RESUMO
Introduction: Bipolar disorder (BD) is a recurrent and disabling psychiatric disorder related to low-grade peripheral inflammation and altered levels of the members of the insulin-like growth factor (IGF) family. The aim of this study was to evaluate the plasma levels of IGF-2, insulin-like growth factor-binding protein 1 (IGFBP-1), IGFBP-3, IGFBP-5, IGFBP-7, and inflammatory markers such as tumor necrosis factor α (TNF-α), monocyte chemoattractant protein 1 (MCP-1), and macrophage inflammatory protein 1ß (MIP-1ß). Methods: We used the Young Mania Rating Scale (YMRS) to determine the severity of the symptomatology, while proteins were measured by enzyme-linked immunosorbent assay (ELISA). We included 20 patients with BD who suffered a manic episode and 20 controls. Some BD patients (n = 10) were evaluated after a period (17 ± 8 days) of pharmacological treatment. Results: No statistical difference was found in IGF-2, IGFBP-1, IGFBP-7, TNF-α, and MIP-1ß levels. However, IGFBP-3 and IGFBP-5 levels were found to be statistically decreased in BD patients. Conversely, the MCP-1 level was significantly increased in BD patients, but their levels were normalized after treatment. Intriguingly, only IGFBP-1 levels were significantly decreased after treatment. No significant correlation was found between the YMRS and any of the proteins studied either before or after treatment or between IGF proteins and inflammatory markers. Discussion: To some extent, IGFBP-3 and IGFBP-5 might be further explored as potential indicators of treatment responsiveness or diagnosis biomarkers in BD.
RESUMO
Bacterial biofilms are hardy, adaptable colonies, evading immune recognition while triggering and sustaining inflammation. The goals for this study were to present a method for testing the immunogenicity of secreted metabolites from pathogenic biofilm and to document whether biofilm treated with a nutraceutical enzyme and botanical blend (NEBB) showed evidence of reprogrammed bacterial metabolism, potentially becoming more recognizable to the immune system. We screened immune-modulating properties of metabolites from established biofilm from Pseudomonas aeruginosa (Pa), Stapholycoccus simulans (Ss), and Borrelia burgdorferi (Bb). Secreted metabolites significantly increased the cytokine production by human peripheral blood mononuclear cells, including Interleukin-1-beta (IL-1ß), Interleukin-6 (IL-6), macrophage inflammatory protein-1-alpha (MIP-1α), tumor necrosis factor-alpha (TNF-α), interleukin-1 receptor antagonist (IL-1ra), and interleukin-10 (IL-10). Pa metabolites triggered the most robust increase in IL-1ß, whereas Bb metabolites triggered the most robust increase in IL-10. NEBB-disrupted biofilm produced metabolites triggering altered immune modulation compared to metabolites from untreated biofilm. Metabolites from NEBB-disrupted biofilm triggered increased MIP-1α levels and reduced IL-10 levels, suggesting a reduced ability to suppress the recruitment of phagocytes compared to untreated biofilm. The results suggest that nutraceutical biofilm disruption offers strategies for inflammation management in chronic infectious illnesses. Further clinical studies are warranted to evaluate clinical correlations in infected human hosts.
RESUMO
Inflammation is one of the key injury factors for spinal cord injury (SCI). Exosomes (Exos) derived from M2 macrophages have been shown to inhibit inflammation and be beneficial in SCI animal models. However, lacking targetability restricts their application prospects. Considering that chemokine receptors increase dramatically after SCI, viral macrophage inflammatory protein II (vMIP-II) is a broad-spectrum chemokine receptor binding peptide, and lysosomal associated membrane protein 2b (Lamp2b) is the key membrane component of Exos, we speculated that vMIP-II-Lamp2b gene-modified M2 macrophage-derived Exos (vMIP-II-Lamp2b-M2-Exo) not only have anti-inflammatory properties, but also can target the injured area by vMIP-II. In this study, using a murine contusive SCI model, we revealed that vMIP-II-Lamp2b-M2-Exo could target the chemokine receptors which highly expressed in the injured spinal cords, inhibit some key chemokine receptor signaling pathways (such as MAPK and Akt), further inhibit proinflammatory factors (such as IL-1ß, IL-6, IL-17, IL-18, TNF-α, and iNOS), and promote anti-inflammatory factors (such as IL-4 and Arg1) productions, and the transformation of microglia/macrophages from M1 into M2. Moreover, the improved histological and functional recoveries were also found. Collectively, our results suggest that vMIP-II-Lamp2b-M2-Exo may provide neuroprotection by targeting the injured spinal cord, inhibiting some chemokine signals, reducing proinflammatory factor production and modulating microglia/macrophage polarization.
Assuntos
Exossomos , Macrófagos , Camundongos Endogâmicos C57BL , Microglia , Traumatismos da Medula Espinal , Animais , Traumatismos da Medula Espinal/patologia , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/genética , Exossomos/metabolismo , Exossomos/transplante , Camundongos , Macrófagos/metabolismo , Microglia/metabolismo , Microglia/efeitos dos fármacos , Microglia/patologia , Proteína 2 de Membrana Associada ao Lisossomo/metabolismo , Proteína 2 de Membrana Associada ao Lisossomo/genética , Polaridade Celular/efeitos dos fármacos , Polaridade Celular/fisiologia , Feminino , Neuroproteção/fisiologia , Transdução de Sinais/efeitos dos fármacos , Quimiocinas/metabolismoRESUMO
Introduction: Sepsis represents a critical medical condition that arises due to an imbalanced host reaction to infection. Central to its pathophysiology are cytokines. However, observational investigations that explore the interrelationships between circulating cytokines and susceptibility to sepsis frequently encounter challenges pertaining to confounding variables and reverse causality. Methods: To elucidate the potential causal impact of cytokines on the risk of sepsis, we conducted two-sample Mendelian randomization (MR) analyses. Genetic instruments tied to circulating cytokine concentrations were sourced from genome-wide association studies encompassing 8,293 Finnish participants. We then evaluated their links with sepsis and related outcomes using summary-level data acquired from the UK Biobank, a vast multicenter cohort study involving over 500,000 European participants. Specifically, our data spanned 11,643 sepsis cases and 474,841 controls, with subsets including specific age groups, 28-day mortality, and ICU-related outcomes. Results and Discussion: MR insights intimated that reduced genetically-predicted interleukin-10 (IL-10) levels causally correlated with a heightened sepsis risk (odds ratio [OR] 0.68, 95% confidence interval [CI] 0.52-0.90, P=0.006). An inverse relationship emerged between monocyte chemoattractant protein-1 (MCP-1) and sepsis-induced mortality. Conversely, elevated macrophage inflammatory protein 1 beta (MIP1B) concentrations were positively linked with both sepsis incidence and associated mortality. These revelations underscore the causal impact of certain circulating cytokines on sepsis susceptibility and its prognosis, hinting at the therapeutic potential of modulating these cytokine levels. Additional research is essential to corroborate these connections.
Assuntos
Citocinas , Sepse , Humanos , Estudos de Coortes , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Sepse/genéticaRESUMO
Polymorphisms of group VIA calcium-independent phospholipase A2 (PLA2G6) are associated with blood C-reactive protein suggesting its role in inflammation. We showed that myeloid-specific Pla2g6-deficiency in Pla2g6M-/- mice led to exaggerated inflammation and fibrosis in a lean fatty liver model. We here investigated whether these mutants display alteration in immune response after treatment with E. coli lipopolysaccharides (LPS) under acute (a single dose) and persistent (four doses) conditions. Without LPS treatment, male Pla2g6M-/- (but not Flox) mice at 12 months of age exhibited splenomegaly and hepatic necrosis, and ~ 30 % of them exhibited autoimmune hepatitis showing lymphoplasma cells with CD3(+) and CD45R(+) staining. Under acute LPS, male mutants showed an elevation of plasma MIP-1α and immunoglobulinA as well as upregulation of hepatic apoptosis and fibrosis PARP-1, Bax, MCP-1, α-SMA, and collagen I proteins. Their bone-marrow-derived macrophages also showed an elevation of MIP-1α release upon LPS stimulation in vitro. Female mutants under acute LPS showed a moderate increase in plasma KC/CXCL1, MCP-1, and IL10, and they showed no remarkable increase in hepatic fibrosis under acute or persistent LPS. Male mutants under persistent LPS displayed an elevation of aspartate aminotransferase, blood eosinophils, and hepatic apoptosis. Moreover, ~30 % of these mutants exhibited eosinophilic sclerosing portal hepatitis associated with an upregulated protein expression of hepatic CD8α, CD68, eosinophilic cationic protein, and Ly6G. Thus, myeloid-PLA2G6 deficiency led to an autoimmune and LPS-induced inflammatory liver disease via MIP-1α in a male-predominant manner. Our results may be applicable to patients with PLA2G6 mutations who undergo bacterial infection and sepsis.
Assuntos
Lipopolissacarídeos , Fosfolipases A2 Independentes de Cálcio , Animais , Feminino , Humanos , Masculino , Camundongos , Quimiocina CCL3 , Escherichia coli , Fibrose , Fosfolipases A2 do Grupo VI , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/metabolismo , Lipopolissacarídeos/farmacologiaRESUMO
Extensive preclinical evidence demonstrates a causative link between insulin signaling dysfunction and the pathogenesis of Alzheimer's disease (AD), and diabetic drugs may represent a promising approach to fighting AD. However, it remains to be determined which antidiabetic drugs are more effective in preventing cognitive impairment. Thus, the present study investigated the effect of dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin on cognitive impairment in middle-aged mice by comparing it with the effect of metformin. We found that DPP-4 activity increased in the hippocampus of middle-aged mice, and DPP-4 was mainly expressed by microglia rather than astrocytes and oligodendrocytes. DPP-4 directly regulated M1/M2 microglia polarization following LPS or IL-4 stimulation, while DPP-4 inhibitor, linagliptin, suppressed M1-polarized activation and induced M2-polarized activation. Both linagliptin and metformin enhanced cognitive ability, increased hippocampal synaptic plasticity and neurogenesis, and decreased age-related oxidative stress and inflammation by regulating microglia polarization in the hippocampus of middle-aged mice. The combination of linagliptin and metformin showed a maximum protective effect compared to the individual drugs alone. Loss of macrophage inflammatory protein-1α (MIP-1α), a DPP-4 substrate, abrogated the cognitive protection and anti-inflammation effects of linagliptin. Therefore, the current investigation exhibits a potential utility for DPP-4 inhibition in attenuating microglia-mediated inflammation and preventing mild cognitive impairment (MCI) in middle-aged mice, and the effect was partly mediated by MIP-1α.
Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Inibidores da Dipeptidil Peptidase IV , Metformina , Camundongos , Animais , Linagliptina/farmacologia , Linagliptina/uso terapêutico , Quimiocina CCL3/farmacologia , Microglia , Inibidores da Dipeptidil Peptidase IV/farmacologia , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Disfunção Cognitiva/tratamento farmacológico , Metformina/farmacologia , Metformina/uso terapêutico , InflamaçãoRESUMO
Carpal tunnel syndrome (CTS) is a common entrapment neuropathy in which one of the body's peripheral nerves becomes pinched or crushed. Transforming growth factor beta 1 (TGF-ß1) plays an important role in the pathogenesis of CTS. An association between TGF-ß1 polymorphisms and the susceptibility or progression of a number of diseases has been reported. In this study, three TGF-ß1 single nucleotide polymorphisms (SNPs), serum TGF-ß1, and macrophage inflammatory protein 1 beta (MIP-1ß) were investigated as potential diagnostic markers for the progression of CTS in Egyptian patients. One hundred CTS patients and 100 healthy controls were recruited for the study. TGF-ß1 SNPs +915G/C, -509C/T and -800G/A were determined by TaqMan genotyping assay. Serum TGF-ß1 and MIP-1ß levels were measured by ELISA. Serum TGF-ß1 and MIP-1ß levels increased significantly and were strongly correlated with the occurrence of CTS. The C allele of +915G/C, the T allele of -509C/T, and the G allele of -800G/A occurred more frequently in patients from CTS than in controls. The serum levels of TGF-ß1 and MIP-1ß in the group of carriers of the genotypes +915G/C GC and CC, the genotype -509C/T TT and the genotype -800G/A GA and AA were significantly higher in CTS patients. TGF-ß1 and its +915G/C, -509C/T, and -800G/A SNPs and MIP-1ß could be useful prognostic markers for the occurrence of CTS.
RESUMO
Severe acute respiratory syndrome coronavirus 2 (SARSCoV2) induced cytokine storm is the major cause of COVID-19 related deaths. Patients have been treated with drugs that work by inhibiting a specific protein partly responsible for the cytokines production. This approach provided very limited success, since there are multiple proteins involved in the complex cell signaling disease mechanisms. We targeted five proteins: Angiotensin II receptor type 1 (AT1R), A disintegrin and metalloprotease 17 (ADAM17), Nuclear FactorKappa B (NFκB), Janus kinase 1 (JAK1) and Signal Transducer and Activator of Transcription 3 (STAT3), which are involved in the SARSCoV2 induced cytokine storm pathway. We developed machine-learning (ML) models for these five proteins, using known active inhibitors. After developing the model for each of these proteins, FDA-approved drugs were screened to find novel therapeutics for COVID19. We identified twenty drugs that are active for four proteins with predicted scores greater than 0.8 and eight drugs active for all five proteins with predicted scores over 0.85. Mitomycin C is the most active drug across all five proteins with an average prediction score of 0.886. For further validation of these results, we used the PyRx software to conduct protein-ligand docking experiments and calculated the binding affinity. The docking results support findings by the ML model. This research study predicted that several drugs can target multiple proteins simultaneously in cytokine storm-related pathway. These may be useful drugs to treat patients because these therapies can fight cytokine storm caused by the virus at multiple points of inhibition, leading to synergistically effective treatments.
RESUMO
Objective:To investigate the change and clinical significance of macrophange inflammtory protein-1α (MIP-1α) and human cartilage glycoprotein 39 (YKL-40) levels in serum and cerebrospinal fluid of children with mycoplasma pneumonia complicated with encephalitis.Methods:A total of 108 children with mycoplasma pneumonia treated in Shishou People′s Hospital from July 2018 to May 2020 were retrospectively selected as the study objects, including 66 patients with encephalitis and 42 patients without encephalitis. Fifty-three healthy children who participated in physical examination during the same period were selected as the normal control group. The levels of MIP-1α and YKL-40 in serum and cerebrospinal fluid were detected by enzyme-linked immunosorbent assay (ELISA). Pearson test was used for correlation analysis. Receiver operating characteristic (ROC) curve was used to evaluate the diagnostic value of MIP-1α and YKL-40 levels in serum and cerebrospinal fluid for mycoplasma pneumonia complicated with encephalitis.Results:The serum levels of MIP-1α and YKL-40 in the encephalitis group and without encephalitis group were higher than those in the normal control group: (84.82 ± 12.85) and (63.46 ± 9.23) mg/L vs. (24.12 ± 2.45) mg/L, (53.46 ± 9.25) and (31.45 ± 7.35) ng/L vs. (23.95 ± 6.38) ng/L, and the serum levels of MIP-1α and YKL-40 in the encephalitis group were higher than those in the without encephalitis group, there were statistical differences ( P<0.05). The cerebrospinal fluid levels of MIP-1α and YKL-40 in the encephalitis group were higher than those in the without encephalitis group: (124.82 ± 20.85) mg/L vs. (113.46 ± 18.23)mg/L, (46.46 ± 10.25) ng/L vs.(22.95 ± 5.38) ng/L, there were statistical differences ( P<0.05). The results of Pearson test showed that the levels of MIP-1α and YKL-40 in serum and cerebrospinal fluid had positively correlated ( r = 0.697, 0.403, P<0.05). ROC curve analysis results showed that the area under the curve (AUC) of serum YKL-40 and MIP-1α levels in the diagnosis of children with mycoplasma pneumonia complicated with encephalitis was 0.845 and 0.885, respectively, and the AUC of combined YKL-40 and MIP-1α levels in the diagnosis of children with mycoplasma pneumonia complicated with encephalitis was 0.943, higher than the level of single index detection. Conclusions:The levels of MIP-1α and YKL-40 in serum and cerebrospinal fluid of children with mycoplasma pneumonia are increased. The combined detection of MIP-1α and YKL-40 can be used as serum markers to predict encephalitis in children with mycoplasma pneumonia.
RESUMO
Literature data regarding the response rate to COVID-19 vaccination in chronic kidney disease (CKD) patients remain inconclusive. Furthermore, studies have reported a relationship between lead exposure and susceptibility to viral infections. This study examined immune responses to COVID-19 vaccines in patients with CKD and lead exposure. Between October and December 2021, 50 lead-exposed CKD patients received two doses of vaccination against COVID-19 at Chang Gung Memorial Hospital. Patients were stratified into two groups based on the median blood lead level (BLL): upper (≥1.30 µg/dL, n = 24) and lower (<1.30 µg/dL, n = 26) 50th percentile. The patients were aged 65.9 ± 11.8 years. CKD stages 1, 2, 3, 4 and 5 accounted for 26.0%, 20.0%, 22.0%, 8.0% and 24.0% of the patients, respectively. Patients in the lower 50th percentile of BLL had a lower proportion of CKD stage 5 than patients in the upper 50th percentile BLL group (p = 0.047). The patients in the lower 50th percentile BLL group also received a higher proportion of messenger RNA vaccines and a lower proportion of adenovirus-vectored vaccines than the patients in the upper 50th percentile BLL group (p = 0.031). Notably, the neutralizing antibody titers were higher in the lower 50th percentile than in the upper 50th percentile BLL group. Furthermore, the circulating levels of granulocyte-colony stimulating factor, interleukin-8, monocyte chemoattractant protein-1 and macrophage inflammatory protein-1α were higher in the upper 50th percentile than in the lower 50th percentile BLL group. Therefore, it was concluded that lead-exposed CKD patients are characterized by an impaired immune response to COVID-19 vaccination with diminished neutralizing antibodies and augmented inflammatory reactions.
Assuntos
COVID-19 , Insuficiência Renal Crônica , Humanos , Chumbo , Vacinas contra COVID-19/efeitos adversos , COVID-19/prevenção & controle , ImunidadeRESUMO
BACKGROUND: Several, clinical and biochemical factors were suggested as risk factors for more severe forms of Covid-19. Macrophage inflammatory protein-1 alpha (MIP-1α, CCL3) is a chemokine mainly involved in cell adhesion and migration. Intracellular adhesion molecule 1 (ICAM-1) is an inducible cell adhesion molecule involved in multiple immune processes. The present study aimed to assess the relationship between baseline serum MIP-1α and ICAM-1 level in critically-ill Covid-19 patients and the severity of computed tomography (CT) findings. METHODS: The study included 100 consecutive critically-ill patients with Covid-19 infection. Diagnosis of infection was established on the basis of RT-PCR tests. Serum MIP-1α and ICAM-1 levels were assessed using commercially available ELISA kits. All patients were subjected to a high-resolution computed tomography assessment. RESULTS: According to the computed tomography severity score, patients were classified into those with moderate/severe (n=49) and mild (n = 51) pulmonary involvement. Severe involvement was associated with significantly higher MIP-1α and ICAM-1 level. Correlation analysis identified significant positive correlations between MIP-1α and age, D-dimer, IL6, in contrast, there was an inverse correlation with INF-alpha. Additionally, ICAM-1 showed significant positive correlations with age, D-Dimer,- TNF-α, IL6,while an inverse correlation with INF-alpha was observed. CONCLUSIONS: MIP-1α and ICAM-1 level are related to CT radiological severity in Covid-19 patients. Moreover, these markers are well-correlated with other inflammatory markers suggesting that they can be used as reliable prognostic markers in Covid-19 patients.
Assuntos
COVID-19 , Proteínas Inflamatórias de Macrófagos , Humanos , Quimiocina CCL3 , Molécula 1 de Adesão Intercelular , Estado Terminal , Interleucina-6 , Arábia Saudita/epidemiologia , Tomografia Computadorizada por Raios XRESUMO
Although the COVID-19 disease has developed into a worldwide pandemic, its pathophysiology remains to be fully understood. Insulin-degrading enzyme (IDE), a zinc-metalloprotease with a high affinity for insulin, has been found in the interactomes of multiple SARS-CoV-2 proteins. However, the relevance of IDE in the innate and adaptative immune responses elicited by circulating peripheral blood mononuclear cells is unknown. Here, we show that IDE is highly expressed on the surface of circulating monocytes, T-cells (both CD4+ and CD4-), and, to a lower extent, in B-cells from healthy controls. Notably, IDE's surface expression was upregulated on monocytes from COVID-19 patients at diagnosis, and it was increased in more severe patients. However, IDE's surface expression was downregulated (relative to healthy controls) 3 months after hospital discharge in all the studied immune subsets, with this effect being more pronounced in males than in females, and thus it was sex-dependent. Additionally, IDE levels in monocytes, CD4+ T-cells, and CD4- T-cells were inversely correlated with circulating insulin levels in COVID-19 patients (both at diagnosis and after hospital discharge). Of note, high glucose and insulin levels downregulated IDE surface expression by ~30% in the monocytes isolated from healthy donors, without affecting its expression in CD4+ T-cells and CD4- T-cells. In conclusion, our studies reveal the sex- and metabolism-dependent regulation of IDE in monocytes, suggesting that its regulation might be important for the recruitment of immune cells to the site of infection, as well as for glucometabolic control, in COVID-19 patients.
Assuntos
COVID-19 , Insulisina , Teste para COVID-19 , Feminino , Glucose , Hospitais , Humanos , Insulina/metabolismo , Insulisina/metabolismo , Leucócitos Mononucleares/metabolismo , Linfócitos/metabolismo , Masculino , Monócitos/metabolismo , SARS-CoV-2 , ZincoRESUMO
Patients with ulcerative colitis (UC) experience diarrhoea, hematochezia and abdominal pain. UC is a well-known health challenge affecting 200-250 per 100 000 individuals worldwide, with a similar prevalence in both sexes and elevated upon activation of gut immune responses. We evaluated the potential therapeutic effects of cycloastragenol in experimentally induced UC rats and examined the modulation of sphingosine kinase (SphK), macrophage inflammatory protein (MIP)-1α and miR-143. We treated UC rats with 30 mg/kg cycloastragenol and assessed gene and protein expression levels of SphK, MIP-1α, B-cell lymphoma 2 (BCL2), BCL2-associated X (BAX), miR-143, NF-κB, tumour necrosis factor (TNF)-α and active caspase-3. Colon sections were examined using electron microscopy; additional sections were stained with haematoxylin-eosin or immunostained with anti-TNF-α and anti-caspase-3 antibodies. Electron microscopy of UC specimens revealed dark distorted goblet cell nuclei with disarranged mucus granules and a nondistinct brush border with atypical microvilli. Haematoxylin-eosin staining showed damaged intestinal glands, severe haemorrhage and inflammatory cell infiltration. Cycloastragenol treatment improved the induced morphological changes. In UC rats, cycloastragenol significantly reduced expression levels of SphK, MIP-1α, BAX, NF-κB, TNF-α and active caspase-3, associated with BCL2 and miR-143 overexpression. Therefore, cycloastragenol protects against UC by modulating SphK/MIP-1α/miR-143, subsequently deactivating inflammatory and apoptotic pathways.
Assuntos
Colite Ulcerativa , MicroRNAs , Animais , Quimiocina CCL3/genética , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Amarelo de Eosina-(YS)/uso terapêutico , Feminino , Masculino , MicroRNAs/genética , NF-kappa B/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool) , Ratos , Sapogeninas , Inibidores do Fator de Necrose Tumoral , Fator de Necrose Tumoral alfa/metabolismo , Proteína X Associada a bcl-2/genéticaRESUMO
Parkinson's disease (PD) is widely considered to be a disabling neurodegenerative disorder, which has been ranked second worldwide just after Alzheimer's disease. Until present, a wide range of studies has focused on the role of circulating inflammatory cytokines in the development of PD. However, the causal relationship between circulating inflammatory cytokines and the risk and age at the onset of PD has not been elucidated. Hence, to evaluate the effects of circulating inflammatory cytokines on the risk or age at the onset of PD more accurately, we conducted this two-sample Mendelian randomization (MR) study involving summary statistics from genome-wide association studies (GWASs). Totally, we included a GWAS for inflammatory cytokines (8,293 participants), a meta-analysis of GWASs for PD risk (482,730 participants), and a GWAS dataset for age at the onset of PD (17,996 patients with PD). A total of 149 and 131 polymorphisms for exploring relationships between 19 inflammatory cytokines and the risk and age at the onset of PD were obtained as instrumental variants. Then, we used a total of five MR methods, including inverse-variance weighted (IVW), Wald ratio, MR Egger regression, weighted median, and MR-pleiotropy residual sum and outlier (MR-PRESSO) methods. Finally, we found a causal association between circulating levels of macrophage inflammatory protein-1 beta (MIP1b) and PD risk in the IVW method (OR: 1.06; 95% CI: 1.02-1.10; P = 0.001). Meanwhile, other MR estimates by weighted median and MR-PRESSO methods yielded similar effect estimates. Besides, we identified a suggestive association of interleukin-16 (IL-16) levels with PD risk (OR: 1.08; 95% CI: 1.00-1.17; P = 0.037). For age at PD onset, there was no evidence supporting its correlation with inflammatory cytokines. Our findings implied that MIP1b and IL-16 may be novel biomarkers and promising therapeutic targets for PD development.
RESUMO
Organ-on-a-chip models have emerged as a powerful tool to model cancer metastasis and to decipher specific crosstalk between cancer cells and relevant regulators of this particular niche. Recently, the sympathetic nervous system (SNS) was proposed as an important modulator of breast cancer bone metastasis. However, epidemiological studies concerning the benefits of the SNS targeting drugs on breast cancer survival and recurrence remain controversial. Thus, the role of SNS signaling over bone metastatic cancer cellular processes still requires further clarification. Herein, we present a novel humanized organ-on-a-chip model recapitulating neuro-breast cancer crosstalk in a bone metastatic context. We developed and validated an innovative three-dimensional printing based multi-compartment microfluidic platform, allowing both selective and dynamic multicellular paracrine signaling between sympathetic neurons, bone tropic breast cancer cells and osteoclasts. The selective multicellular crosstalk in combination with biochemical, microscopic and proteomic profiling show that synergistic paracrine signaling from sympathetic neurons and osteoclasts increase breast cancer aggressiveness demonstrated by augmented levels of pro-inflammatory cytokines (e.g. interleukin-6 and macrophage inflammatory protein 1α). Overall, this work introduced a novel and versatile platform that could potentially be used to unravel new mechanisms involved in intracellular communication at the bone metastatic niche.
RESUMO
Immune-mediated necrotizing myopathy (IMNM) is a pathologically defined diagnosis of idiopathic inflammatory myopathies. Adequate studies on cytokines of IMNM is lacking. We measured serum levels of 27 cytokines/chemokines in 22 IMNM patients, 10 sporadic inclusion body myositis (IBM) patients, and 23 other neurological disorders (ONDs) patients. In IMNM patients, the correlations between clinical features and cytokine/chemokine levels, and changes in cytokine/chemokine levels after immunosuppressive therapy were examined. Compared with ONDs patients, IMNM patients had significantly increased serum levels of several cytokines. In particular, IP-10 and MIP-1α levels were prominently increased, decreased after immunosuppressive-therapy, and correlated with serum creatine kinase levels. IP-10 and MIP-1α could play important roles in the IMNM pathogenesis.
Assuntos
Doenças Autoimunes , Miosite , Doenças Autoimunes/diagnóstico , Quimiocina CCL3 , Quimiocina CXCL10 , Citocinas , Humanos , Músculo Esquelético/patologiaRESUMO
The purpose of this study is to characterize the inflammatory cytokine profile in rhegmatogenous retinal detachments (RRDs) compared to surgical controls. Vitreous humor was collected from patients undergoing vitrectomy for RRD and noninflammatory vitreoretinal diseases. A quantitative immunoassay was used to measure the levels of 36 cytokine markers. Linear regression analysis with the duration of detachment as the predictor and log-transformed cytokine levels as the outcome was conducted for normally distributed cytokines as determined by the Shapiro-Wilk test. The analysis was adjusted for age, sex, and race. The Kruskal-Wallis test was used for cytokines not normally distributed. Twenty-seven RRD cases and thirteen control cases were studied. Between all RRDs and controls, fibroblast growth factor 2 (FGF2) (p = 0.0029), inducible protein-10(IP-10) (p = 0.0021), monocyte chemoattractant protein-1 (MCP-1) (p = 0.0040), interleukin (IL)-16 (p = 0.018), IL-8 (p = 0.0148), IL-6 (p = 0.0071), eotaxin (p = 0.0323), macrophage inflammatory protein (MIP)-1 alpha (p = 0.0149), MIP-1 beta (p = 0.0032), and the thymus and activation regulated cytokine (TARC) (p = 0.0121) were elevated in RRD cases. Between acute RRDs (n = 16) and controls, FGF2 (p = 0.0001), IP10 (p = 0.0027), MCP-1 (p = 0.0015), MIP-1ß (p = 0.0004), IL-8 (p = 0.0146), and IL-6 (p = 0.0031) were elevated. Determining alterations in inflammatory cytokine profiles may aid in understanding their impact on RRD development, clinical course, and complications before and after surgical repair.
RESUMO
Objective:To investigate the level of gingival crevicular fluid and serum gingival sulcus fluid Dickkopf-1 (DKK-1), macrophage inflammatory protein-1α (MIP-1α) and interleukin (IL)-17 in patients with chronic periodontitis and their clinical significance.Methods:80 patients with chronic periodontitis (observation group) and 40 healthy periodontal subjects (control group) were prospectively selected. The gingival index (GI), bleeding index (BI), probe depth (PD), loss of attachment (AL) levels were compared between the two groups. The IL-6, IL-8, tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), DKK1, MIP-1α and IL-17 levels in the gingival sulcus fluid and serum of the two groups were compared, and the correlation of DKK-1, MIP-1α and IL-17 levels with periodontal indexes and inflammatory factors in the observation group were analyzed. The DKK-1, MIP-1α and IL-17 levels in the gingival crevicular fluid and serum before and after treatment were compared among the patients with different disease degrees.Results:The levels of GI, BI, PD and AL in the observation group [(2.11±0.36)points, (3.76±0.65)points, (4.56±0.78)mm, (4.06±0.49)mm, respectively] were higher than those of the control group [(0.53±0.08)points, (1.61±0.33)points, (2.13±0.29)mm, 0 mm, respectively] (all P<0.05). The levels of IL-6, IL-8, TNF-α, DKK-1, MIP-1α and IL-17 in gingival crevicular fluid of the observation group [(65.23±9.30)ng/L, (310.19±42.95)ng/L, (40.46±9.70)ng/L, (13.70±3.62)μg/L, (19.67±8.14)μg/L, (315.84±53.76)pg/μl] were higher than those of the control group [(36.81±5.61)ng/L, (178.21±25.73)ng/L, (26.43±5.76)ng/L, (7.41±2.02)μg/L, (6.23±1.99)μg/L, (266.64±46.27)pg/μl, respectively] (all P<0.05). The serum levels of IL-8, TNF-α, DKK-1, MIP-1α and IL-17 in the observation group were also higher than those in the control group (all P<0.05). In the observation group, the levels of DKK-1, MIP-1α and IL-17 in gingival crevicular fluid and serum were positively correlated with eriodontal indexes (GI, BI, PD, AL) and the IL-8 and TNF-α levels (all P<0.05). In the observation group, the levels of DKK-1, MIP-1α and IL-17 in gingival crevicular fluid and serum of mild patients were lower than those of moderate to severe patients, and the levels of DKK-1, MIP-1α and IL-17 in mild and moderate to severe patients after treatment were also lower than those before treatment, with statistically significant difference (all P<0.05). Conclusions:The levels of DKK-1, MIP-1α and IL-17 in gingival crevicular fluid and serum of patients with chronic periodontitis are increased, which are closely related to the occurrence and development of chronic periodontitis. Detection of these indicators has certain significance for the diagnosis and treatment of the disease.
RESUMO
The mechanisms underlying the antineoplastic effects of oxicams have not been fully elucidated. We aimed to assess the effect of classic and novel oxicams on the expression/secretion of macrophage-associated chemokines (RTqPCR/Luminex xMAP) in colorectal adenocarcinoma cells, and on the expression of upstream the non-steroidal anti-inflammatory drug (NSAID)-activated genes NAG1, NFKBIA, MYD88, and RELA, as well as at the chemokine profiling in colorectal tumors. Meloxicam downregulated CCL4 9.9-fold, but otherwise the classic oxicams had a negligible/non-significant effect. Novel analogues with a thiazine ring substituted with arylpiperazine and benzoyl moieties significantly modulated chemokine expression to varying degree, upregulated NAG1 and NFKBIA, and downregulated MYD88. They inhibited CCL3 and CCL4, and their effect on CCL2 and CXCL2 depended on the dose and exposure. The propylene linker between thiazine and piperazine nitrogens and one arylpiperazine fluorine substituent characterized the most effective analogue. Only CCL19 and CXCL2 were not upregulated in tumors, nor was CXCL2 in tumor-adjacent tissue compared to normal mucosa. Compared to adjacent tissue, CCL4 and CXCL2 were upregulated, while CCL2, CCL8, and CCL19 were downregulated in tumors. Tumor CCL2 and CCL7 increased along with advancing T and CCL3, and CCL4 along with the N stage. The introduction of arylpiperazine and benzoyl moieties into the oxicam scaffold yields effective modulators of chemokine expression, which act by upregulating NAG1 and interfering with NF-κB signaling.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antineoplásicos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Meloxicam/farmacologia , Piroxicam/farmacologia , Idoso , Anti-Inflamatórios não Esteroides/química , Antineoplásicos/química , Células CACO-2 , Quimiocinas/antagonistas & inibidores , Quimiocinas/metabolismo , Neoplasias Colorretais/metabolismo , Feminino , Células HCT116 , Humanos , Macrófagos/metabolismo , Masculino , Meloxicam/análogos & derivados , Piroxicam/análogos & derivadosRESUMO
Asthma is a complicated lung disease, which has increased morbidity and mortality rates in worldwide. There is an overlap between asthma pathophysiology and mitochondrial dysfunction and MSCs may have regulatory effect on mitochondrial dysfunction and treats asthma. Therefore, immune-modulatory effect of MSCs and mitochondrial signaling pathways in asthma was studied. After culturing of MSCs and producing asthma animal model, the mice were treated with MSCs via IV via IT. BALf's eosinophil Counting, The levels of IL-4, -5, -13, -25, -33, INF-γ, Cys-LT, LTB4, LTC4, mitochondria genes expression of COX-1, COX-2, ND1, Nrf2, Cytb were measured and lung histopathological study were done. BALf's eosinophils, the levels of IL-4, -5, -13, -25, -33, LTB4, LTC4, Cys-LT, the mitochondria genes expression (COX-1, COX-2, Cytb and ND-1), perivascular and peribronchial inflammation, mucus hyper-production and hyperplasia of the goblet cell in pathological study were significantly decreased in MSCs-treated asthma mice and reverse trend was found about Nrf-2 gene expression, IFN-γ level and ratio of the INF-γ/IL-4. MSC therapy can control inflammation, immune-inflammatory factors in asthma and mitochondrial related genes, and prevent asthma immune-pathology.