Complement C3 Research Articles

Eculizumab in myasthenia gravis: A review.

Eculizumab, a monoclonal antibody against complement C5, is a novel therapy to treat refractory myasthenia gravis (MG). The present review was undertaken to study the role of eculizumab in MG. This includes the drug's mechanism, pharmacokinetics, clinical trial findings, tolerability, side effects, safety, dosage, administration, and cost. An English-language search for relevant items was undertaken using Embase and PubMed from 1946 to present. Clinical trial registries/databases and websites were also searched for relevant data. Keywords were eculizumab and MG. The present review found 103 articles after initial screening. Current data support eculizumab as an effective, safe, and tolerable drug in cases of refractory MG. However, its cost can prevent it from being widely accessible to a majority of the general population.

Patient Characteristics Associated with Concurrent Klebsiella pneumoniae Infection and Severe Pulmonary Tuberculosis.

This study aims to investigate the clinical characteristics associated with concurrent Klebsiella pneu-moniae (K. pneumoniae) infection in hospitalized patients with severe pulmonary tuberculosis. A retrospective study was conducted on hospitalized severe pulmonary tuberculosis patients between January 2019 and December 2020. Among the 487 patients with severe pulmonary tuberculosis, a positive sputum culture for K. pneumoniae was reported in 76 patients (15.6%, 61 males and 15 females). Among these patients, 27 (35.5%) and 49 (64.5%) patients were with and without K. pneumoniae infection, respectively. Compared to patients without K. pneumoniae infection, patients with K. pneumoniae infection had higher mortality (16.3% vs. 40.7%, p = 0.02), and lower inhibitory/cytotoxic CD8 count (24.2 ± 9.9 vs. 17.8 ± 8.0, p = 0.02), complement C4 (0.3 ± 0.1 vs. 0.2 ± 0.1, p = 0.01), and retinol-binding protein level (32.2 ± 22.2 vs. 22.4 ± 11.8, p = 0.02). Furthermore, the acute Physiology and Chronic Health Evaluation II score was associated with the K. pneumoniae infection in severe pulmonary tuberculosis patients. It can be concluded that a significant number of severe pulmonary tuberculosis patients can have concurrent K. pneumoniae infection. Immunity, nutritional status, and disease severity are associated with the concurrent infection of K. pneumoniae in these patients.

The concept of gene therapy for glaucoma: the dream that has not come true yet.

Gene therapies, despite of being a relatively new therapeutic approach, have a potential to become an important alternative to current treatment strategies in glaucoma. Since glaucoma is not considered a single gene disease, the identified goals of gene therapy would be rather to provide neuroprotection of retinal ganglion cells, especially, in intraocular-pressure-independent manner. The most commonly reported type of vector for gene delivery in glaucoma studies is adeno-associated virus serotype 2 that has a high tropism to retinal ganglion cells, resulting in long-term expression and low immunogenic profile. The gene therapy studies recruit inducible and genetic animal models of optic neuropathy, like DBA/2J mice model of high-tension glaucoma and the optic nerve crush-model. Reported gene therapy-based neuroprotection of retinal ganglion cells is targeting specific genes translating to growth factors (i.e., brain derived neurotrophic factor, and its receptor TrkB), regulation of apoptosis and neurodegeneration (i.e., Bcl-xl, Xiap, FAS system, nicotinamide mononucleotide adenylyl transferase 2, Digit3 and Sarm1), immunomodulation (i.e., Crry, C3 complement), modulation of neuroinflammation (i.e., erythropoietin), reduction of excitotoxicity (i.e., CamKIIα) and transcription regulation (i.e., Max, Nrf2). On the other hand, some of gene therapy studies focus on lowering intraocular pressure, by impacting genes involved in both, decreasing aqueous humor production (i.e., aquaporin 1), and increasing outflow facility (i.e., COX2, prostaglandin F2α receptor, RhoA/RhoA kinase signaling pathway, MMP1, Myocilin). The goal of this review is to summarize the current state-of-art and the direction of development of gene therapy strategies for glaucomatous neuropathy.

Mass Spectrometry Proteomics Characterization of Plasma Biomarkers for Colorectal Cancer Associated With Inflammation.

Colorectal cancer (CRC) prognosis is determined by the disease stage with low survival rates for advanced stages. Current CRC screening programs are mainly using colonoscopy, limited by its invasiveness and high cost. Therefore, non-invasive, cost-effective, and accurate alternatives are urgently needed. This retrospective multi-center plasma proteomics study was performed to identify potential blood-based biomarkers in 36 CRC patients and 26 healthy volunteers by high-resolution mass spectrometry proteomics followed by the validation in an independent CRC cohort (60 CRC patients and 44 healthy subjects) of identified selected biomarkers. Among the 322 identified plasma proteins, 37 were changed between CRC patients and healthy volunteers and were associated with the complement cascade, cholesterol metabolism, and SERPIN family members. Increased levels in CRC patients of the complement proteins C1QB, C4B, and C5 as well as pro-inflammatory proteins, lipopolysaccharide-binding protein (LBP) and serum amyloid A4, constitutive (SAA4) were revealed for first time. Importantly, increased level of C5 was verified in an independent validation CRC cohort. Increased C4B and C8A levels were correlated with cancer-associated inflammation and CRC progression, while cancer-associated inflammation was linked to the acute-phase reactant leucine-rich alpha-2-glycoprotein 1 (LRG1) and ceruloplasmin. Moreover, a 4-protein signature including C4B, C8A, apolipoprotein C2 (APO) C2, and immunoglobulin heavy constant gamma 2 was changed between early and late CRC stages. Our results suggest that C5 could be a potential biomarker for CRC diagnosis. Further validation studies will aid the application of these new potential biomarkers to improve CRC diagnosis and patient care.

Acute phase proteins in patients with recurrent pulmonary tuberculosis

Objective. Study of initial levels of acute phase proteins in patients with pulmonary tuberculosis with and without relapse as predictors of unfavorable disease progression. Materials and methods. 2 groups of patients were examined: the base group - 55 patients with pulmonary tuberculosis with relapse and the control group - 55 patients with pulmonary tuberculosis without relapse. Acute phase protein content was studied in patients before and after the intensive phase of treatment. The content of complement factors C3 and C4, haptoglobin, ceruloplasmin, properdin, C-reactive protein, IL-6, VSH, leukocyte content was studied. Results. The obtained results reveal that acute phase proteins can be considered basic predictors of ineffective antituberculosis treatment: the high indices of leukocyte, C-reactive protein, IL-6, ESR, and haptoglobin.

СИСТЕМНОЕ ВОСПАЛЕНИЕ У БОЛЬНЫХ СО СТАБИЛЬНОЙ ИШЕМИЧЕСКОЙ БОЛЕЗНЬЮ СЕРДЦА В ПОСТКОВИДНОМ ПЕРИОДЕ В ЗАВИСИМОСТИ ОТ ТЯЖЕСТИ ПЕРЕНЕСЕННОЙ COVID-19

Background. In the post-covid period, systemic inflammation plays an important role in the development of coronary heart disease (CHD) and has a significant impact on the cardiovascular system by improving inflammatory responses, which may lead to progression of atherosclerosis, worsen the condition, and increase the likelihood of complications in patients with stable CHD. Objective. To evaluate clinical and laboratory indices of systemic inflammation in patients with stable coronary heart disease in the post-covid period depending on the severity of COVID-19. Material and methods. An observational descriptive study of two parallel groups including 416 patients with stable CHD who underwent COVID-19 more than 12 weeks ago was conducted. Patients were divided into two groups according to the severity of COVID-19 in the acute period. Group 1 included 203 patients (male 132 (65.3%), female 71 (34.7%)) aged 59.7±6.9 years who had mild SARS-CoV-2 infection; Group 2 included 213 patients (male 132 (62.0%), female 81 (38.0%)) aged 61.1±6.1 years who had moderate COVID-19. Monocyte chemoattractant protein-1 (MCP-1); vascular endothelial growth factor (VEGF); interleukins; interleukins (ILs): IL-1β, IL-4, IL-6, IL-8, IL-10, and IL-18 were determined by PCR. The C3 and C4 components of the complement system were also determined by the immunoturbidimetric method. Statistical calculations were performed in the RStudio software (version 2022.07.2+576, USA) in the R language (version 4.1.3 (2022-03-10), Austria). Results. Uncontrolled hypertension (p<0.001) and grade II obesity (p=0.005) were more frequent in the group of patients with stable CHD who underwent moderate COVID-19. In the same group, type 2 DM (p=0.031), atrial fibrillation (p = 0.029), and grade III angina pectoris (p=0.006) were more frequent, and Simpson's EF was lower (p<0.001) compared to the group of patients with mild SARS-CoV-2 infection. In patients with IBS who underwent COVID-19 of moderate severity, there was a statistically significant increase in the levels of pro-inflammatory cytokines - MCP-1, TNF-α, IL-1β (p<0.01) and the C3 component of the complement system (p=0.048) compared to patients with a mild course of infection in the acute period. In patients with stable coronary heart disease who underwent COVID-19, significant correlations were observed between the studied pro-inflammatory blood markers. Multiple and strongest associations were found for MCP-1, IL-10, IL-1β, IL-2, VEGF and the components of the complement system C3 and C4, which can be used as markers of the unfavorable course of the post-acute period in patients with IBS. Conclusion. Patients with stable CHD who underwent moderate SARS-CoV-2 infection are characterized by a higher incidence of uncontrolled AH, type 2 DM, and atrial fibrillation in the remote period. These patients also have higher levels of pro-inflammatory cytokines MCP-1, TNF-α and IL-1β, which correlate significantly with the severity of the disease and can serve as a predictor of its progression.

A new alternative: inhibiting complement activation in patients with IgA nephropathy

Mesangial complement C3 deposits, reflecting alternative and possibly lectin pathway activation, are characteristic in biopsies of patients with IgA nephropathy (IgAN). A recent randomized controlled trial tested the efficacy and safety of iptacopan, a factor B inhibitor, in patients with IgAN. Iptacopan dose-dependently reduced proteinuria, and there was a pronounced decrease of urinary C5b-9. This offers the perspective of "personalizing" therapy, which would be a unique feature of this novel approach to IgAN. A phase III clinical trial (APPLAUSE-IgAN) is ongoing.

New treatment strategies for paroxysmal nocturnal hemoglobinuria: the guideline update and novel complement-targeting drugs

The 2022 update of the Japanese guidelines for paroxysmal nocturnal hemoglobinuria (PNH) introduced refined diagnostic criteria and a new classification of disease severity, marking a significant advance in the clinical approach to this condition. Notably, this revision articulated 10 clinical questions designed to provide a thorough framework for addressing key aspects of PNH management. This includes guidance on interpreting diagnostic flowcharts and broader clinical considerations such as treatment approaches and individual patient circumstances. Following the guideline update, innovative therapeutic agents, including the complement C3 inhibitor pegcetacoplan, the factor D inhibitor danicopan, a novel C5 inhibitor crovalimab and the factor B inhibitor iptacopan have been approved in Japan. Although consistent mitigation of intravascular hemolysis remains the principal therapeutic goal in PNH management, there is a recognized need to refine approaches for managing residual anemia and fatigue, with future strategies likely to be informed by emerging real-world evidence.

The phenotypic characteristics and course of chronic obstructive pulmonary disease (COPD) and their association with serum complement C3 levels

The phenotypic characteristics and course of chronic obstructive pulmonary disease (COPD) and their association with serum complement C3 levels

Prototype Salivary Assay for Quantification of Two Biomarkers for In Vitro Diagnosis of Endometriosis.

Endometriosis, a very common disease in women, is characterized by endometrial structures outside the uterine cavity. The lack of a reliable noninvasive diagnostic test and the often nonspecific symptoms of this pathology are responsible for the delay in definitive diagnosis of this disease. Recently, through a proteomics approach, our research group has identified two potential diagnostic markers for endometriosis in serum (Zn-alpha2-glycoprotein and complement C3 precursor). In this article, we describe the experimental conditions of a simple ELISA for rapid quantification of these two biomarkers in the saliva of patients with endometriosis. Finally, preliminary experiments on a small cohort of patients and controls have confirmed the potential diagnostic value of this assay.

Multifaktorska etiologija atipičnog hemolitičko uremijskog sindroma - prikaz slučaja

Abstract: Introduction: Hemolytic uremic syndromes are characterized by the simultaneous occurrence of hemolytic anemia, microangiopathy, thrombocytopenia, and acute renal insufficiency. In terms of the clinical prodrome, they can be classified as typical, which is more common and occurs in 90% of cases, often preceded by diarrheal syndrome induced by enterohemorrhagic Escherichia coli. Alternatively, there is an atypical and rarer form associated with pneumococcal infection, dysregulation of the alternative complement pathway, and cases involving the use of cyclosporine. Hemolytic anemia is confirmed in laboratory analyses (presence of fragmented red blood cells, decreased hemoglobin, undetectable haptoglobin values, and elevated LDH values), along with thrombocytopenia and an increase in nitrogenous substances (urea and creatinine). Case report: The report details the case of an 18-month-old girl who experienced acute renal insufficiency subsequent to a respiratory infection. Ten days preceding admission, the patient exhibited nasal discharge, and during the seven days leading up to hospitalization, she presented with fever. Furthermore, two days prior to admission, the onset of persistent vomiting and abdominal pain occurred. Suspected of bowel intussusception, the patient underwent a surgical assessment where acute surgical pathology was ruled out. The absence of urination, coupled with heightened urea and creatinine levels, prompted consideration of hemolytic-uremic syndrome, later confirmed as atypical during hospitalization. This was grounded in the clinical presentation, devoid of diarrhea syndrome but marked by nasal discharge over the preceding ten days. The administration of fresh frozen plasma yielded no improvement, and there were decreased values of the C3 complement component, H factor, and reduced ADAMTS13 activity. The lack of verotoxins from enterohemorrhagic Escherichia coli further supported the diagnosis of atypical hemolytic-uremic syndrome. After the first dose of eculizumab, a terminal complement C5 component inhibitor, the girl recovered renal function and established diuresis. Conclusion: The prompt diagnosis of atypical hemolytic-uremic syndrome is challenging due to nonspecific symptoms like nasal discharge, vomiting, fatigue, and abdominal pain. Laboratory analyses, lacking specific criteria, make it difficult to conclusively identify aHUS at the disease's onset. In Serbia, pneumococcal immunization is recommended as a preventive measure, administered through a conjugated vaccine in three doses starting from the second month of life. Rapid and accurate differentiation between typical and atypical HUS is crucial for effective treatment and prognosis. Typical HUS requires hemodialysis and plasmapheresis, whereas atypical HUS is managed with plasmapheresis, immunosuppressive therapy, and eculizumab. Administering eculizumab heightens the risk of meningococcal infection by inhibiting the C5 complement component. Therefore, it is crucial not to disregard the importance of meningococcal immunization.

The role of IgG4 in systemic lupus erythematosus: Implications for pathogenesis and therapy.

Immunoglobulin (Ig) G4 has a distinctive nature, and its involvement in autoimmune disorders is a subject of ongoing debate and uncertainty. A growing body of evidence indicates that IgG4 may play a pathogenic role in the development of systemic lupus erythematosus (SLE).The IgG4 autoantibodies have the capability to bind autoantigens in a competitive manner with other Ig classes, thereby forming immune complexes (ICs)that are noninflammatory in nature. This is due to the low affinity of IgG4 for both the Fc receptors and the C1 complement molecule, which results in a diminished inflammatory response in individuals with SLE. The present study aims to elucidate the significance of IgG4 in SLE. The present discourse pertains to the nascent and suggested modalities through which IgG4 might participate in the pathogenesis of SLE and the potential ramifications for therapeutic interventions in SLE.

Complement components regulates ferroptosis in CVB3 viral myocarditis by interatction with TFRC

BackgroundDysregulated cell death machinery and an excessive inflammatory response in Coxsackievirus B3(CVB3)-infected myocarditis are hallmarks of an abnormal host response. Complement C4 and C3 are considered the central components of the classical activation pathway and often participate in the response process in the early stages of virus infection. MethodsIn our study, we constructed a mouse model of CVB3-related viral myocarditis via intraperitoneal injection of Fer-1 and detected myocarditis and ferroptosis markers in the mouse myocardium. Then, we performed co-IP and protein mass spectrometry analyses to explore which components interact with the ferroptosis gene transferrin receptor (TFRC). Finally, functional experiments were conducted to verify the role of complement components in regulating ferroptosis in CVB3 infection. ResultsIt showed that the ferroptosis inhibitor Fer-1 could alleviate the inflammation in viral myocarditis as well as ferroptosis. Mechanistically, during CVB3 infection, the key factor TFRC was activated and inhibited by Fer-1. Fer-1 effectively prevented the consumption of complement C3 and overload of the complement product C4b. Interestingly, we found that TFRC directly interacts with complement C4, leading to an increase in the product of C4b and a decrease in the downstream complement C3. Functional experiments have also confirmed that regulating the complement C4/C3 pathway can effectively rescue cell ferroptosis caused by CVB3 infection. ConclusionsIn this study, we found that ferroptosis occurs through crosstalk with complement C4 in viral myocarditis through interaction with TFRC and that regulating the complement C4/C3 pathway may rescue ferroptosis in CVB3-infected cardiomyocytes.

Observational study of blood complement levels of components before infusion

To investigate the changes in complement content in component blood before clinical transfusion. According to different preparation processes, storage temperatures and time periods, 180 specimens of plasma from the same source of 20 people were left at different stages of the preparation process. Homologous specimens were concentrated in the same batch of experiments to observe the changes in complement C3 and C4 content under different storage temperature and process stage grouping conditions. Using the same specimen to detect C3 and C4 content, the detection results of homologous specimens were sorted into nine groups according to different storage temperatures and preparation process stages for comparison.and there is no significant difference between simple -40°C and -60°C storage at different temperatures. Storage at 4°C for 7 days can significantly reduce complement content. Virus inactivation preparation process can significantly reduce complement content. Repeated freezing and thawing during the processing of frozen plasma can change complement content. Correlation analysis of complement C3 and C4 content determination experiments showed that the changes of the two under different conditions such as temperature, preparation process and storage time were significantly positively correlated. The storage temperature and storage time of frozen plasma, repeated freezing and thawing, centrifugal concentration and light inactivation can affect the complement content.

Identification, diversity, and evolution analysis of thioester-containing protein family in Pacific oyster (Crassostrea gigas) and immune response to biotic and abiotic stresses

Thioester-containing proteins (TEPs) play a vital role in the innate immune response to biotic and abiotic stresses. In this study, the TEPs in C. gigas were identified, and their gene structure, phylogenetic relationships, collinearity relationships, expression profiles, sequence diversity, and alternative splicing were analyzed. Eight Tep genes were identified in C. gigas genome. Functional analysis and evolutionary relationships indicated a high level of homology to other mollusks TEPs. The transcriptome quantitative analysis results showed that the Tep genes in C. gigas respond to heat stress and Vibrio stress. Alternative splicing analysis revealed four Tep genes (designated A2M_1, CD109_3, CD109_5, complement C3) encode multiple alternative splice variants. Analysis of gene structure and multiple alignments revealed that seven CD109_5 variants are produced through the alternative splicing of the 19th exon, which encodes the highly variable central region. Sequence diversity analysis revealed thirteen missense variants within the 19th exon region of these seven CD109_5 alternative splice variants. Furthermore, the differential alternative splicing analysis showed significant induction of CD109_5, A2M_1 and A2M_2 variants after infection with V. parahaemolyticus. This study explores the Tep genes of C. gigas, providing insights into the molecular mechanisms underlying the involvement of C. gigas TEPs in innate immunity.

Use of cardiac troponin I, lactic acid, procalcitonin, and serum complement C3 as prognostic indicators in patients with sepsis

Sepsis is a heterogeneous syndrome caused by the immune response to severe infection. This study aimed to investigate the value of cardiac troponin I, lactic acid, procalcitonin, and serum complement C3 levels for predicting death in patients with sepsis. Patients with sepsis who were hospitalized in the Department of Critical Care Medicine at our hospital between June 2017 and October 2022 were included in this retrospective study and divided into a survival group and a death group according to their survival status after 28 days. The Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment (SOFA) scores, and levels of cardiac troponin I, lactic acid, procalcitonin, and serum complement C3 were measured. A total of 516 patients were included in the analysis. Multivariable analysis showed that the APACHE II score (P < .001), SOFA score (P < .001), and cardiac troponin I (P < .001), lactic acid (P = .002), procalcitonin (P < .001), and serum complement C3 (P = .01) levels were independent predictors of sepsis death. The area under the receiver operating characteristic curve (AUC) was 0.882 (95% CI: 0.794–0.941) in patients with sepsis predicted using a combination of cardiac troponin I, lactic acid, procalcitonin, and serum complement C3 levels, which was better than the predictive value of cardiac troponin I (AUC: 0.734, 95% CI: 0.628–0.824), lactic acid (AUC: 0.686, 95% CI: 0.576–0.781), procalcitonin (AUC: 0.727, 95% CI: 0.620–0.817), or serum complement C3 (AUC: 0.684, 95% CI: 0.575–0.780) alone. Cardiac troponin I, lactic acid, and procalcitonin levels are independent predictors of death, whereas serum complement C3 protects against death in patients with sepsis. The combination of cardiac troponin I, lactic acid, procalcitonin, and serum complement C3 levels has a better predictive value for death than any single measure alone in patients with sepsis.

Peripheral Inflammatory and Immune Landscape in Multiple System Atrophy: A Cross-Sectional Study.

Neuroinflammation might contribute to the pathogenesis of multiple systemic atrophy (MSA). However, specific alterations in the peripheral inflammatory and immune profiles of patients with MSA remain unclear. To determine the peripheral inflammatory and immune profiles of patients with MSA and their potential value as biomarkers for facilitating clinical diagnosis and monitoring disease severity. This cross-sectional study included 235, 240, and 235 patients with MSA, patients with Parkinson's disease (PD), and healthy controls (HCs), respectively. Inflammatory and immune parameters were measured in peripheral blood, differences between groups were assessed, and clusters were analyzed. Associations between the parameters and clinical characteristics of MSA were assessed using Spearman and partial correlation analyses. Significant differences were observed especially in monocytes, neutrophils-to-lymphocyte ratio (NLR) and neutrophils-to-lymphocyte ratio (MPV) between MSA patients and HCs (P < 0.01). Monocytes and uric acid (UA) levels were also significantly different between the MSA and PD patients (P < 0.05). The combination of NLR and MPV distinguished MSA-P patients from HCs (areas under the curve = 0.824). In addition, complement components C4 and C3 were significantly correlated with the Scale Outcomes in PD for Autonomic Symptoms and Wexner scale, whereas immunoglobulin G (IgG) was significantly correlated with scores of Unified Multiple System Atrophy Rating Scale (P < 0.05). In MSA patients, monocytes, NLR and MPV might serve as potential diagnostic biomarkers, whereas MLR, C3, C4, and IgG significantly correlate with disease severity. © 2023 International Parkinson and Movement Disorder Society.

Reduction of Complements C3 and C4 in Saliva and Serum of Patients Suffering SARS-CoV-2 Infection

Background: The complement system plays a role in chronic immune activation during viral infections. Objectives: This study aimed to evaluate the levels of saliva and serum complements C3 and C4 in coronavirus disease 2019 (COVID-19) patients and healthy individuals. Methods: This cross-sectional study included 36 severe and 22 critical COVID-19 hospitalized patients and 22 healthy individuals. Serum and unstimulated salivary C3 and C4 levels were assessed using the immunoturbidimetric method and analyzed using one-way analysis of variance (ANOVA) with the Student-Newman-Keuls test as a post hoc analysis. Results: Salivary C3 and C4 levels were significantly lower in patients with severe and critical COVID-19 than in healthy individuals. There was no significant difference between the groups infected with severe and critical COVID-19. Serum C3 and C4 levels were lower in critical COVID-19 patients than in healthy individuals; nevertheless, no significant difference was observed between severe COVID-19 patients and healthy individuals. Additionally, serum C4 levels were lower in critical COVID-19 patients than in severe COVID-19 patients. Conclusions: It appears that serum and salivary C3 and C4 levels decrease in patients with COVID-19 infection.

Novel insights into DEHP-induced zebrafish spleen damage: Cellular apoptosis, mitochondrial dysfunction, and innate immunity

DEHP (Di(2-ethylhexyl) phthalate) is the most abundant phthalate component detected in environmental samples as it is widely used in the manufacturing of children's toys, medical devices and furniture. Due to its wide prevalence and propensity to accumulate in the food chain, significant concerns have risen about the safety profile of DEHP. Here, we used a zebrafish model to investigate the toxicity mechanisms of DEHP. Our results indicated that exposure to DEHP altered the ROS content in zebrafish spleen and inhibited the activities of antioxidant enzymes SOD and CAT, detoxification enzyme GSH-Px and induced histopathological damage. In addition, elucidated the mechanism of DEHP significantly promoted apoptosis and caused damage in spleen cells through the bax/bcl-2 pathway. Further genetic testing demonstrated significant alterations in mitochondrial biogenesis, fission, and fusion-related genes and suggested potential mechanistic pathways, including GM10532/m6A/FIS1 axis, the STAT3/POA1 axis, and the NFR1/TFAM axis. Serological and genomic analysis indicated that DEHP exposure activated the C3 complement cascade immune pathway and interfered with innate immune function. IBRv2 analysis proposes that innate immunity may serve as a signal indicator of early toxic responses to DEHP pollutants. This study provided comprehensive cellular and genetic data for DEHP toxicity studies and emphasized the need for future management and remediation of DEHP contamination. It also provides data to specifically support the health risk assessments of DEHP, as well as contributing to broader health and environmental research.

LONGITUDINAL CHANGES IN PROTEOMIC BIOMARKERS IN ALZHEIMER’S DISEASE AND CARDIOVASCULAR DISEASE

Abstract Alzheimer’s disease (AD) and cardiovascular diseases (CVDs) commonly co-occur in older adults. This correlation prompts an investigation into the potential shared risk factors linking AD and CVDs, and the potential direct causative role of cardiovascular risk factors in AD. The cohort comprised 566 older adults including 111 individuals with AD, 58 without AD, 383 with mild cognitive impairment (MCI), 410 with CVD and 156 without CVD from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). The multivariable linear mixed model (LMM) was used to investigate the associations of AD and CVD on longitudinal changes of 146 proteomic biomarkers (measured at baseline and 12-month follow-up), while adjusted for age, gender, education, racial groups, and APOE-ε4 alleles. The LMM showed that AD and CVD were associated with longitudinal changes in 48 and 46 proteomic biomarkers, respectively (p&amp;lt; 0.05). Interestingly, both AD and CVD were associated with longitudinal changes in 14 proteomic biomarkers (A1Micro, ApoH, B2M, BNP, Complement C3, Cystatin C, KIM1, NGAL, PPP, TIM1, THP, TFF3, TM, and VEGF). Furthermore, the single biggest risk gene for sporadic AD, APOE-ε4 was associated with 22 proteomic biomarkers. Moreover, MCI and CVD were associated with 13 proteomic biomarkers (A1Micro, ApoD, AXL, BNP, Calcitonin, CD40, C-peptide, pM, PPP, THP, TNFR2, TTR, and VEGF), while MCI, CVD and APOE-ε4 were associated with four proteomic biomarkers (A1Micro, Calcitonin, THP, and TNFR2). This study provides valuable insights into the shared and distinct pathophysiological mechanisms at play, offering a stepping-stone towards a deeper comprehension of the interrelationship between AD and CVDs.