Hiperamonemia , Microglia , Ratos Wistar , Receptores de Interleucina-17 , Animais , Hiperamonemia/metabolismo , Microglia/metabolismo , Cerebelo/metabolismo , Masculino , Ratos , Receptores de Interleucina-17/metabolismo , Doenças Neuroinflamatórias/metabolismo , Interleucina-17/metabolismo , Encefalopatia Hepática/metabolismo , Transdução de Sinais , Modelos Animais de DoençasRESUMO
PURPOSE: This study aimed to verify whether there is a difference in biomarker levels in the gingival crevicular fluid between premenopausal and postmenopausal women undergoing orthodontic treatment. METHODS: As eligibility criteria, prospective or retrospective observational studies evaluating women undergoing orthodontic treatment (P), comparing postmenopausal (E) and premenopausal (C) women, and analyzing differences in gingival crevicular fluid biomarkers (O) were included. An electronic search was conducted in seven databases (PubMed, Scopus, Web of Science, LILACS, The Cochrane Library, Embase, and EBSCO: Dentistry & Oral Science) and one grey literature source (Google Scholar). All databases were searched from September 2022 to March 2023. After duplicate exclusion and data extraction, the Newcastle-Ottawa scale was applied to assess the quality and risk of bias, and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool was used to verify the certainty of evidence. RESULTS: Three case-control studies that analyzed receptor activator of nuclear factor kappaB ligand (RANKL), osteopontin (OPN), and interleukin (IL)-17A levels were included. One study reported a significant difference for RANKL and another for OPN levels. A third study reported that there was a higher expression of IL17A in the postmenopausal group. However, the small number of articles limits our systematic review. The heterogeneity and imprecision in the study results cast doubt on the findings' internal validity. CONCLUSION: The studies reported alterations in biomarker levels but differed in their conclusions. Therefore, further studies must include other types of bone and inflammatory biomarkers in female patients who are pre- or postmenopausal and undergoing orthodontic treatment. REGISTRATION: The review was registered at the Open Science Framework ( https://doi.org/10.17605/OSF.IO/Q9YZ8 ).
Assuntos
Biomarcadores , Líquido do Sulco Gengival , Osteopontina , Pós-Menopausa , Humanos , Líquido do Sulco Gengival/química , Líquido do Sulco Gengival/metabolismo , Feminino , Biomarcadores/análise , Biomarcadores/metabolismo , Osteopontina/análise , Osteopontina/metabolismo , Pré-Menopausa/metabolismo , Ligante RANK/análise , Ligante RANK/metabolismo , Interleucina-17/análise , Interleucina-17/metabolismo , Ortodontia CorretivaRESUMO
The primary objective of the present study was to assess the impact of amber LED photobiomodulation (PBM) on human monocytes and lymphocytes that were polarized into proinflammatory and regulatory/reparative phenotypes. Human leukocytes were polarized with LPS or LPS + IL-4 for 2 h and irradiated after 2 and 6 h with amber LED (590 nm). Cell absorbance spectrum and gene and protein expression of IL-1ß, IL-6, IL-10, IL-17, TNF-α and IFNγ determined after 24 h. The results showed that irradiation did not significantly alter absorbance of non-polarized monocytes, whereas irradiated polarized monocytes presented reduction in absorbance in 625-850 nm region. Irradiated monocytes polarized with LPS + IL-4 presented reduction in absorbance in 600-725 nm region compared to non-irradiated group. Irradiated non-polarized lymphocytes presented absorbance peaks between 650 and 820 nm not seen in non-irradiated group. No difference was found in absorbance pattern of polarized lymphocytes after irradiation. Irradiation led to reduction in protein synthesis of IL-6 and TNFα in monocytes polarized to proinflammatory phenotype and increase in production of IL-17 in lymphocytes. Irradiation reduced production of IL-10 in monocytes and lymphocytes polarized to immunoregulatory phenotype. In conclusion, amber LED modulates light absorbance and expression of important cytokines in inflammatory/repair processes in monocytes and lymphocytes.
Assuntos
Interleucina-10 , Monócitos , Humanos , Monócitos/metabolismo , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Interleucina-17/metabolismo , Interleucina-4/metabolismo , Lipopolissacarídeos/farmacologia , Células Cultivadas , Citocinas/metabolismo , Linfócitos/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Multiple sclerosis, and its murine model experimental autoimmune encephalomyelitis (EAE), is a neurodegenerative autoimmune disease of the CNS characterized by T cell influx and demyelination. Similar to other autoimmune diseases, therapies can alleviate symptoms but often come with side effects, necessitating the exploration of new treatments. We recently demonstrated that the Cullin-RING E3 ubiquitin ligase 4b (CRL4b) aided in maintaining genome stability in proliferating T cells. In this study, we examined whether CRL4b was required for T cells to expand and drive EAE. Mice lacking Cul4b (Cullin 4b) in T cells had reduced EAE symptoms and decreased inflammation during the peak of the disease. Significantly fewer CD4+ and CD8+ T cells were found in the CNS, particularly among the CD4+ T cell population producing IL-17A, IFN-γ, GM-CSF, and TNF-α. Additionally, Cul4b-deficient CD4+ T cells cultured in vitro with their wild-type counterparts were less likely to expand and differentiate into IL-17A- or IFN-γ-producing effector cells. When wild-type CD4+ T cells were activated in vitro in the presence of the recently developed CRL4 inhibitor KH-4-43, they exhibited increased apoptosis and DNA damage. Treatment of mice with KH-4-43 following EAE induction resulted in stabilized clinical scores and significantly reduced numbers of T cells and innate immune cells in the CNS compared with control mice. Furthermore, KH-4-43 treatment resulted in elevated expression of p21 and cyclin E2 in T cells. These studies support that therapeutic inhibition of CRL4 and/or CRL4-related pathways could be used to treat autoimmune disease.
Assuntos
Encefalomielite Autoimune Experimental , Esclerose Múltipla , Camundongos , Animais , Interleucina-17/metabolismo , Proteínas Culina/metabolismo , Linfócitos T CD4-Positivos , Camundongos Endogâmicos C57BLRESUMO
Objective: To evaluate the effect of pharmacological modulation of HIF-1 on the expression of IL-33 and IL-17 in a murine model of allergic pulmonary inflam- mation (API) with different degrees of severity. Methods: 5 mice/group received ovalbumin (OVA) 1(mild), 2(moderate) or 3(severe) challenges via i.t. prior to allergen sensitization, in addition to the HIF-1 induction or inhibition groups, received EDHB (OVA+EDHB) i.p. or 2ME (OVA+2ME) i.t. respectively. Control groups received saline solution (SS) in the same way. HE (inflammatory infiltrate), PAS (mucus production) and immunohistochemical staining for HIF-1a, IL-33, IL-17 were performed, quantitatively analyzing by digital pathology. Results: We obtained different degrees of severity with a greater number of challenges, increasing the expression of HIF-1, correlating with the expression of IL-33/IL-17. Increasing or decreasing, respectively by pharmacological modulation. Conclusions: The above suggests that the high expression of HIF-1 favors the production of IL-33 and IL-17 contributing to the damage in lung tissue and the severity of the disease and these can be regulated through the modulation of HIF- 1.
Objetivo: Evaluar el efecto de la modulación farmacológica de HIF-1 en la expresión de IL-33 e IL-17 en un modelo murino de inflamación alérgica pulmonar (IAP) con diferentes grados de severidad. Métodos: 5 ratones/grupo recibieron ovoalbúmina (OVA) 1(leve), 2(moderada) o 3(severa) retos vía i.t. previa sensibilización como alergeno, además los grupos de inducción o inhibición de HIF-1a, recibieron EDHB (OVA+EDHB) i.p. o 2ME (OVA+2ME) i.t. respectivamente. Los grupos controles recibieron solución salina (SS) de igual forma. Se realizaron tinciones de HE (infiltrado inflamatorio), PAS (producción de moco) e inmunohistoquímicas de HIF-1a, IL-33, IL-17, analizando cuantitativamente por patología digital. Resultados: Obtuvimos diferentes grados de severidad a mayor número de retos, incrementando la expresión de HIF-1, correlacionando con la expresión de IL- 33/IL-17. Aumentando o disminuyendo, respectivamente por la modulación farmacológica. Conclusiones: Lo anterior sugiere que la alta expresión de HIF-1 favorece la producción de IL-33 e IL-17 contribuyendo al daño en el tejido pulmonar y la severi- dad de la enfermedad y estas pueden ser reguladas a través de la modulación de HIF-1.