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Mixed features presentation in bipolar disorder (BD) represents the most severe form of the disease. BD may lead to cognitive and functional deterioration, a process known as neuroprogression, which appears to be exacerbated by increased serum levels of CCL11, a neuroprogression-related cytokine. Metabolic syndrome (MetS) is highly prevalent in BD, and it is known that the presence of MetS may increase inflammation, which may contribute to increased CCL11 levels, and consequently impact on the severity of the disorder. What is not known is whether the MetS mediates the association between CCL11 levels and the presence of mood episodes with mixed features in BD. Therefore, the aim of this study was to investigate the mediating effect of MetS on the relationship between CCL11 levels and the presence of mood episodes with mixed features in BD, in a population-based study. This is a cross-sectional study that included 184 young adults, 92 with BD and 92 populational controls, matched by sex and age. BD diagnosis was assessed using the Mini International Neuropsychiatric Interview - PLUS. Mood episodes with mixed features was defined according to DSM-IV and DSM-5 criteria. MetS was defined according to the National Cholesterol Education Program (NCEP/ATP III). Substance use was assessed through the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST). CCL11 serum levels were analyzed using the multiplex analysis method Luminex 200™ system. The mediation model was tested using the MedMod module of the JAMOVI 2.4.8 software. Mediation analysis indicated a trend towards significance of MetS mediating the association between CCL11 and the presence of a mood episode with mixed features in BD (p = 0.065). Individuals with BD presenting with a mood episode with mixed features and MetS may have accelerated neuroprogression due to the influence of MetS on CCL11 levels, therefore, assessing for MetS occurrence in this population and implementing early interventions to prevent its development may be effective ways of delaying cognitive impairments related to this cytokine.
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Transtorno Bipolar , Quimiocina CCL11 , Síndrome Metabólica , Humanos , Masculino , Feminino , Transtorno Bipolar/sangue , Adulto , Síndrome Metabólica/sangue , Síndrome Metabólica/epidemiologia , Adulto Jovem , Quimiocina CCL11/sangue , Estudos TransversaisRESUMO
BACKGROUND: The liver serves as a metabolic hub within the human body, playing a crucial role in various essential functions, such as detoxification, nutrient metabolism, and hormone regulation. Therefore, protecting the liver against endogenous and exogenous insults has become a primary focus in medical research. Consequently, the potential hepatoprotective properties of multiple 4-phenyltetrahydroquinolines inspired us to thoroughly study the influence of four specially designed and synthesized derivatives on carbon tetrachloride (CCl4)-induced liver injury in rats. METHODS AND RESULTS: Seventy-seven Wistar albino male rats weighing 140 ± 18 g were divided into eleven groups to investigate both the toxicity profile and the hepatoprotective potential of 4-phenyltetrahydroquinolines. An in-vivo hepatotoxicity model was conducted using CCl4 (1 ml/kg body weight, a 1:1 v/v mixture with corn oil, i.p.) every 72 h for 14 days. The concurrent treatment of rats with our newly synthesized compounds (each at a dose of 25 mg/kg body weight, suspended in 0.5% CMC, p.o.) every 24 h effectively lowered transaminases, preserved liver tissue integrity, and mitigated oxidative stress and inflammation. Moreover, the histopathological examination of liver tissues revealed a significant reduction in liver fibrosis, which was further supported by the immunohistochemical analysis of α-SMA. Additionally, the expression of the apoptotic genes BAX and BCL2 was monitored using real-time PCR, which showed a significant decrease in liver apoptosis. Further investigations unveiled the ability of the compounds to significantly decrease the expression of autophagy-related proteins, Beclin-1 and LC3B, consequently inhibiting autophagy. Finally, our computer-assisted simulation dockingonfirmed the obtained experimental activities. CONCLUSION: Our findings suggest that derivatives of 4-phenyltetrahydroquinoline demonstrate hepatoprotective properties in CCl4-induced liver damage and fibrosis in rats. The potential mechanism of action may be due to the inhibition of autophagy in liver cells.
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Autofagia , Tetracloreto de Carbono , Doença Hepática Induzida por Substâncias e Drogas , Quinolinas , Ratos Wistar , Animais , Autofagia/efeitos dos fármacos , Masculino , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Ratos , Quinolinas/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/patologia , Fígado/metabolismo , Substâncias Protetoras/farmacologia , Apoptose/efeitos dos fármacos , Modelos Animais de DoençasRESUMO
COVID-19 has a broad clinical spectrum, ranging from asymptomatic-mild form to severe phenotype. The severity of COVID-19 is a complex trait influenced by various genetic and environmental factors. Ethnic differences have been observed in relation to COVID-19 severity during the pandemic. It is currently unknown whether genetic variations may contribute to the increased risk of severity observed in Latin-American individuals The aim of this study is to investigate the potential correlation between gene variants at CCL2, OAS1, and DPP9 genes and the severity of COVID-19 in a population from Quito, Ecuador. This observational case-control study was conducted at the Carrera de Biologia from the Universidad Central del Ecuador and the Hospital Quito Sur of the Instituto Ecuatoriano de Seguridad Social (Quito-SUR-IESS), Quito, Ecuador. Genotyping for gene variants at rs1024611 (A>G), rs10774671 (A>G), and rs10406145 (G>C) of CCL2, OAS1, and DPP9 genes was performed on 100 COVID-19 patients (43 with severe form and 57 asymptomatic-mild) using RFLP-PCR. The genotype distribution of all SNVs throughout the entire sample of 100 individuals showed Hardy Weinberg equilibrium (P=0.53, 0.35, and 0.4 for CCL2, OAS1, and DPP9, respectively). The HWE test did not find any statistically significant difference in genotype distribution between the study and control groups for any of the three SNVs. The multivariable logistic regression analysis showed that individuals with the GG of the CCL2 rs1024611 gene variant had an increased association with the severe COVID-19 phenotype in a recessive model (P = 0.0003, OR = 6.43, 95% CI 2.19-18.89) and for the OAS1 rs10774671 gene variant, the log-additive model showed a significant association with the severe phenotype of COVID-19 (P=0.0084, OR=3.85, 95% CI 1.33-11.12). Analysis of haplotype frequencies revealed that the coexistence of GAG at CCL2, OAS1, and DPP9 variants, respectively, in the same individual increased the presence of the severe COVID-19 phenotype (OR=2.273, 95% CI: 1.271-4.068, P=0.005305). The findings of the current study suggests that the ethnic background affects the allele and genotype frequencies of genes associated with the severity of COVID-19. The experience with COVID-19 has provided an opportunity to identify an ethnicity-based approach to recognize genetically high-risk individuals in different populations for emerging diseases.
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2',5'-Oligoadenilato Sintetase , COVID-19 , Quimiocina CCL2 , Polimorfismo de Nucleotídeo Único , SARS-CoV-2 , Índice de Gravidade de Doença , Humanos , Equador/epidemiologia , Feminino , Masculino , Estudos de Casos e Controles , Adulto , 2',5'-Oligoadenilato Sintetase/genética , COVID-19/genética , Pessoa de Meia-Idade , Quimiocina CCL2/genética , SARS-CoV-2/genética , Predisposição Genética para Doença , Genótipo , Frequência do Gene , Idoso , Adulto JovemRESUMO
Adverse pregnancy outcomes have been associated with the presence of glyphosate (G) in umbilical cord, serum, and urine samples from pregnant women. Our aim was to study the effect of G on blastocyst implantation using an in vitro mouse model, and the migration and acquisition of endothelial phenotype of the human trophoblastic HTR8/SVneo (H8) cells. In mouse blastocysts, no differences in attachment time and implantation outgrowth area were observed after G exposure. H8 cell migration was stimulated by 0.625 µM G without cytotoxicity. After 6 h, the mRNA expression of vascular endothelial growth factor (VEGF) and C-C motif chemokine ligand 2 (CCL2) was upregulated in H8 cells exposed to 1.25 µM G when compared vehicle-treated cells (p ≤ 0.05). No differences were observed in interleukin 11, VEGF receptor 1, and coagulation factor II thrombin receptor in H8 cells exposed to different concentrations of G for 6 h compared to the vehicle. Interestingly, exposure to G did not alter angiogenesis as measured by a tube formation assay. Taken all together, these results suggest that G exposure may contribute as a risk factor during pregnancy, due to its ability to alter trophoblast migration and gene expression.
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Blastocisto , Movimento Celular , Implantação do Embrião , Glicina , Glifosato , Trofoblastos , Trofoblastos/efeitos dos fármacos , Trofoblastos/metabolismo , Movimento Celular/efeitos dos fármacos , Humanos , Animais , Feminino , Camundongos , Glicina/análogos & derivados , Glicina/toxicidade , Glicina/farmacologia , Blastocisto/efeitos dos fármacos , Blastocisto/metabolismo , Implantação do Embrião/efeitos dos fármacos , Neovascularização Fisiológica/efeitos dos fármacos , Linhagem Celular , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Gravidez , Herbicidas/toxicidade , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , AngiogêneseRESUMO
Blood biochemistry represents a minimally invasive tool for monitoring sea turtle health, assessing injured sea turtles and supporting conservation strategies. In Grenada, West Indies, plasma biochemical variables were examined in 33 nesting leatherback (Dermochelys coriacea), 49 foraging green (Chelonia mydas), 49 foraging hawksbill (Eretmochelys imbricata) and 12 nesting hawksbill sea turtles sampled between 2017 and 2022. Plasma biochemistry reference intervals are described herein except for nesting hawksbills, which are represented by descriptive statistics due to the low sample size. Select analyte concentrations were positively correlated with curved carapace length in leatherbacks (chloride), green turtles (total protein, albumin and globulin) and foraging hawksbills (total protein, albumin and phosphorus). Cholesterol (7.8 mmol/l ± 1.6 SD) and triglyceride (6.9 mmol/l ± 1.9 SD) concentrations were significantly higher in leatherbacks compared to foraging green turtles, foraging hawksbills and nesting hawksbills (P < 0.001 for all). Cholesterol was significantly higher in nesting hawksbills compared to foraging green turtles (P = 0.050) and foraging hawksbills (P = 0.050). Foraging hawksbills demonstrated significantly higher aspartate transaminase activities than leatherbacks (P = 0.002), green turtles (P = 0.009) and nesting hawksbills (P < 0.001). Biochemical results provide baseline population health data and support guidance for treatments during clinical sea turtle rehabilitation efforts. They also provide insight into species-specific physiologic differences and preludes further studies to better characterize the impacts of life-stage class on biochemistry reference intervals to better support wild sea turtle populations in Grenada.
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Chronic HIV-1 infection can cause neurological illness, also known as HIV-associated neurocognitive disorders (HAND). The elevated level of pro-inflammatory cytokines and chemokines, such as C-C Chemokine Ligand 5 (CCL5/RANTES), is one of the ways of causing HIV-1-mediated neuroinflammation. C-C Chemokine Receptor 5 (CCR5) is the main coreceptor for viral entry into host cells and for mediating induction of CCL5/RANTES. CCR5 and CCL5 are part of a correlated axis of immune pathways used for effective protection against the HIV-1 virus. The purpose of this paper was to review the literary knowledge about the immunopathological relationship between this immune complex and neuroAIDS. A systematic review of the literature was conducted based on the selection and search of articles, available in English, Spanish, or Portuguese in the time frame of 1990-2022, of primary and secondary types in the PUBMED, Science Direct, SciELO, and LILACS databases through descriptors (MeSH) together with "AND": "CCR5"; "CCL5"; "neurological manifestations"; or "HIV". The methodological quality of the articles was assessed using the JBI Checklists and the PRISMA 2020 writing guidelines were followed. A total of 36 articles were included in the final composition of the review. The main cells of the CNS affected by neuroAIDS are: neurons; microglia; astrocytes; and oligodendrocytes. Molecular devices and their associations with cellular injuries have been described from the entry of the virus into the host's CNS cell to the generation of mental disorders. Furthermore, divergent results were found about the levels of CCL5/RANTES secretion and the generation of immunopathogenesis, while all condensed research for CCR5 indicated that elevation of this receptor causes more neurodegenerative manifestations. Therefore, new therapeutic and interventional strategies can be conditioned on the immunological direction proposed in this review for the disease.
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Mayaro virus (MAYV) is an emerging arbovirus member of the Togaviridae family and Alphavirus genus. MAYV infection causes an acute febrile illness accompanied by persistent polyarthralgia and myalgia. Understanding the mechanisms involved in arthritis caused by alphaviruses is necessary to develop specific therapies. In this work, we investigated the role of the CCL2/CCR2 axis in the pathogenesis of MAYV-induced disease. For this, wild-type (WT) C57BL/6J and CCR2-/- mice were infected with MAYV subcutaneously and evaluated for disease development. MAYV infection induced an acute inflammatory disease in WT mice. The immune response profile was characterized by an increase in the production of inflammatory mediators, such as IL-6, TNF, and CCL2. Higher levels of CCL2 at the local and systemic levels were followed by the significant recruitment of CCR2+ macrophages and a cellular response orchestrated by these cells. CCR2-/- mice showed an increase in CXCL-1 levels, followed by a replacement of the macrophage inflammatory infiltrate by neutrophils. Additionally, the absence of the CCR2 receptor protected mice from bone loss induced by MAYV. Accordingly, the silencing of CCL2 chemokine expression in vivo and the pharmacological blockade of CCR2 promoted a partial improvement in disease. Cell culture data support the mechanism underlying the bone pathology of MAYV, in which MAYV infection promotes a pro-osteoclastogenic microenvironment mediated by CCL2, IL-6, and TNF, which induces the migration and differentiation of osteoclast precursor cells. Overall, these data contribute to the understanding of the pathophysiology of MAYV infection and the identification future of specific therapeutic targets in MAYV-induced disease.IMPORTANCEThis work demonstrates the role of the CCL2/CCR2 axis in MAYV-induced disease. The infection of wild-type (WT) C57BL/6J and CCR2-/- mice was associated with high levels of CCL2, an important chemoattractant involved in the recruitment of macrophages, the main precursor of osteoclasts. In the absence of the CCR2 receptor, there is a mitigation of macrophage migration to the target organs of infection and protection of these mice against bone loss induced by MAYV infection. Much evidence has shown that host immune response factors contribute significantly to the tissue damage associated with alphavirus infections. Thus, this work highlights molecular and cellular targets involved in the pathogenesis of arthritis triggered by MAYV and identifies novel therapeutic possibilities directed to the host inflammatory response unleashed by MAYV.
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Infecções por Alphavirus , Artrite , Quimiocina CCL2 , Receptores CCR2 , Animais , Camundongos , Alphavirus , Infecções por Alphavirus/imunologia , Artrite/imunologia , Artrite/virologia , Quimiocina CCL2/imunologia , Interleucina-6/imunologia , Camundongos Endogâmicos C57BL , Receptores CCR2/imunologia , Camundongos Knockout , Masculino , Doenças Ósseas/virologiaRESUMO
Leprosy is a chronic infectious disease caused by the intracellular bacillus Mycobacterium leprae (M. leprae), which is known to infect skin macrophages and Schwann cells. Although adipose tissue is a recognized site of Mycobacterium tuberculosis infection, its role in the histopathology of leprosy was, until now, unknown. We analyzed the M. leprae capacity to infect and persist inside adipocytes, characterizing the induction of a lipolytic phenotype in adipocytes, as well as the effect of these infected cells on macrophage recruitment. We evaluated 3T3-L1-derived adipocytes, inguinal adipose tissue of SWR/J mice, and subcutaneous adipose tissue biopsies of leprosy patients. M. leprae was able to infect 3T3-L1-derived adipocytes in vitro, presenting a strong lipolytic profile after infection, followed by significant cholesterol efflux. This lipolytic phenotype was replicated in vivo by M. leprae injection into mice inguinal adipose tissue. Furthermore, M. leprae was detected inside crown-like structures in the subcutaneous adipose tissue of multibacillary patients. These data indicate that subcutaneous adipose tissue could be an important site of infection, and probably persistence, for M. leprae, being involved in the modulation of the innate immune control in leprosy via the release of cholesterol, MCP-1, and adiponectin.
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Hanseníase , Mycobacterium leprae , Camundongos , Animais , Humanos , Mycobacterium leprae/fisiologia , Lipólise , Adipócitos/patologia , Imunidade , ColesterolRESUMO
Leprosy is a chronic infectious disease caused by the intracellular bacillus Mycobacterium leprae (M. leprae), which is known to infect skin macrophages and Schwann cells. Although adipose tissue is a recognized site of Mycobacterium tuberculosis infection, its role in the histopathology of leprosy was, until now, unknown. We analyzed the M. leprae capacity to infect and persist inside adipocytes, characterizing the induction of a lipolytic phenotype in adipocytes, as well as the effect of these infected cells on macrophage recruitment. We evaluated 3T3-L1-derived adipocytes, inguinal adipose tissue of SWR/J mice, and subcutaneous adipose tissue biopsies of leprosy patients. M. leprae was able to infect 3T3-L1-derived adipocytes in vitro, presenting a strong lipolytic profile after infection, followed by significant cholesterol efflux. This lipolytic phenotype was replicated in vivo by M. leprae injection into mice inguinal adipose tissue. Furthermore, M. leprae was detected inside crown-like structures in the subcutaneous adipose tissue of multibacillary patients. These data indicate that subcutaneous adipose tissue could be an important site of infection, and probably persistence, for M. leprae, being involved in the modulation of the innate immune control in leprosy via the release of cholesterol, MCP-1, and adiponectin.
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Humanos , Animais , Ratos , Mycobacterium leprae/fisiologia , Adipócitos/patologia , LipóliseRESUMO
PURPOSE: The CCR5/CCL5 axis is essential for interactions between malignant cells and microenvironment components, promoting tumor progression in oral squamous cell carcinoma (OSCC). This study aims to evaluate the association of CCL5 and CCR5 with the behavior of oral cancer and assess the therapeutic potential of a CCR5 antagonist. METHODS: A retrospective study to analyze CCR5 and CCL5 expression on paraffin-embedded tissues was performed. In cell lines, rhCCL5 was added to induce CCR5-related pathways, and Maraviroc and shRNA against CCR5 were used to neutralize the receptor. Finally, an in vivo murine orthotopic xenograft model of tongue cancer was used to evaluate Maraviroc as an oncologic therapy. After 15 days, the mice were killed, and the primary tumors and cervical lymph nodes were analyzed. RESULTS: The expression of CCR5 was associated with clinical stage and metastasis, and CCL5 was related to overall survival. Adding rhCCL5 induced cell proliferation, while shRNA and Maraviroc reduced it in a dose-dependent manner. Maraviroc treatment also increased apoptosis and modified cytoskeletal organization. In vivo, Maraviroc reduced neck metastasis. CONCLUSIONS: The effects of CCR5 antagonists in OSCC have been poorly studied, and this study reports in vitro and in vivo evidence for the effects of Maraviroc in OSCC. Our results suggest that the CCR5/CCL5 axis plays a role in oral cancer behavior, and that its inhibition is a promising new therapy alternative.
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Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Humanos , Animais , Camundongos , Maraviroc/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço , Estudos Retrospectivos , Linhagem Celular Tumoral , Neoplasias Bucais/tratamento farmacológico , RNA Interferente Pequeno/metabolismo , Microambiente Tumoral , Quimiocina CCL5/genética , Quimiocina CCL5/metabolismoRESUMO
Introduction: Eotaxin-1/CCL11 is a pivotal chemokine crucial for eosinophil homing to the lungs of asthmatic patients. Recent studies also suggest that CCL11 is involved in the aging process, as it is upregulated in elderly, and correlated with shorter telomere length in leukocytes from asthmatic children. Despite its potential pro-aging effects, the precise contribution of CCL11 and the underlying mechanisms involved in the promotion of cellular senescence remains unclear. Therefore, the primary goal of this study was to explore the role of CCL11 on senescence development and the signaling pathways activated by this chemokine in lung fibroblasts. Methods: To investigate the targets potentially modulated by CCL11, we performed an in silico analysis using PseudoCell. We validated in vitro the activation of these targets in the human lung fibroblast cell line MRC-5 following rhCCL11 exposure. Finally, we performed differential gene expression analysis in human airway epithelial cells of asthmatic patients to assess CCL11 signaling and activation of additional senescent markers. Results: Our study revealed that eotaxin-1/CCL11 promote reactive oxygen secretion (ROS) production in lung fibroblasts, accompanied by increased activation of the DNA damage response (DDR) and p-TP53 and γH2AX. These modifications were accompanied by cellular senescence promotion and increased secretion of senescence-associated secretory phenotype inflammatory cytokines IL-6 and IL-8. Furthermore, our data show that airway epithelial lung cells from atopic asthmatic patients overexpress CCL11 along with aging markers such as CDKN2A (p16INK4a) and SERPINE1. Discussion: These findings provide new insights into the mechanisms underlying the pro-aging effects of CCL11 in the lungs of asthmatic patients. Understanding the role of CCL11 on senescence development may have important implications for the treatment of age-related lung diseases, such as asthma.
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Asma , Pulmão , Criança , Humanos , Idoso , Quimiocina CCL11/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Pulmão/metabolismo , Asma/metabolismo , Senescência Celular , Fibroblastos/metabolismoRESUMO
Genetic polymorphisms in genes that encode natural ligands of CCR5 (the main human HIV coreceptor), such as CCL5/RANTES, can alter the levels of secretion of these peptides. This article sought to review the relationship between single nucleotide polymorphisms (SNPs) of CCL5/RANTES and HIV-1 disease susceptibility. A meta-analysis was conducted through 17 articles found from January 1999 to December 2022 in the PUBMED, Science Direct, Medline, and SciELO databases. A total of three SNPs were identified and investigated under their dominant genotypic model and through a fixed-effects model. In terms of the SNP rs2107538 (G > A), in Africa and Asia, it has a protective role (OR = 0.56; 95% CI = 0.41-0.76; p = 0.0002, and OR = 0.88; 95% CI = 0.76-1.02; p = 0.08, respectively). In terms of the SNP rs2280788 (C > G), in Europe and America, it shows a higher risk role (OR = 1.92; 95% CI = 1.06-3.47; p = 0.03, and OR = 0.94; 95% CI = 0.94-1.11; p = 0.04, respectively), but in the population of Asia, with its mutant allele, it has a protective role (OR = 0.76; 95% CI = 0.63-0.93; p = 0.007). In terms of the SNP rs2280789 (T > C), no significant associations were found. Both SNPs rs2107538 and rs2280788 have a positive transcriptional effect on the RANTES/CCL5 gene, while SNP rs2280789 causes a decrease in gene expression levels. This study suggests that there is an association between the increased expression of CCL5/RANTES and a lower risk of AIDS. Therefore, further studies are needed to arrive at a definitive conclusion, and these results may help establish scientific bases for effective HIV/AIDS control strategies.
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Síndrome da Imunodeficiência Adquirida , Infecções por HIV , Soropositividade para HIV , HIV-1 , Humanos , Polimorfismo de Nucleotídeo Único , HIV-1/genética , Infecções por HIV/genética , Quimiocina CCL5/genéticaRESUMO
Theracurmin is a nanoparticle formulation derived from curcumin, a bioactive compound known for its antioxidant and anti-inflammatory properties. Trypanosoma cruzi, the etiological agent of Chagas disease, triggers an intense inflammatory response in mammals and also causes severe tissue damage. To evaluate the immunomodulatory and antiparasitic effects of Theracurmin, Swiss mice were experimentally infected with 103 trypomastigote forms of the Colombian strain of T. cruzi and submitted to daily therapy with 30 mg/kg of Theracurmin. In addition, daily benznidazole therapy (100 mg/kg) was performed as a positive control. We evaluated the systemic and tissue parasitism, the survival and the body mass rate, the release of inflammatory mediators (TNF, IL-6, IL-15, CCL2 and creatine kinase) and the tissue inflammation at day 30 post-infection. Theracurmin therapy reduced the parasitemia curve without altering the animals' survival rate, and it protected mice from losing body mass. Theracurmin also reduced CCL2 in cardiac tissue, IL-15 in cardiac and skeletal tissue, and plasma CK. Even without effects on TNF and IL-6 production and tissue amastigote nests, Theracurmin reduced the leukocyte infiltrate in both evaluated tissues, even in the case of more effective results observed to the benznidazole treatment. Our data suggest Theracurmin has an immunomodulatory (CCL2, IL-15, CK and tissue leukocyte infiltration) and a trypanocidal effect (on circulating parasites) during experimental infection triggered by the Colombian strain of T. cruzi. Further investigations are necessary to comprehend the Theracurmin role performed in combination with benznidazole or other potential anti-T. cruzi chemical compounds.
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Chronic liver diseases are a group of pathologies affecting the liver with high prevalence worldwide. Among them, cholestatic chronic liver diseases (CCLD) are characterized by alterations in liver function and increased plasma bile acids. Secondary to liver disease, under cholestasis, is developed sarcopenia, a skeletal muscle dysfunction with decreased muscle mass, strength, and physical function. CCL5/RANTES is a chemokine involved in the immune and inflammatory response. Indeed, CCL5 is a myokine because it is produced by skeletal muscle. Several studies show that bile acids induce CCL5/RANTES expression in liver cells. However, it is unknown if the expression of CCL5/RANTES is changed in the skeletal muscle of mice with cholestatic liver disease. We used a murine model of cholestasis-induced sarcopenia by intake of hepatotoxin 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC diet), in which we detected the mRNA levels for ccl5. We determined that mice fed the DDC diet presented high levels of serum bile acids and developed typical features of sarcopenia. Under these conditions, we detected the ccl5 gene expression in diaphragm muscle showing elevated mRNA levels compared to mice fed with a standard diet (chow diet). Our results collectively suggest an increased ccl5 gene expression in the diaphragm muscle concomitantly with elevated serum bile acids and the development of sarcopenia.
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Colestase , Hepatopatias , Sarcopenia , Camundongos , Animais , Sarcopenia/patologia , Diafragma/metabolismo , Diafragma/patologia , Regulação para Cima , Quimiocina CCL5/metabolismo , Colestase/complicações , Colestase/metabolismo , Colestase/patologia , Fígado/metabolismo , Ácidos e Sais Biliares , Hepatopatias/metabolismo , Expressão Gênica , Camundongos Endogâmicos C57BLRESUMO
Congenital toxoplasmosis can cause neurological and eye damage, behavioral alterations, or death in fetuses or babies born to Toxoplasma gondii-infected women. Several pieces of evidence suggest that socioeconomic, environmental, and inflammatory patterns linked to the maternal immune response partly drive the pathogenesis of this disease. However, immunoregulation induced by T. gondii infection during gestation is not completely understood. The aim of this study was to assess the association between T. gondii seropositivity and concentrations of plasma markers (CCL2, CXCL16, IL-17, and IL-33) in Brazilian pregnant women. Inflammatory markers were measured by immunoassays in the plasma of 131 pregnant women (13 to 46 years old). The prevalence of T. gondii infections was 45.8% (n = 60) in this population. The concentrations of CCL2, CXCL16, and IL-33 were higher in T. gondii-seropositive than in seronegative pregnant women, while the opposite was observed for IL-17 levels. In IgG+ women, a strong correlation between IL-17 and IL-33 (r = 0.7508, p = 0.0001) and a moderate correlation between CXCL16/IL-17 (r = 0.7319, p = 0.0001) and CXCL16/CCL2 (r = 0.3519, p = 0.0098) was observed. In uninfected women, a strong correlation was found between IL-17 and CXCL16 (r = 0.6779, p = 0.0001) but moderate between IL-17 and IL-33 (r = 0.4820, p = 0.0001). In summary, our data suggest that plasma upregulation of CCL2, CXCL16, and IL-33 might exert a potential protective role in the mother/fetus/parasite axis and, in addition, multiparous women are more likely to be infected with T. gondii than primiparous women.
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Toxoplasma , Toxoplasmose , Feminino , Gravidez , Humanos , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Toxoplasmose/epidemiologia , Interleucina-17 , Gestantes , Regulação para Cima , Interleucina-33 , Brasil/epidemiologia , Anticorpos Antiprotozoários , Estudos Soroepidemiológicos , Imunoglobulina M , Quimiocina CXCL16 , Quimiocina CCL2RESUMO
INTRODUCTION AND OBJECTIVES: Administration of carbon tetrachloride (CCl4), along with an hepatopathogenic diet, is widely employed as a chemical inducer to replicate human nonalcoholic steatohepatitis (NASH) in rodents; however, the role of the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome in this model remains unclear. We aimed to determine the relevance of NLRP3 inflammasome activation in the development of NASH induced by CCl4 along with an hepatopathogenic diet in male Wistar rats. MATERIALS AND METHODS: Animals were fed either a high fat, sucrose, and cholesterol diet (HFSCD) or a HFSCD plus intraperitoneal injections of low doses of CCl4 (400 mg/kg) once a week for 15 weeks. Liver steatosis, inflammation, fibrosis, and NLRP3 inflammasome activation were evaluated using biochemical, histological, ultrastructural, and immunofluorescence analyses, western blotting, and immunohistochemistry. RESULTS: Our experimental model reproduced several aspects of the human NASH pathophysiology. NLRP3 inflammasome activation was induced by the combined effect of HFSCD plus CCl4 and significantly increased levels of both proinflammatory and profibrogenic cytokines and collagen deposition in the liver; thus, NASH severity was higher in the HFSCD+CCl4 group than that in the HFSCD group, to which CCl4 was not administered. Hepatic stellate cells, the most profibrogenic cells, were activated by HFSCD plus CCl4, as indicated by elevated levels of α-smooth muscle actin. Thus, activation of the NLRP3 inflammasome, triggered by low doses of CCl4, exacerbates the severity of NASH. CONCLUSIONS: Our results indicate that NLRP3 inflammasome activation plays a key role and may be an important therapeutic target for NASH treatment.
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Hepatopatia Gordurosa não Alcoólica , Humanos , Ratos , Animais , Masculino , Camundongos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Inflamassomos/efeitos adversos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Ratos Wistar , Fígado/patologia , Colesterol , Dieta Hiperlipídica/efeitos adversos , Camundongos Endogâmicos C57BLRESUMO
[This corrects the article DOI: 10.3389/fonc.2019.01306.].
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Introduction: Osteolytic bone metastasis in advanced breast cancer stages are a major complication for patient´s quality life and a sign of low survival prognosis. Permissive microenvironments which allow cancer cell secondary homing and later proliferation are fundamental for metastatic processes. The causes and mechanisms behind bone metastasis in breast cancer patients are still an unsolved puzzle. Therefore, in this work we contribute to describe bone marrow pre-metastatic niche in advanced breast cancer patients. Results: We show an increase in osteoclasts precursors with a concomitant imbalance towards spontaneous osteoclastogenesis which can be evidenced at bone marrow and peripheral levels. Pro-osteoclastogenic factors RANKL and CCL-2 may contribute to bone resorption signature observed in bone marrow. Meanwhile, expression levels of specific microRNAs in primary breast tumors may already indicate a pro-osteoclastogenic scenario prior to bone metastasis. Discussion: The discovery of prognostic biomarkers and novel therapeutic targets linked to bone metastasis initiation and development are a promising perspective for preventive treatments and metastasis management in advanced breast cancer patients.
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BACKGROUND: Postoperative cognitive dysfunction is widely recognized as severe postoperative central nervous dysfunction and has a significant impact on the 'patient's physical and mental health. METHODS: Postoperative models of tibial fracture in aged rats were established, including the control group, model group, CCL11 protein injection group, and saline injection group. Morris water maze test was used to detect the behavioral characteristics of rats. Enzyme-Linked Immunosorbent Assay was used or determine the content of CCL11 and CXCL10. Immunofluorescence staining was used to detect the distribution of CD14+CD163+macrophages in colon tissues and CD11b+CCR3+microglia cells in hippocampal tissues. Western blot analyzed NOX1 and STAT3 expression in hippocampus tissues. RESULTS: Water maze test results confirmed severe cognitive impairment in CCL11 rats. The content of CCL11 and CXCL10 in the CCL11 group was much higher than that of the model group. The distribution of macrophage and microglia cells in the CCL11 model group was greater than that in the model group and the saline group. The expression of NOX1 and STAT3 in the CCL11 group was higher compared with the model group. CONCLUSION: Abnormal macrophage function and excessive CCL11 secretion were observed in the rats with lower limb fractures after surgery. Postoperative central inflammation in rats with lower limb fracture induced postoperative cognitive dysfunction through the gut-brain axis molecular mechanism.
Assuntos
Disfunção Cognitiva , Complicações Cognitivas Pós-Operatórias , Animais , Eixo Encéfalo-Intestino , Disfunção Cognitiva/etiologia , Hipocampo/metabolismo , Inflamação/metabolismo , Complicações Cognitivas Pós-Operatórias/etiologia , RatosRESUMO
BACKGROUND: The aim of this feasibility study was to investigate the concentration level of CCL-20/MIP-3α, BAFF/BLyS, IL-23, RANKL, and Osteoprotegerin in the Peri-Implant Crevicular Fluid (PICF), from patients diagnosed with peri-implant mucositis and peri-implantitis, and to compare them with PICF from patients with healthy implants. METHODS: Participants with at least one dental implant with healthy peri-implant tissues, peri-implant mucositis, or peri-implantitis were included. PICF was collected using paper strips from healthy and diseased peri-implant sites (n = 19). Biomarker levels were analyzed using a custom Multiplex ELISA Assay Kit. RESULTS: In comparison to peri-implant health, the peri-implant mucositis group showed an increased concentration of CCL-20 MIP-3α, BAFF/BLyS, IL-23, RANKL, and Osteoprotegerin. The peri-implantitis group had the lowest median concentration of Osteoprotegerin (1963 ng/mL); this group had a similar concentration of RANKL (640.84 ng/mL) when compared to the peri-implant health group. BAFF/BLyS (17.06 ng/mL) showed the highest concentration in the peri-implantitis group. CONCLUSIONS: This feasibility study suggests that IL-23 and RANKL may help to elucidate the pathogenesis during the conversion from peri-implant health to peri-implantitis. Further research is required in BAFF/BLyS for the early diagnosis of peri-implantitis.