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1.
Artigo em Inglês | MEDLINE | ID: mdl-39007843

RESUMO

Staphylococcus aureus (S. aureus) is an opportunistic infectious pathogen, which causes a high mortality rate during bloodstream infections. The early detection of virulent strains in patients' blood samples is of medical interest for rapid diagnosis. The main virulent factors identified in patient isolates include leukocidins that bind to specific membrane receptors and lyse immune cells and erythrocytes. Duffy antigen receptor for chemokines (DARC) on the surface of specific cells is a main target of leukocidins such as gamma-hemolysin AB (HlgAB) and leukocidin ED (LukED). Among them, HlgAB is a conserved and critical leukocidin that binds to DARC and forms pores on the cell membranes, leading to cell lysis. Current methods are based on ELISA or bacterial culture, which takes hours to days. For detecting HlgAB with faster response and higher sensitivity, we developed a biosensor that combines single-walled carbon nanotube field effect transistors (swCNT-FETs) with immobilized DARC receptors as biosensing elements. DARC was purified from a bacterial expression system and successfully reconstituted into nanodiscs that preserve binding capability for HlgAB. Dynamic light scattering (DLS) and scanning electron microscopy (SEM) showed an increase of the DARC-containing nanodisc size in the presence of HlgAB, indicating the formation of HlgAB prepore or pore complexes. We demonstrate that this sensor can specifically detect the leukocidins HlgA and HlgAB in a quantitative manner within the dynamic range of 1 fM to 100 pM with an LOD of 0.122 fM and an LOQ of 0.441 fM. The sensor was challenged with human serum spiked with HlgAB as simulated clinical samples. After dilution for decreasing nonspecific binding, it selectively detected the toxin with a similar detection range and apparent dissociation constant as in the buffer. This biosensor was demonstrated with remarkable sensitivity to detect HlgAB rapidly and has the potential as a tool for fundamental research and clinical applications, although this sensor cannot differentiate between HlgAB and LukED as both have the same receptor.

2.
PeerJ ; 12: e17477, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39006008

RESUMO

Objective: The primary objective is to study the impact of gut microbiota and their interactions with diverse immunological markers on the development of rheumatoid arthritis. Methods: This study was performed in Astana, Kazakhstan, and included 77 Kazakh female patients older than 18 years, who met the American College of Rheumatology 2010 classification criteria for rheumatoid arthritis (RA), and 113 healthy controls. The DNA was extracted from fecal samples obtained from all study participants for subsequent sequencing at the 16S rRNA gene V1-V3 locus, facilitating the analysis of the gut microbiome. The Multiplex immunoassay was employed to measure the concentrations of inflammatory cytokines, chemokines, and immunoglobulins in both fecal and plasma samples. Results: Our taxonomic analysis revealed significant differences in the composition of the gut microbiota between the healthy control cohort and the cohort with rheumatoid arthritis RA. Alpha diversity was significantly lower in the RA group. Lachnospiraceae were the most abundant taxon and found to be crucial, showing correlations with immunological markers such as IL5. Additionally, Lachnospiraceae and Oscillospiraceae exhibited the most predictable power and distinguished the composition of both study groups. Conclusion: Our study identifies key differences in the gut microbiome of RA patients, revealing distinct microbial patterns and specific taxa abundance. We highlight potential biomarkers in immunological and bacterial pathways, offering insights into RA development and indicating possibilities for personalized treatment.


Assuntos
Artrite Reumatoide , Fezes , Microbioma Gastrointestinal , RNA Ribossômico 16S , Humanos , Artrite Reumatoide/imunologia , Artrite Reumatoide/microbiologia , Microbioma Gastrointestinal/imunologia , Feminino , Pessoa de Meia-Idade , Adulto , Fezes/microbiologia , RNA Ribossômico 16S/genética , Estudos de Casos e Controles , Cazaquistão , Biomarcadores/sangue , Citocinas/metabolismo , Citocinas/genética , Citocinas/imunologia , Citocinas/sangue
3.
Cureus ; 16(6): e62310, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-39006715

RESUMO

This review offers a comprehensive review of the signals and the paramount role neuroinflammation plays in neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis. The study explores the sophisticated interactions between microglial, astrocytic, and dendritic cells and how neuroinflammation affects long-term neuronal damage and dysfunction. There are specific pathways related to the mentioned inflammatory processes, including Janus kinases/signal transducer and activator of transcriptions, nuclear factor-κB, and mitogen-activated protein kinases pathways. Neuroinflammation is argued to be a double-edged sword, being not only a protective agent that prevents further neuron damage but also the causative factor in more cell injury development. This concept of contrasting inflammation with neuroprotection advocates for the use of therapeutic techniques that seek to modulate neuroinflammatory responses as part of the neurodegeneration treatment. The recent research findings are integrated with the established knowledge to help present a comprehensive image of neuroinflammation's impact on neurodegenerative diseases and its implications for future therapy.

4.
Int J Mol Sci ; 25(13)2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-39000516

RESUMO

The ligands of chemokine receptors 2 and 5 (CCR2 and CCR5, respectively) are associated with the pathomechanism of neuropathic pain development, but their role in painful diabetic neuropathy remains unclear. Therefore, the aim of our study was to examine the function of these factors in the hypersensitivity accompanying diabetes. Additionally, we analyzed the analgesic effect of cenicriviroc (CVC), a dual CCR2/CCR5 antagonist, and its influence on the effectiveness of morphine. An increasing number of experimental studies have shown that targeting more than one molecular target is advantageous compared with the coadministration of individual pharmacophores in terms of their analgesic effect. The advantage of using bifunctional compounds is that they gain simultaneous access to two receptors at the same dose, positively affecting their pharmacokinetics and pharmacodynamics and consequently leading to improved analgesia. Experiments were performed on male and female Swiss albino mice with a streptozotocin (STZ, 200 mg/kg, i.p.) model of diabetic neuropathy. We found that the blood glucose level increased, and the mechanical and thermal hypersensitivity developed on the 7th day after STZ administration. In male mice, we observed increased mRNA levels of Ccl2, Ccl5, and Ccl7, while in female mice, we observed additional increases in Ccl8 and Ccl12 levels. We have demonstrated for the first time that a single administration of cenicriviroc relieves pain to a similar extent in male and female mice. Moreover, repeated coadministration of cenicriviroc with morphine delays the development of opioid tolerance, while the best and longest-lasting analgesic effect is achieved by repeated administration of cenicriviroc alone, which reduces pain hypersensitivity in STZ-exposed mice, and unlike morphine, no tolerance to the analgesic effects of CVC is observed until Day 15 of treatment. Based on these results, we suggest that targeting CCR2 and CCR5 with CVC is a potent therapeutic option for novel pain treatments in diabetic neuropathy patients.


Assuntos
Antagonistas dos Receptores CCR5 , Neuropatias Diabéticas , Modelos Animais de Doenças , Receptores CCR2 , Receptores CCR5 , Animais , Camundongos , Neuropatias Diabéticas/tratamento farmacológico , Masculino , Receptores CCR2/antagonistas & inibidores , Receptores CCR2/metabolismo , Feminino , Receptores CCR5/metabolismo , Receptores CCR5/genética , Antagonistas dos Receptores CCR5/farmacologia , Antagonistas dos Receptores CCR5/uso terapêutico , Morfina/farmacologia , Morfina/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/complicações , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Hiperalgesia/tratamento farmacológico , Imidazóis , Sulfóxidos
5.
Cancers (Basel) ; 16(13)2024 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-39001488

RESUMO

Soluble CD26 (sCD26), a glycoprotein with dipeptidyl peptidase (DPP4) enzymatic activity, can contribute to early diagnosis of colorectal cancer and advanced adenomas and has been studied, including for prognostic purposes, across various other types of cancer and disease. The latest research in this field has confirmed that most, though not all, serum/plasma sCD26 is related to inflammation. The shedding and/or secretion of sCD26 from different immune cells are being investigated, and blood DPP4 activity levels do not correlate very strongly with protein titers. Some of the main substrates of this enzyme are key chemokines involved in immune cell migration, and both soluble and cell-surface CD26 can bind adenosine deaminase (ADA), an enzyme involved in the metabolism of immunosuppressor extracellular adenosine. Of note, there are T cells enriched in CD26 expression and, in mice tumor models, tumor infiltrating lymphocytes exhibited heightened percentages of CD26+ correlating with tumor regression. We employed sCD26 as a biomarker in the follow-up after curative resection of colorectal cancer for the early detection of tumor recurrence. Changes after treatment with different biological disease-modifying antirheumatic drugs, including Ig-CTLA4, were also observed in rheumatoid arthritis. Serum soluble CD26/DPP4 titer variation has recently been proposed as a potential prognostic biomarker after a phase I trial in cancer immunotherapy with a humanized anti-CD26 antibody. We propose that dynamic monitoring of sCD26/DPP4 changes, in addition to well-known inflammatory biomarkers such as CRP already in use as informative for immune checkpoint immunotherapy, may indicate resistance or response during the successive steps of the treatment. As tumor cells expressing CD26 can also produce sCD26, the possibility of sorting immune- from non-immune-system-originated sCD26 is discussed.

6.
Cells ; 13(13)2024 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-38994928

RESUMO

Activation of the CXCL12/CXCR4/ACKR3 axis is known to aid myocardial repair through ischemia-triggered hypoxia-inducible factor-1α (HIF-1α). To enhance the upregulation of HIF-1α, we administered roxadustat, a novel prolyl hydroxylase inhibitor (PHI) clinically approved by the European Medicines Agency 2021 for the treatment of renal anemia, with the purpose of improving LV function and attenuating ischemic cardiomyopathy. METHODS: We evaluated roxadustat's impact on HIF-1 stimulation, cardiac remodeling, and function after MI. Therefore, we analyzed nuclear HIF-1 expression, the mRNA and protein expression of key HIF-1 target genes (RT-PCR, Western blot), inflammatory cell infiltration (immunohistochemistry), and apoptosis (TUNEL staining) 7 days after MI. Additionally, we performed echocardiography in male and female C57BL/6 mice 28 days post-MI. RESULTS: We found a substantial increase in nuclear HIF-1, associated with an upregulation of HIF-1α target genes like CXCL12/CXCR4/ACKR3 at the mRNA and protein levels. Roxadustat increased the proportion of myocardial reparative M2 CD206+ cells, suggesting beneficial alterations in immune cell migration and a trend towards reduced apoptosis. Echocardiography showed that roxadustat treatment significantly preserved ejection fraction and attenuated subsequent ventricular dilatation, thereby reducing adverse remodeling. CONCLUSIONS: Our findings suggest that roxadustat is a promising clinically approved treatment option to preserve myocardial function by attenuating adverse remodeling.


Assuntos
Glicina , Subunidade alfa do Fator 1 Induzível por Hipóxia , Isoquinolinas , Camundongos Endogâmicos C57BL , Infarto do Miocárdio , Remodelação Ventricular , Animais , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/patologia , Infarto do Miocárdio/metabolismo , Camundongos , Remodelação Ventricular/efeitos dos fármacos , Glicina/análogos & derivados , Glicina/farmacologia , Glicina/uso terapêutico , Masculino , Feminino , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Isoquinolinas/farmacologia , Isoquinolinas/uso terapêutico , Apoptose/efeitos dos fármacos , Quimiocina CXCL12/metabolismo , Quimiocina CXCL12/genética , Miocárdio/patologia , Miocárdio/metabolismo
7.
Artigo em Inglês | MEDLINE | ID: mdl-39002068

RESUMO

PURPOSE: We evaluated T- and B-cell receptor (TCR and BCR) repertoire diversity and 38 serum cytokines in pre- and post-treatment peripheral blood of 66 patients with triple-negative breast cancer (TNBC) who received neoadjuvant chemotherapy plus durvalumab and assessed associations with pathologic response and immune-related adverse events (irAEs) during treatment. METHODS: Genomic DNA was isolated from buffy coat for TCR and BCR clonotype profiling using the Immunoseq platform and diversity was quantified with Pielou's evenness index. MILLIPLEX MAP Human Cytokine/Chemokine Magnetic Bead Panel was used to measure serum cytokine levels, which were compared between groups using moderated t-statistic with Benjamini-Hochberg correction for multiple testing. RESULTS: TCR and BCR diversity was high (Pielou's index > 0.75) in all samples. Baseline receptor diversities and change in diversity pre- and post-treatment were not associated with pathologic response or irAE status, except for BCR diversity that was significantly lower post-treatment in patients who developed irAE (unadjusted p = 0.0321). Five cytokines increased after treatment in patients with pathologic complete response (pCR) but decreased in patients with RD, most prominently IL-8. IFNγ, IL-7, and GM-CSF levels were higher in pre-treatment than in post-treatment samples of patients who developed irAEs but were lower in those without irAEs. CONCLUSION: Baseline peripheral blood cytokine levels may predict irAEs in patients treated with immune checkpoint inhibitors and chemotherapy, and increased post-treatment B-cell clonal expansion might mediate irAEs.

8.
Heliyon ; 10(12): e32351, 2024 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-38988534

RESUMO

Chronic obstructive pulmonary disease (COPD) is a respiratory inflammatory disease. Psoralen (PSO) is the main pharmacological component identified from Bu-Shen-Fang-Chuan formula which has been traditionally used in treatment of COPD, yet its efficacy in COPD inflammation were unreported. In this study, we aimed to elucidate the anti-inflammatory potential of PSO in COPD and unravel the underlying mechanisms, focusing on T lymphocyte recruitment and the modulation of chemokines, namely monokine induced by interferon-gamma (CXCL9), interferon inducible protein 10 (CXCL10), and interferon inducible T-Cell alpha chemoattractant (CXCL11). In vitro, RAW264.7 was stimulated by interferon (IFN)-γ + cigarette smoke extract (CSE) and were treated with PSO (2.5, 5, 10 µM), then the levels of chemokines and the activation of Janus kinase (JAK)/Signal transducer and activator of transcription 1 (STAT1) pathway were analyzed by real time PCR and western blot. In vivo, a murine model was established by intraperitoneal injection of CSE on day 1, 8, 15, and 22, then treated with PSO (10 mg/kg). Our experiments in vitro illustrated that PSO reduced the levels of CXCL9, CXCL10, and CXCL11, and decreased the protein phosphorylation levels of JAK2 and STAT1. Additionally, PSO effectively improved inflammatory infiltration and decreased the proportion of CD8+ T cells in CSE-exposed mice. Furthermore, PSO reduced the levels of CXCL9, CXCL10, and CXCL11 in bronchoalveolar lavage fluid (BALF) and lung tissue, and decreased the protein phosphorylation levels of JAK2 and STAT1. In conclusion, our results revealed the therapeutic potential of PSO for COPD inflammation, possibly mediated through the regulation of CD8+ T cell recruitment and chemokines via the JAK2/STAT1 signaling pathway.

9.
J Indian Soc Periodontol ; 28(1): 113-121, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38988958

RESUMO

Background: Periodontal disease is associated with immune dysregulation, and cytokines released can add on to the coronavirus disease 2019 (COVID-19)-associated cytokine storm, further worsening the related adverse outcomes. Specific studies investigating cytokine levels in COVID-19 patients with periodontal disease are lacking. Examining the correlation between these conditions could aid in categorizing risk categories, determining referrals, and strengthening oral hygiene protocols. The current study sought to evaluate cytokine levels in the saliva of COVID-19-positive patients with and without periodontal disease. Materials and Methods: Twenty-six COVID-19-positive patients were subjected to periodontal examination, saliva collection, and assessment of cytokine levels through cytokine bead-based multiplex assay, using fluorescence-encoded beads with flow cytometry (BD FACS LSRFortessa). Eleven cytokines were assessed (interleukin [IL] 2, 4, 6, 10, 17A, and interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-α), chemokine ligand 2 (CCL2/monocyte chemoattractant protein-1), C-X-C motif chemokine ligand (CXCL) 8/IL 8, CXCL 9/monokine-induced gamma interferon [MIG]), and CXCL 10 (chemokine IFN-gamma inducible protein 10 kDa). The cytokine levels of the recruited subjects were also compared graphically with the salivary cytokine levels reported in the literature for health, COVID-19, and periodontal disease alone. Results: Out of 26 COVID-19-positive patients, 17 had periodontal disease. Levels of all cytokines were raised in patients with both diseases when compared to values reported in literature for health, periodontal disease alone, or COVID-19 alone. However, there was no statistical difference among the recruited subjects for IL-2, IL-4, IL-6, IL-10, IL-17A, IFN-gamma, TNF-α, CCL2, CXCL 8, and CXCL 10. MIG levels were found to be higher in periodontally healthy, COVID-19-positive subjects (P = 0.01). Conclusions: Periodontal disease might contribute to the COVID-19-induced cytokine storm, potentially amplifying its impact.

10.
Artigo em Inglês | MEDLINE | ID: mdl-38989580

RESUMO

BACKGROUND: Aortic stenosis (AS) is driven by progressive inflammatory and fibrocalcific processes regulated by circulating inflammatory and valve resident endothelial and interstitial cells. The impact of platelets, platelet-derived mediators, and platelet-monocyte interactions on the acceleration of local valvular inflammation and mineralization is presently unknown. METHODS: We prospectively enrolled 475 consecutive patients with severe symptomatic AS undergoing aortic valve replacement. Clinical workup included repetitive echocardiography, analysis of platelets, monocytes, chemokine profiling, aortic valve tissue samples for immunohistochemistry, and gene expression analysis. RESULTS: The patients were classified as fast-progressive AS by the median ∆Vmax of 0.45 m/s per year determined by echocardiography. Immunohistological aortic valve analysis revealed enhanced cellularity in fast-progressive AS (slow- versus fast-progressive AS; median [interquartile range], 247 [142.3-504] versus 717.5 [360.5-1234]; P<0.001) with less calcification (calcification area, mm2: 33.74 [27.82-41.86] versus 20.54 [13.52-33.41]; P<0.001). MIF (macrophage migration inhibitory factor)-associated gene expression was significantly enhanced in fast-progressive AS accompanied by significantly elevated MIF plasma levels (mean±SEM; 6877±379.1 versus 9959±749.1; P<0.001), increased platelet activation, and decreased intracellular MIF expression indicating enhanced MIF release upon platelet activation (CD62P, %: median [interquartile range], 16.8 [11.58-23.8] versus 20.55 [12.48-32.28], P=0.005; MIF, %: 4.85 [1.48-9.75] versus 2.3 [0.78-5.9], P<0.001). Regression analysis confirmed that MIF-associated biomarkers are strongly associated with an accelerated course of AS. CONCLUSIONS: Our findings suggest a key role for platelet-derived MIF and its interplay with circulating and valve resident monocytes/macrophages in local and systemic thromboinflammation during accelerated AS. MIF-based biomarkers predict an accelerated course of AS and represent a novel pharmacological target to attenuate progression of AS.

11.
Artigo em Inglês | MEDLINE | ID: mdl-39029637

RESUMO

Primary graft dysfunction (PGD) is a complication of lung transplantation that continues to cause significant morbidity. The Th2 immune response has been shown to counteract tissue-damaging inflammation. We hypothesized that Th2 cytokines/chemokines in blood would be associated with protection from PGD. Utilizing pre-transplant sera from the multicenter Clinical Trials in Organ Transplantation (CTOT-20) study, we evaluated Th2 cytokines/chemokines in 211 patients. Increased concentrations of Th2 cytokines were associated with freedom from PGD, namely IL-4 (Odds Ratio (OR) 0.66 (95% CI 0.45-0.99), p=0.043), IL-9 (OR 0.68 (95% CI 0.49-0.94), p=0.019), IL-13 (OR 0.73 (95% CI 0.55-0.96), p=0.023), and IL-6 (OR 0.74 (95% CI 0.56-0.98), p=0.036). Multivariable regression performed for each cytokine including clinically relevant covariables confirmed these associations and additionally demonstrated association with IL-5 (OR 0.57 (95% CI 0.36-0.89), p=0.014) and IL-10 (OR 0.55 (95% CI 0.32-0.96), p=0.035). Higher levels of Th2 immune response prior to lung translant appear to have a protective effect against PGD, which parallels the Th2 role in resolving inflammation and tissue injury. Pre-transplant cytokine assessments could be utilized for recipient risk stratification.

12.
Front Med (Lausanne) ; 11: 1368977, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38947241

RESUMO

Intestinal fibrosis is a common complication of chronic intestinal diseases with the characteristics of fibroblast proliferation and extracellular matrix deposition after chronic inflammation, leading to lumen narrowing, structural and functional damage to the intestines, and life inconvenience for the patients. However, anti-inflammatory drugs are currently generally not effective in overcoming intestinal fibrosis making surgery the main treatment method. The development of intestinal fibrosis is a slow process and its onset may be the result of the combined action of inflammatory cells, local cytokines, and intestinal stromal cells. The aim of this study is to elucidate the pathogenesis [e.g., extracellular matrix (ECM), cytokines and chemokines, epithelial-mesenchymal transition (EMT), differentiation of fibroblast to myofibroblast and intestinal microbiota] underlying the development of intestinal fibrosis and to explore therapeutic advances (such as regulating ECM, cytokines, chemokines, EMT, differentiation of fibroblast to myofibroblast and targeting TGF-ß) based on the pathogenesis in order to gain new insights into the prevention and treatment of intestinal fibrosis.

13.
Curr Med Chem ; 2024 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-38967082

RESUMO

BACKGROUND: Neglected parasitic diseases constitute a broad spectrum of clinical conditions that, in the chronic phase, lack effective therapies for the target population. The utilization of vaccines based on liposomal nanocarrier systems is emerging, thereby enhancing clinical outcomes in various comorbidities. Consequently, this study aims to assess the immunological activity induced by liposomal nanocarriers against neglected parasitic diseases. METHODS: For the review, the Pubmed, Embase, and Lilacs databases were used using the descriptors vaccine, parasite, and liposome. The following inclusion criteria were adopted: in vivo and in vitro experimental articles. As exclusion criteria: book chapters, editorials, literature reviews and duplicate articles found during the database search. RESULTS: A total of 226 articles were identified, from which 34 were selected for review. The primary diseases identified included Babesia bovis, Entamoeba histolytica, Leishmania braziliensis, Leishmania donovani, Leishmania major, Leishmania infantum, Plasmodium falciparum, Plasmodium chabaudi, Plasmodium chabaudi, Plasmodium yoelii, Toxoplasma gondii and Trypanosoma cruzi. An elevation in cytokines such as GM-CSF, MCP-1, INF-γ, TNF-α, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, and IL-17 was observed in the studies evaluated regarding the parasitic diseases. Furthermore, cytokines such as IL-4, IL-10, and TGF-ß were diminished with the administration of the vaccine systems in those studies. CONCLUSION: Therefore, the administration of liposomal nanovaccine systems can effectively ameliorate the clinical condition of patients by modulating their immunological profile.

14.
Vet Microbiol ; 296: 110172, 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38971118

RESUMO

TAK1-binding protein 1 (TAB1) assembles with TAK1 through its C-terminal domain, leading to the self-phosphorylation and activation of TAK1, which plays an important role in the activation of NF-κB and MAPK signaling pathway. Pseudorabies virus (PRV) is the pathogen of Pseudorabies (PR), which belongs to the Alphaherpesvirus subfamily and causes serious economic losses to the global pig industry. However, the impact of swine TAB1 (sTAB1) on PRV infection has not been reported. In this study, evidence from virus DNA copies, virus titer and western blotting confirmed that sTAB1 could inhibit PRV replication and knockout of sTAB1 by CRISPR-Cas9 gene editing system could promote PRV replication. Further mechanistic studies by real-time PCR and luciferase reporter gene assay demonstrated that sTAB1 could enhance the production of inflammatory factors and chemokines, IFN-ß transcription level and IFN-ß promoter activity after PRV infection. In summary, we clarify the underlying mechanism of sTAB1 in inhibiting PRV replication for the first time, which provides a new idea for preventing PRV infection and lays a foundation for PRV vaccine development.

15.
Cancer Immunol Immunother ; 73(9): 169, 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38954024

RESUMO

Insofar as they play an important role in the pathogenesis of colorectal cancer (CRC), this study analyzes the serum profile of cytokines, chemokines, growth factors, and soluble receptors in patients with CRC and cancer-free controls as possible CRC signatures. Serum levels of 65 analytes were measured in patients with CRC and age- and sex-matched cancer-free controls using the ProcartaPlex Human Immune Monitoring 65-Plex Panel. Of the 65 tested analytes, 8 cytokines (CSF-3, IFN-γ, IL-12p70, IL-18, IL-20, MIF, TNF-α and TSLP), 8 chemokines (fractalkine, MIP-1ß, BLC, Eotaxin-1, Eotaxin-2, IP-10, MIP-1a, MIP-3a), 2 growth factors (FGF-2, MMP-1), and 4 soluble receptors (APRIL, CD30, TNFRII, and TWEAK), were differentially expressed in CRC. ROC analysis confirmed the high association of TNF-α, BLC, Eotaxin-1, APRIL, and Tweak with AUC > 0.70, suggesting theranostic application. The expression of IFN-γ, IL-18, MIF, BLC, Eotaxin-1, Eotaxin-2, IP-10, and MMP1 was lower in metastatic compared to non-metastatic CRC; only AUC of MIF and MIP-1ß were > 0.7. Moreover, MDC, IL-7, MIF, IL-21, and TNF-α are positively associated with tolerance to CRC chemotherapy (CT) (AUC > 0.7), whereas IL-31, Fractalkine, Eotaxin-1, and Eotaxin-2 were positively associated with resistance to CT. TNF-α, BLC, Eotaxin-1, APRIL, and Tweak may be used as first-line early detection of CRC. The variable levels of MIF and MIP-1ß between metastatic and non-metastatic cases assign prognostic nature to these factors in CRC progression. Regarding tolerance to CT, MDC, IL-7, MIF, IL-21, and TNF-α are key when down-regulated or resistant to treatment is observed.


Assuntos
Neoplasias Colorretais , Citocinas , Humanos , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/sangue , Neoplasias Colorretais/patologia , Feminino , Masculino , Citocinas/sangue , Citocinas/metabolismo , Pessoa de Meia-Idade , Idoso , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Quimiocinas/sangue , Quimiocinas/metabolismo , Resultado do Tratamento , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/metabolismo , Adulto , Prognóstico , Estudos de Casos e Controles
16.
Front Immunol ; 15: 1396349, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39011040

RESUMO

Introduction: Immunogenic cell death (ICD) has emerged as a novel option for cancer immunotherapy. The key determinants of ICD encompass antigenicity (the presence of antigens) and adjuvanticity, which involves the release of damage-associated molecular patterns (DAMPs) and various cytokines and chemokines. CX3CL1, also known as neurotactin or fractalkine, is a chemokine involved in cellular signalling and immune cell interactions. CX3CL1 has been denoted as a "find me" signal that stimulates chemotaxis of immune cells towards dying cells, facilitating efferocytosis and antigen presentation. However, in the context of ICD, it is uncertain whether CX3CL1 is an important mediator of the effects of ICD. Methods: In this study, we investigated the intricate role of CX3CL1 in immunogenic apoptosis induced by mitoxantrone (MTX) in cancer cells. The Luminex xMAP technology was used to quantify murine cytokines, chemokines and growth factors to identify pivotal regulatory cytokines released by murine fibrosarcoma MCA205 and melanoma B16-F10 cells undergoing ICD. Moreover, a murine tumour prophylactic vaccination model was employed to analyse the effect of CX3CL1 on the activation of an adaptive immune response against MCA205 cells undergoing ICD. Furthermore, thorough analysis of the TCGA-SKCM public dataset from 98 melanoma patients revealed the role of CX3CL1 and its receptor CX3CR1 in melanoma patients. Results: Our findings demonstrate enhanced CX3CL1 release from apoptotic MCA205 and B16-F10 cells (regardless of the cell type) but not if they are undergoing ferroptosis or accidental necrosis. Moreover, the addition of recombinant CX3CL1 to non-immunogenic doses of MTX-treated, apoptotically dying cancer cells in the murine prophylactic tumour vaccination model induced a robust immunogenic response, effectively increasing the survival of the mice. Furthermore, analysis of melanoma patient data revealed enhanced survival rates in individuals exhibiting elevated levels of CD8+ T cells expressing CX3CR1. Conclusion: These data collectively underscore the importance of the release of CX3CL1 in eliciting an immunogenic response against dying cancer cells and suggest that CX3CL1 may serve as a key switch in conferring immunogenicity to apoptosis.


Assuntos
Apoptose , Quimiocina CX3CL1 , Animais , Quimiocina CX3CL1/metabolismo , Camundongos , Humanos , Linhagem Celular Tumoral , Camundongos Endogâmicos C57BL , Melanoma Experimental/imunologia , Feminino , Morte Celular Imunogênica , Citocinas/metabolismo
17.
Front Immunol ; 15: 1421076, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39011039

RESUMO

Cognitive impairment is a decline in people's ability to think, learn, and remember, and so forth. Cognitive impairment is a global health challenge that affects the quality of life of thousands of people. The condition covers a wide range from mild cognitive impairment to severe dementia, which includes Alzheimer's disease (AD) and Parkinson's disease (PD), among others. While the etiology of cognitive impairment is diverse, the role of chemokines is increasingly evident, especially in the presence of chronic inflammation and neuroinflammation. Although inflammatory chemokines have been linked to cognitive impairment, cognitive impairment is usually multifactorial. Researchers are exploring the role of chemokines and other inflammatory mediators in cognitive dysfunction and trying to develop therapeutic strategies to mitigate their effects. The pathogenesis of cognitive disorders is very complex, their underlying causative mechanisms have not been clarified, and their treatment is always one of the challenges in the field of medicine. Therefore, exploring its pathogenesis and treatment has important socioeconomic value. Chemokines are a growing family of structurally and functionally related small (8-10 kDa) proteins, and there is growing evidence that pro-inflammatory chemokines are associated with many neurobiological processes that may be relevant to neurological disorders beyond their classical chemotactic function and play a crucial role in the pathogenesis and progression of cognitive disorders. In this paper, we review the roles and regulatory mechanisms of pro-inflammatory chemokines (CCL2, CCL3, CCL4, CCL5, CCL11, CCL20, and CXCL8) in cognitive impairment. We also discuss the intrinsic relationship between the two, hoping to provide some valuable references for the treatment of cognitive impairment.


Assuntos
Comunicação Celular , Quimiocinas , Disfunção Cognitiva , Humanos , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/imunologia , Disfunção Cognitiva/metabolismo , Quimiocinas/metabolismo , Animais , Inflamação/imunologia , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo
18.
Cell Rep Med ; 5(7): 101622, 2024 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-38917802

RESUMO

Progressive multifocal leukoencephalopathy (PML) has been associated with different forms of immune compromise. This study analyzes the chemokine signals and attracted immune cells in cerebrospinal fluid (CSF) during PML to define immune cell subpopulations relevant for the PML immune response. In addition to chemokines that indicate a general state of inflammation, like CCL5 and CXCL10, the CSF of PML patients specifically contains CCL2 and CCL4. Single-cell transcriptomics of CSF cells suggests an enrichment of distinct CD4+ and CD8+ T cells expressing chemokine receptors CCR2, CCR5, and CXCR3, in addition to ITGA4 and the genetic PML risk genes STXBP2 and LY9. This suggests that specific immune cell subpopulations migrate into the central nervous system to mitigate PML, and their absence might coincide with PML development. Monitoring them might hold clues for PML risk, and boosting their recruitment or function before therapeutic immune reconstitution might improve its risk-benefit ratio.


Assuntos
Movimento Celular , Sistema Nervoso Central , Quimiocinas , Leucoencefalopatia Multifocal Progressiva , Humanos , Leucoencefalopatia Multifocal Progressiva/patologia , Leucoencefalopatia Multifocal Progressiva/imunologia , Quimiocinas/metabolismo , Quimiocinas/genética , Movimento Celular/genética , Sistema Nervoso Central/patologia , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/imunologia , Linfócitos T CD8-Positivos/imunologia , Masculino , Feminino , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Pessoa de Meia-Idade , Idoso
19.
Curr Issues Mol Biol ; 46(6): 6100-6111, 2024 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-38921035

RESUMO

This study examines the synergistic interaction between the immunomodulatory functions of lactic acid bacteria postbiotics and the anti-inflammatory properties of Smilax china L. extract through a combined fermentation process. Using atopic dermatitis (AD) as a model, characterized by an immune imbalance that leads to skin inflammation, we developed a fermented product, MB-2006, and compared its effects to those of the heat-killed probiotics Lactobacillus acidophilus (LAC) and Lactobacillus rhamnosus (LRH). Our experiments focused on elucidating the mechanism of action of MB-2006 in AD-like HaCaT keratinocyte cells, particularly its impact on the NF-κB pathway, a pivotal regulator of inflammation. MB-2006 proved more effective in reducing inflammation markers, such as IL-4 and thymic stromal lymphopoietin (TSLP), and in inhibiting NF-κB activation compared to LAC and LRH. Significantly, MB-2006 also reduced the expression of thymus- and activation-regulated chemokine (TARC), highlighting a synergistic effect that enhances its therapeutic potential. These results suggest that the combined fermentation of Smilax china L. extract with lactic acid bacteria enhanced both the anti-inflammatory and immunomodulatory effects, presenting a promising integrative approach to treating conditions like AD. Further studies are needed to validate these results in clinical settings and fully explore the potential of this synergistic fermentation process.

20.
Mol Neurobiol ; 2024 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-38861234

RESUMO

Chemokines are vital in post-cerebral ischemia inflammatory reactions. We investigate the possible relationship between plasma chemokines and short-term and long-term outcomes after stroke. This study included 235 patients (median age, 72 years; 49.8% female) suffering from ischemic stroke, or transient ischemic attack admitted to the hospital within 24 h of onset. We evaluated chemokines CCL2, CCL5, CXCL8, CXCL9, and CXCL10 in plasma samples collected upon admission. Further, we assessed functional outcomes at 3- and 12-months, all-cause fatality over 5 years, and episodes of delirium within the first 7 days of admission. Multivariate analysis revealed an association between higher CXCL10 levels and an increased risk of poor functional outcomes at 3 months (OR: 3.02, 95%CI: 1.22-7.46, p = 0.016) and 12 months (OR: 2.32, 95%CI: 1.03-5.26, p = 0.043), as well as an increased death risk (HR: 1.79, 95%CI: 1.04-3.07, p = 0.036). High CXCL8 levels independently predicted poor functional outcomes at 12 months (OR: 2.69, 95%CI: 1.39-6.31, p = 0.005) and a higher 5-year case fatality rate (HR: 1.90, 95%CI: 1.23-2.93, p = 0.004). Elevated CXCL9 levels also predicted unfavourable functional outcomes at 12 months (OR: 2.45, 95%CI: 1.07-5.61, p = 0.034). In univariate analysis, increased levels of CXCL8, CXCL9, and CXCL10 showed an association with delirium, although this link was not evident in the multivariate analysis. Plasma CXCL8 and CXCL10 show potential as prognostic biomarkers for stroke outcomes and as therapeutic targets suitable for reverse translation.

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