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Biomedicine & Pharmacotherapy =... Apr 2024Riboflavin (RF) as a photosensitizer has been used in corneal surgery and the inactivation of blood products. However, the effect of RF on immune cells after ultraviolet...
Riboflavin (RF) as a photosensitizer has been used in corneal surgery and the inactivation of blood products. However, the effect of RF on immune cells after ultraviolet (UV) light stimulation has not been investigated. This study pioneered a novel application method of RF. Firstly, UV-stimulated RF was co-cultured with human peripheral blood mononuclear cells in vitro, and the apoptosis rate of lymphocyte subsets, cell proliferation inhibition rate and concentrations of IL-1β, IL-6, IL-10, TNF-α were assessed. UV-stimulated RF was then administered intravenously to mice via the tail vein for a consecutive period of 5 days. The levels of immunoglobulin (IgG, IgM, IgA), complement (C3, C4) and cytokines (IFN-γ, IL-4, IL17, TGF-β) were detected by ELISA. Flow cytometry was employed to analyze the populations of CD3+T, CD4+T, CD8+T and CD4+T/CD8+T cells in spleen lymphocytes of mice. The data showed that UV-stimulated RF can effectively induce apoptosis in lymphocytes, and different lymphocyte subtypes exhibited varying degrees of treatment tolerance. Additionally, the proliferative capacity of lymphocytes was suppressed, while their cytokine secretion capability was augmented. The animal experiments demonstrated that UV-stimulated RF led to a significant reduction observed in serum immunoglobulin and complement levels, accompanied by an elevation in IFN-γ, IL-17 and TGF-β levels, as well as a decline in IL-4 level. In summary, the results of both in vitro and in vivo experiments have demonstrated that UV-stimulated RF, exhibits the ability to partially inhibit immune function. This novel approach utilizing RF may offer innovative perspectives for diseases requiring immunosuppressive treatment.
Topics: Humans; Mice; Animals; Leukocytes, Mononuclear; Interleukin-4; Mice, Inbred BALB C; Cytokines; Riboflavin; Transforming Growth Factor beta; Immunoglobulins; CD4-Positive T-Lymphocytes
PubMed: 38401513
DOI: 10.1016/j.biopha.2024.116278 -
International Journal of Molecular... Feb 2024Complement component 4 binding protein α () is an immune gene which is responsible for the complement regulation function of by binding and inactivating the Complement...
Complement component 4 binding protein α () is an immune gene which is responsible for the complement regulation function of by binding and inactivating the Complement component C4b () component of the classical Complement 3 () invertase pathway. Our previous findings revealed that was differentially expressed by comparing the transcriptome in high-fat and low-fat bovine mammary epithelial cell lines (BMECs) from Chinese Holstein dairy cows. In this study, a gene knockout BMECs line model was constructed via using a CRISPR/Cas9 system to investigate the function of in lipid metabolism. The results showed that levels of triglyceride (TG) were increased, while levels of cholesterol (CHOL) and free fatty acid (FFA) were decreased ( < 0.05) after knocking out in BMECs. Additionally, most kinds of fatty acids were found to be mainly enriched in the pathway of the biosynthesis of unsaturated fatty acids, linoleic acid metabolism, fatty acid biosynthesis, and regulation of lipolysis in adipocyte. Meanwhile, the RNA-seq showed that most of the differentially expressed genes (DEGs) are related to PI3K-Akt signaling pathway. The expressions of 3-Hydroxy-3-Methylglutaryl-CoA Synthase 1 (HMGCS1), Carnitine Palmitoyltransferase 1A (CPT1A), Fatty Acid Desaturase 1 (FADS1), and Stearoyl-Coenzyme A desaturase 1 (SCD1) significantly changed when the gene was knocked out. Collectively, gene, which is an immune gene, played an important role in lipid metabolism in BMECs. These findings provide a new avenue for animal breeders: this gene, with multiple functions, should be reasonably utilized.
Topics: Animals; Cattle; Female; Complement C4; Epithelial Cells; Fatty Acids; Lipid Metabolism; Mammary Glands, Animal; Milk; Phosphatidylinositol 3-Kinases; Transcriptome
PubMed: 38397050
DOI: 10.3390/ijms25042375 -
Journal of Cancer Research and Clinical... Feb 2024Immune checkpoint inhibitors (ICIs) dramatically changed the prognosis of patients with NSCLC. Unfortunately, a reliable predictive biomarker is still missing. Commonly... (Observational Study)
Observational Study
PURPOSE
Immune checkpoint inhibitors (ICIs) dramatically changed the prognosis of patients with NSCLC. Unfortunately, a reliable predictive biomarker is still missing. Commonly used biomarkers, such as PD-L1, MSI, or TMB, are not quite accurate in predicting ICI efficacy.
METHODS
In this prospective observational cohort study, we investigated the predictive role of erythrocytes, thrombocytes, innate and adaptive immune cells, complement proteins (C3, C4), and cytokines from peripheral blood of 224 patients with stage III/IV NSCLC treated with ICI alone (pembrolizumab, nivolumab, and atezolizumab) or in combination (nivolumab + ipilimumab) with chemotherapy. These values were analyzed for associations with the response to the treatment and survival endpoints.
RESULTS
Higher baseline Tregs, MPV, hemoglobin, and lower monocyte levels were associated with favorable PFS and OS. Moreover, increased baseline basophils and lower levels of C3 predicted significantly improved PFS. The levels of the baseline immature granulocytes, C3, and monocytes were significantly associated with the occurrence of partial regression at the first restaging. Multiple studied parameters (n = 9) were related to PFS benefit at the time of first restaging as compared to baseline values. In addition, PFS nonbenefit group showed a decrease in lymphocyte count after three months of therapy. The OS benefit was associated with higher levels of lymphocytes, erythrocytes, hemoglobin, MCV, and MPV, and a lower value of NLR after three months of treatment.
CONCLUSION
Our work suggests that parameters from peripheral venous blood may be potential biomarkers in NSCLC patients on ICI. The baseline values of Tregs, C3, monocytes, and MPV are especially recommended for further investigation.
Topics: Humans; Lung Neoplasms; Nivolumab; Immune Checkpoint Inhibitors; Immunophenotyping; Prospective Studies; Antineoplastic Agents, Immunological; Carcinoma, Non-Small-Cell Lung; Biomarkers; Hemoglobins; B7-H1 Antigen
PubMed: 38383923
DOI: 10.1007/s00432-024-05628-2 -
Cureus Jan 2024Adult-onset Still's disease (AOSD) causes fever, rash, pharyngalgia, and arthralgia through autoinflammation. Its complement titer has not previously received attention...
Adult-onset Still's disease (AOSD) causes fever, rash, pharyngalgia, and arthralgia through autoinflammation. Its complement titer has not previously received attention because this usually increases during the inflammatory process. Our female patient in her 60s was admitted to the hospital with fever, rash, arthralgia, and pharyngalgia. Her white blood cell count was 19,130/μL, hemoglobin was 11.0 g/dL, platelet count was 26.0 × 10/μL, and ferritin titer was 6,175 ng/mL. Anti-nuclear antibodies and anti-neutrophil cytoplasmic antibodies were negative. The presence of infectious diseases and malignancies was excluded. She was diagnosed with hypocomplementemia at the onset of AOSD because of her low complement component 4 (C4) titer (<5.0 mg/dL). Her complement component 3 (C3) titer was 104.5 mg/dL, which was within normal limits. There was no sign of thrombotic microangiopathy (TMA) or hemophagocytosis. She was treated with high-dose corticosteroids, including pulse methylprednisolone therapy, cyclosporine, methotrexate, and intravenous immunoglobulin, but was resistant to these, and her disease repeatedly flared up. Treatment with intravenous cyclophosphamide eventually led to remission. Post-treatment, her C4 titer increased to within the normal range. Although hypocomplementemia with TMA or hemophagocytosis has been reported in AOSD patients, our patient showed no sign of either at disease onset. Hypocomplementemia of AOSD may be a sign of high disease activity and could be a predictive marker for resistance to standard therapy.
PubMed: 38374851
DOI: 10.7759/cureus.52605 -
International Journal of General... 2024This research aimed to explore the correlation between antiphospholipid antibodies (aPLs) and complement activation in lupus nephritis (LN) patients.
OBJECTIVE
This research aimed to explore the correlation between antiphospholipid antibodies (aPLs) and complement activation in lupus nephritis (LN) patients.
METHODS
A retrospective analysis was carried out on patients diagnosed with LN based on renal biopsy from June 2019 to June 2022. The study assessed levels of IgM, IgA, and IgG subtypes of anticardiolipin antibodies (aCLs) and anti-β2-glycoprotein I (anti-β2-GPI) antibodies. Pathological and clinical data were collected concurrently with the renal biopsy.
RESULTS
The analysis included 76 LN patients, with 44.7% testing positive for aPLs. LN patients with positive aPLs exhibited increased hematuria, higher SLEDAI scores, reduced serum C3 and C4 levels, and more C1q deposits in the glomerulus compared to those with negative aPLs (<0.05). Correlation analysis demonstrated the inverse relationships between IgG-aCL levels and serum C3 and C4 levels (r=-0.29, =0.005; r=-0.24, =0.016, respectively), as well as a positive correlation with C4 deposits in the glomerulus (r=0.20, =0.041).
CONCLUSION
This investigation suggests that aPLs, particularly IgG-aCLs, may be associated with the severity of LN and could contribute to the activation of classical complement pathways.
PubMed: 38356686
DOI: 10.2147/IJGM.S449509 -
Infection Apr 2024This study investigates the potential of inflammatory parameters (IP), symptoms, and patient-related outcome measurements as biomarkers of severity and their ability to...
PURPOSE
This study investigates the potential of inflammatory parameters (IP), symptoms, and patient-related outcome measurements as biomarkers of severity and their ability to predict tuberculosis (TB) evolution.
METHODS
People with TB were included prospectively in the Stage-TB study conducted at five clinical sites in Barcelona (Spain) between April 2018 and December 2021. Data on demographics, epidemiology, clinical features, microbiology, and Sanit George Respiratory Questionnaire (SGRQ) and Kessler-10 as Health-Related Quality of Life (HRQoL) were collected at three time points during treatment. C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), neutrophil/lymphocyte, and monocyte/lymphocyte ratios (NLR and MLR), complement factors C3, C4, and cH50, clinical and microbiological data, and HRQoL questionnaires were assessed at baseline, 2 months, and 6 months. Their ability to predict sputum culture conversion (SCC) and symptom presence after 2 months of treatment was also analysed.
RESULTS
The study included 81 adults and 13 children with TB. The CRP, ESR, NLR, and MLR values, as well as the presence of symptoms, decreased significantly over time in both groups. Higher IP levels at baseline were associated with greater bacillary load and persistent symptoms. Clinical severity at baseline predicted a delayed SCC. Kessler-10 improved during follow-up, but self-reported lung impairment (SGRQ) persisted in all individuals after 6 months.
CONCLUSIONS
IP levels may indicate disease severity, and sustained high levels are linked to lower treatment efficacy. Baseline clinical severity is the best predictor of SCC. Implementing health strategies to evaluate lung function and mental health throughout the disease process may be crucial for individuals with TB.
Topics: Adult; Child; Humans; Prospective Studies; Quality of Life; Tuberculosis; Longitudinal Studies; C-Reactive Protein
PubMed: 38349459
DOI: 10.1007/s15010-024-02184-2 -
Frontiers in Genetics 2023Age-related macular degeneration (AMD) is the leading cause of central vision loss in the elderly. One-third of the genetic contribution to this disease remains...
Age-related macular degeneration (AMD) is the leading cause of central vision loss in the elderly. One-third of the genetic contribution to this disease remains unexplained. We analyzed targeted sequencing data from two independent cohorts (4,245 cases, 1,668 controls) which included genomic regions of known AMD loci in 49 genes. At a false discovery rate of <0.01, we identified 11 low-frequency AMD variants (minor allele frequency <0.05). Two of those variants were present in the complement gene, including the replacement of the residues that contribute to the Rodgers-1/Chido-1 blood group antigens: [VDLL1207-1210ADLR (V1207A)] with discovery odds ratio (OR) = 1.7 ( = 3.2 × 10) which was replicated in the UK Biobank dataset (3,294 cases, 200,086 controls, OR = 1.52, = 0.037). A novel variant associated with reduced risk for AMD in our discovery cohort was P1120T, one of the four C4A-isotypic residues. Gene-based tests yielded aggregate effects of nonsynonymous variants in 10 genes including , which were associated with increased risk of AMD. In human eye tissues, immunostaining demonstrated C4A protein accumulation in and around endothelial cells of retinal and choroidal vasculature, and total C4 in soft drusen. Our results indicate that C4A protein in the complement activation pathways may play a role in the pathogenesis of AMD.
PubMed: 38348408
DOI: 10.3389/fgene.2023.1274743 -
Kidney International Reports Feb 2024IgA nephropathy's (IgAN's) MEST-C classification relationship with complement activation is still not fully understood because of limited and conflicting evidence. Our...
INTRODUCTION
IgA nephropathy's (IgAN's) MEST-C classification relationship with complement activation is still not fully understood because of limited and conflicting evidence. Our study aimed to delineate this relationship through a systematic review.
METHODS
We adhered to the Preferred Reporting Items for Systematic Review and Meta-analysis guidelines and conducted a systematic review, utilizing databases like MEDLINE (PubMed), Embase, Scopus, and Cochrane from January 2016 (year of updated MEST-C classification) to January 2023. We specifically selected studies that employed established methods to evaluate complement activation and the MEST-C classification.
RESULTS
A total of 34 studies with 10,082 patients were included. Among these, 7 studies focused on the pediatric population (500 patients), and 22 studies involved 8128 patients from Asian populations. C4d, C3, C5b9, MBL, C4, and factor H-related protein 5 (FHR5) were the most frequently studied complement proteins in relation to the MEST-C classification. Complement activation assessment was primarily conducted using immunofluorescence and immunohistochemistry on kidney biopsy specimens. All complement proteins investigated showed associations with the C1-2 class. Notably, FB, FH, MASP1/3, MASP2, C5a, and C5b9 from the alternative, lectin, and terminal pathways were uniquely present in the C1-2 class. Whereas C3, FHR5, C4, and C4d were associated with all the MEST-C classes.
CONCLUSION
We found evidence supporting the involvement of alternative and lectin complement pathways across all MEST-C classes. All examined complement factors were associated with the C1-2 class, emphasizing the critical role of complement activation, possibly at the endothelial surface. These findings may guide the development of personalized treatment strategies targeting complement pathways in relation to the MEST-C lesions.
PubMed: 38344730
DOI: 10.1016/j.ekir.2023.11.005 -
Schizophrenia (Heidelberg, Germany) Feb 2024Schizophrenia is a severe mental illness and a major risk factor for suicide, with approximately 50% of schizophrenia patients attempting and 10% dying from suicide....
Schizophrenia is a severe mental illness and a major risk factor for suicide, with approximately 50% of schizophrenia patients attempting and 10% dying from suicide. Although genetic components play a significant role in schizophrenia risk, the underlying genetic risk factors for suicide are poorly understood. The complement component C4 gene, an immune gene involved in the innate immune system and located in the major histocompatibility complex (MHC) region, has been identified to be strongly associated with schizophrenia risk. In addition, recent findings have also suggested that the MHC region has been associated with suicide risk across disorders, making C4 a potential candidate of interest for studying suicidality in schizophrenia patients. Despite growing interest in investigating the association between the C4 gene and schizophrenia, to our knowledge, no work has been done to examine the potential of C4 variants as suicide risk factors in patients with schizophrenia. In this study, we investigated the association between different C4 copy number variants and predicted C4 brain expression with suicidal outcomes (suicide attempts/suicidal ideation). We directly genotyped 434 schizophrenia patients to determine their C4A and C4B copy number variants. We found the C4AS copy number to be marginally and negatively associated with suicide risk, potentially being protective against suicide attempts (OR = 0.49; p = 0.05) and suicidal ideation (OR = 0.65; p = 0.07). Furthermore, sex-stratified analyses revealed that there are no significant differences between males and females. Our preliminary findings encourage additional studies of C4 and potential immune dysregulation in suicide.
PubMed: 38341430
DOI: 10.1038/s41537-024-00440-w -
Journal of Veterinary Internal Medicine 2024High concentrations of complement factors are presented in serum of animal epilepsy models and human patients with epilepsy.
BACKGROUND
High concentrations of complement factors are presented in serum of animal epilepsy models and human patients with epilepsy.
OBJECTIVES
To determine whether complement dysregulation occurs in dogs with idiopathic epilepsy (IE).
ANIMALS
The study included 49 dogs with IE subgrouped into treatment (n = 19), and nontreatment (n = 30), and 29 healthy dogs.
METHODS
In this case-control study, the serum concentrations of the third (C3) and fourth (C4) components of the complement system were measured using a canine-specific ELISA kit.
RESULTS
Serum C3 and C4 concentrations were significantly higher in dogs with IE (C3, median; 4.901 [IQR; 3.915-6.673] mg/mL, P < .001; C4, 0.327 [0.134-0.557] mg/mL, P = .03) than in healthy control dogs (C3, 3.550 [3.075-4.191] mg/mL; C4, 0.267 [0.131-0.427] mg/mL). No significant differences were observed in serum C3 and C4 concentrations between dogs in the treatment (C3, median; 4.894 [IQR; 4.192-5.715] mg/mL; C4, 0.427 [0.143-0.586] mg/mL) and nontreatment groups (C3, 5.051 [3.702-7.132] mg/mL; C4, 0.258 [0.130-0.489] mg/mL). Dogs with a seizure frequency >3 times/month had significantly higher serum C3 (6.461 [4.695-8.735] mg/mL; P < .01) and C4 (0.451 [0.163-0.675] mg/mL; P = .01) concentrations than those with a seizure frequency ≤3 times/month (C3, 3.859 [3.464-5.142] mg/mL; C4, 0.161 [0.100-0.325] mg/mL).
CONCLUSIONS AND CLINICAL IMPORTANCE
Dysregulation of classical complement pathway was identified in IE dogs. Serum C3 and C4 concentrations could be diagnostic biomarkers for IE in dogs with higher seizure frequency.
Topics: Humans; Dogs; Animals; Complement C3; Complement C4; Case-Control Studies; Epilepsy; Seizures; Dog Diseases
PubMed: 38329151
DOI: 10.1111/jvim.17008