Component 3 Levels Research Articles

C3 glomerulonephritis with genetically confirmed C3 deficiency in a pediatric patient: a case report

Complement component 3 glomerulonephritis (C3GN) is a rare kidney disease characterized by complement dysregulation that results in prominent complement component 3 (C3) deposition in the kidneys. The clinical course of C3GN varies from mild hematuria to progressive chronic kidney disease. In most patients, C3GN is driven by acquired factors, namely, autoantibodies that target C3 or C5 convertases. Genetic variations in complement-related genes are less frequent. We report the case of a 9-yearold Korean boy who presented with microscopic hematuria and a persistently low C3 level and had biopsy findings of C3GN, with the presence of a C3 gene mutation: a frameshift mutation associated with C3 deficiency. However, the patient did not exhibit any other symptoms of complement deficiency. Direct DNA sequencing of his family members revealed the same genetic mutation in his father and older brother. This case report is significant because there are very few such reports worldwide concerning gene mutations related to C3 deficiency to be discovered in patients with C3GN. Explaining C3GN pathogenesis is challenging; therefore, additional research is required in the future.

Serum proteomic analysis uncovers novel serum biomarkers for depression.

The identification of depression primarily relies on the clinical symptoms and psychiatric evaluation of the patient, in the absence of objective and quantifiable biomarkers within clinical settings. This study aimed to explore potential serum biomarkers associated with depression. Serum samples from a training group comprising 48 depression patients and 48 healthy controls underwent proteomic analysis. Magnetic bead-based weak cation exchange (MB-WCX) and MALDI-TOF-MS were used in combination. To screen the differential peaks, ClinProTools software was employed. The proteins were identified using LC-MS/MS. ELISA was employed to confirm the expression of entire protein in the serum of the verification cohort, which encompassed 48 individuals who had been diagnosed with Depression and 48 healthy controls who were collected prospectively. Subsequently, logistic regression analysis was conducted to determine the diagnostic efficacy of the aforementioned predictors. Five potential biomarker peaks indicating depression were identified in serum samples (peak 1, m/z: 1868.21; peak 2, m/z: 1062.35; peak 3, m/z: 1452.12; peak 4, m/z: 1208.72; peak 5, m/z: 1619.58). All of these peaks had higher expression in the pre-therapy group and were confirmed to be Tubulin beta chain (TUBB), Inter-alpha-trypsin inhibitor heavy chain H4 (ITIH4), Complement component 3 (C3), and Complement C4A precursor (C4A) by ELISA validation. Multivariate logistic regression analysis revealed that serum levels of TUBB, ITIH4, C3, and C4A were significant independent risk factors for the development of depression. Depression is a prevalent psychiatric condition. Timely detection is challenging, resulting in poor prognoses for patients. Our study on plasma proteomics for depression demonstrated that TUBB, ITIH4, C3, and C4A differentiate between depression patients and healthy controls. The proteins that were identified could potentially function as biomarkers for the diagnosis of depression. Pinpointing these biomarkers could enable early identification of depression, which would advance precise treatment.

The role of MASP1 in the complement system and expression characteristics in response to GCRV infection in grass carp

The grass carp (Ctenopharyngodon idella) constitutes a significant economic resource within the aquaculture sector of our nation, yet it has been chronically afflicted by the Grass Carp Reovirus (GCRV) disease. The complement system, a vital component of fish's innate immunity, plays a crucial role in combating viral infections. This research investigates the potential role of MASP1, a key molecule in the lectin pathway of the complement system, in the GCRV infection in grass carp. An analysis of the molecular characteristics of MASP1 in grass carp revealed that its identity and similarity percentages range from 35.10 to 91.00 % and 35.30–91.00 %, respectively, in comparison to other species. Phylogenetically, MASP1 in C. idella aligns closely with species such as Danio rerio, Cyprinus carpio, and Carassius carassius, exhibiting chromosomal collinearity with the zebrafish. Subsequent tissue analysis in both healthy and GCRV-infected grass carp indicated that MASP1's basal expression was predominantly in the liver. Post-GCRV infection, MASP1 expression in various tissues exhibited temporal variations: peaking in the liver on day 5, spleen on day 7, and kidney on day 14. Furthermore, employing Complement Component 3 (C3) as a benchmark for complement system activation, it was observed that MASP1 could activate and cleave C3 to C3b. MASP1 also demonstrated an inhibitory effect on GCRV replication (compared with the control group, VP2 and VP7 decreased by 6.82-fold and 4.37-fold) and enhanced the expression of antiviral genes, namely IRF3, IRF7 and IFN1 (compared with the control group, increased 2.25-fold, 45.38-fold and 22.37-fold, respectively). In vivo protein injection experiments substantiated MASP1's influence on the relative mRNA expression levels of C3 in various tissues and its protein expression in serum. This study also verified that C3 could modulate the expression of antiviral genes such as IFN1 and IRF3.

Normobaric hyperoxia alleviates complement C3-mediated synaptic pruning and brain injury after intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) is a common cerebrovascular disease, and the complement cascade exacerbates brain injury after ICH. As the most abundant component of the complement system, complement component 3 (C3) plays essential roles in all three complement pathways. However, the effects of C3 on neurological impairment and brain injury in ICH patients and the related mechanism have not been fully elucidated. Normobaric hyperoxia (NBO) is regarded as a treatment for ICH patients, and recent clinical studies also have confirmed the neuroprotective role of NBO against acute ICH-mediated brain damage, but the underlying mechanism still remains elusive. In the present study, we investigated the effects of complement C3 on NBO-treated ICH patients and model mice, and the underlying mechanism of NBO therapy in ICH-mediated brain injury. Hemorrhagic injury resulted in the high plasma C3 levels in ICH patients, and the plasma C3 levels were closely related to hemorrhagic severity and clinical outcomes after ICH. BO treatment alleviated neurologic impairments and rescued the hemorrhagic-induced increase in plasma C3 levels in ICH patients and model mice. Moreover, the results indicated that NBO exerted its protective effects of on brain injury after ICH by downregulating the expression of C3 in microglia and alleviating microglia-mediated synaptic pruning. Our results revealed that NBO exerts its neuroprotective effects by reducing C3-mediated synaptic pruning, which suggested that NBO therapy could be used for the clinical treatment of ICH.

Gut complement induced by the microbiota combats pathogens and spares commensals

Canonically, the complement system is known for its rapid response to remove microbes in the bloodstream. However, relatively little is known about a functioning complement system on intestinal mucosal surfaces. Herein, we report the local synthesis of complement component 3 (C3) in the gut, primarily by stromal cells. C3 is expressed upon commensal colonization and is regulated by the composition of the microbiota in healthy humans and mice, leading to an individual host's specific luminal C3 levels. The absence of membrane attack complex (MAC) components in the gut ensures that C3 deposition does not result in the lysis of commensals. Pathogen infection triggers the immune system to recruit neutrophils to the infection site for pathogen clearance. Basal C3 levels directly correlate with protection against enteric infection. Our study reveals the gut complement system as an innate immune mechanism acting as a vigilant sentinel that combats pathogens and spares commensals.

Cell-autonomous regulation of complement C3 by factor H limits macrophage efferocytosis and exacerbates atherosclerosis

Complement factor H (CFH) negatively regulates consumption of complement component 3 (C3), thereby restricting complement activation. Genetic variants in CFH predispose to chronic inflammatory disease. Here, we examined the impact of CFH on atherosclerosis development. In a mouse model of atherosclerosis, CFH deficiency limited plaque necrosis in a C3-dependent manner. Deletion of CFH in monocyte-derived inflammatory macrophages propagated uncontrolled cell-autonomous C3 consumption without downstream C5 activation and heightened efferocytotic capacity. Among leukocytes, Cfh expression was restricted to monocytes and macrophages, increased during inflammation, and coincided with the accumulation of intracellular C3. Macrophage-derived CFH was sufficient to dampen resolution of inflammation, and hematopoietic deletion of CFH in atherosclerosis-prone mice promoted lesional efferocytosis and reduced plaque size. Furthermore, we identified monocyte-derived inflammatory macrophages expressing C3 and CFH in human atherosclerotic plaques. Our findings reveal a regulatory axis wherein CFH controls intracellular C3 levels of macrophages in a cell-autonomous manner, evidencing the importance of on-site complement regulation in the pathogenesis of inflammatory diseases.

Rosmarinic acid alone or in combination with Lactobacillus rhamnosus ameliorated resistance to ammonia stress in the rainbow trout, Oncorhynchus mykiss: growth, immunity, antioxidant defense and liver functions

Abstract Rosmarinic acid (RS) and Lactobacillus rhamnosus (LR) were added singularly or in combination to rainbow trout (Oncorhynchus mykiss) diets to test their efficacy in the protection against ammonia stress. Fish (31.4±0.6 g) were randomly allocated to six groups in three replicates, as follows: T1: basic food as control, T2: LR with a concentration of 1.5 × 108 CFU /g, T3: LR with a concentration of 3 × 108 CFU/g, T4: 1 g RS/kg, T5: 3 g RS/kg, and T6: 1.5 × 108 CFU/g LR + 1 g RS/kg and T7: 3 × 108 CFU/g LR + 3 g RS/kg. After 60 days feeding, fish were exposed to ammonia stress. After the feeding period, the supplemented fish had the highest final body weight (FW), weight gain (WG), and specific growth rate (SGR), and the lowest feed conversion ratio (FCR) as compared with the control group (P<0.05). Amylase, protease and lipase activities were noticed markedly higher in fish supplemented with 1.5 × 108 CFU/g LR + 1 g RS/kg and 1.5 × 108 CFU/g LR diets compared to the control (P<0.05). Generally, fish in supplemented diets, particularly T2 and T6 groups, had the highest lysozyme, alternative complement activity (ACH50), total Ig, nitroblue tetrazolium test (NBT), myeloperoxidase (MPO), complement component 3 (C3), complement component 4 (C4), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx). On the other hand, T2 and T6 groups had the lowest malondialdehyde (MDA), glucose, and cortisol concentrations as well as alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH) enzyme levels when compared with the control (P<0.05). After ammonia stress, fish in the supplemented groups, particularly T2 and T6, generally showed significantly higher values of lysozyme, ACH50, total Ig, NBT, MPO, C3, C4, SOD, CAT, GPx and lower levels of MDA, glucose, cortisol, ALT, ALP, LDH when compared with the control (P<0.05). In conclusion, a combined administration of RS and L. rhamnosus effectively improved growth performance and health status as well as enhanced the resistance of rainbow trout against ammonia toxicity.

Experimental Investigation of Immunoglobulin and Complement Concentrations in Exposure to IVIG, HBIG, Rituximab, Tocilizumab, and Bevacizumab

Background: Immunoglobulins (Igs) are produced in plasma cells in response to glycoprotein like immunogens and they are also used as therapeutics in the pharmaceutical industry. It may be important to know the effects of therapeutic Igs on Ig levels during therapy to eliminate any misconceptions about the immunity of patients. Objective: This study aimed to investigate the effects of monoclonal antibody (mAb) derivative drugs and therapeutic antibody (intravenous Ig [IVIG] and hepatitis B immune globulin [HBIG]) treatments on blood IgG, IgA, IgM, IgE, complement component 3 (C3), and complement component 4 (C4) levels. Methods: N Protein Control SL / Low (Siemens, Marburg, Germany, Lot: 084654) was used as the control solution. Aliquots of IVIG, HBIG, rituximab, tocilizumab, and bevacizumab (20 µL) were added to 180 µL of the control solution, and the solutions were vortexed (5 s). The samples were studied using a Dade Behring BN II (Siemens, Marburg, Germany) nephelometer. All measurements were repeated three times by performing the same process in which distilled water (20 µL) was added to the control solution to determine the target value, and the average values were taken. The bias formula was used to calculate the amount by which the results deviated from the target value. Results: IVIG caused the greatest deviation (45.97%) to IgG levels. HBIG, rituximab, tocilizumab, and bevacizumab caused the IgG level to deviate by 0.81%, 9.68%, 27.42%, and 30.65%, respectively. In the IgA test, tocilizumab increased the reading by 8.66%, while the other therapeutics caused reductions in the reading, with the smallest and largest changes caused by HBIG (-0.93%) and bevacizumab (-4.98%). Tocilizumab increased the IgE level by 0.48%, and rituximab and bevacizumab reduced the IgE level by - 0.21% with -8.47%, respectively. Tocilizumab, IVIG, and HBIG caused 1.41%, 2.70%, and 4.32% deviations, respectively, in the C3 levels. Whereas bevacizumab (-1.08%) and rituximab (-5.41%) caused reductions in the C3 levels. Tocilizumab, HBIG, rituximab, IVIG, and bevacizumab caused deviations of 0.87%, -2.31%, -3.76%, -6.36%, -8.38%, respectively, in the C4 levels. Conclusion: Deviations in measured IgG levels after therapeutic Ig and mAb infusions may cause errors in clinical decisions. It is recommended that Ig levels be measured before infusion or when the therapeutic drug has been eliminated from the blood.

High plasma complement C4 levels as a novel predictor of clinical outcome in intracerebral hemorrhage.

The complement cascade is activated and contributes to the brain injury after intracerebral hemorrhage (ICH). Complement component 4 (C4), an important component of complement cascade, has been associated with severity of neurological impairment that occurs during ICH. However, the correlation of plasma complement C4 levels with hemorrhagic severity and clinical outcome in ICH patients has not been reported. This study is a monocentric, real-world, cohort study. In this study, we measured the plasma complement C4 levels of 83 ICH patients and 78 healthy controls. The hematoma volume, the National Institutes of Health Stroke Scale (NIHSS) score, the Glasgow Coma Scale (GCS) score, and the permeability surface (PS) were used to assess and quantify neurological deficit following ICH. Logistic regression analysis was configured to determine the independent relation of plasma complement C4 levels to hemorrhagic severity and clinical outcomes. The contribution of complement C4 to secondary brain injury (SBI) was assessed by changes in plasma C4 levels between admission and at day 7 after ICH. There was a significant elevation of plasma complement C4 levels in ICH patients than in healthy controls (40.48 ± 1.07 vs. 35.25 ± 0.60, p < 0.0001), and the plasma complement C4 levels were closely related to the hemorrhagic severity. Moreover, plasma complement C4 levels of patients were positively correlated with the hematoma volume (r = 0.501, p < 0.001), NIHSS score (r = 0.362, p < 0.001), the GCS score (r = -0.490, p < 0.001), and PS (r = 0.683, p = 0.045) following ICH. Logistic regression analysis also confirmed that patients with high plasma complement C4 levels show a poor clinical outcome after ICH (p < 0.001). Meanwhile, the elevated plasma levels at day 7 after ICH indicated the correlation of complement C4 with SBI (p < 0.01). Plasma complement C4 levels are significantly elevated in ICH patients and positively correlated with the illness severity. Thus, these findings highlight the importance of complement C4 in brain injury after ICH and provide a novel predictor of clinical outcome for this disease.

Value of complement component 3 in predicting the prognosis of children with sepsis

To investigate changes in complement component 3 (C3) levels in children with sepsis and its correlation with the severity of sepsis and to explore the significance of C3 in predicting mortality in children with sepsis. A retrospective analysis was conducted on 529 children with sepsis who were admitted to the Pediatric Intensive Care Unit in Hunan Children's Hospital between November 2019 and September 2021. The children were categorized into two groups based on their prognosis at day 28 after sepsis diagnosis: the survival group (n=471) and the death group (n=58). Additionally, the children were divided into normal C3 group (n=273) and reduced C3 group (n=256) based on the median C3 level (0.77 g/L) within 24 hours of admission. Clinical data and laboratory markers were compared between the groups, and assess the predictive value of C3 levels in relation to sepsis-related mortality. The death group exhibited significantly lower C3 levels compared to the survival group (P<0.05). Multivariate logistic regression analysis revealed that higher pediatric Sequential Organ Failure Assessment (p-SOFA) scores and lower C3 levels were closely associated with sepsis-related mortality (P<0.05). The receiver operating characteristic curve (ROC) analysis demonstrated that combination of p-SOFA scores and C3 levels yielded an area under the ROC curve of 0.852, which was higher than that of each indicator alone (P<0.05). C3 can serve as an indicator to assess the severity and prognosis of sepsis in children. The combination of p-SOFA scores and C3 levels holds good predictive value for mortality in children with sepsis.

Homeostatic, Non-Canonical Role of Macrophage Elastase in Vascular Integrity.

Matrix metalloproteinase (MMP)-12 is highly expressed in abdominal aortic aneurysms and its elastolytic function has been implicated in the pathogenesis. This concept is challenged, however, by conflicting data. Here, we sought to revisit the role of MMP-12 in abdominal aortic aneurysm. Apoe-/- and Mmp12-/-/Apoe-/- mice were infused with Ang II (angiotensin). Expression of neutrophil extracellular traps (NETs) markers and complement component 3 (C3) levels were evaluated by immunostaining in aortas of surviving animals. Plasma complement components were analyzed by immunoassay. The effects of a complement inhibitor, IgG-FH1-5 (factor H-immunoglobulin G), and macrophage-specific MMP-12 deficiency on adverse aortic remodeling and death from rupture in Ang II-infused mice were determined. Unexpectedly, death from aortic rupture was significantly higher in Mmp12-/-/Apoe-/- mice. This associated with more neutrophils, citrullinated histone H3 and neutrophil elastase, markers of NETs, and C3 levels in Mmp12-/- aortas. These findings were recapitulated in additional models of abdominal aortic aneurysm. MMP-12 deficiency also led to more pronounced elastic laminae degradation and reduced collagen integrity. Higher plasma C5a in Mmp12-/- mice pointed to complement overactivation. Treatment with IgG-FH1-5 decreased aortic wall NETosis and reduced adverse aortic remodeling and death from rupture in Ang II-infused Mmp12-/- mice. Finally, macrophage-specific MMP-12 deficiency recapitulated the effects of global MMP-12 deficiency on complement deposition and NETosis, as well as adverse aortic remodeling and death from rupture in Ang II-infused mice. An MMP-12 deficiency/complement activation/NETosis pathway compromises aortic integrity, which predisposes to adverse vascular remodeling and abdominal aortic aneurysm rupture. Considering these new findings, the role of macrophage MMP-12 in vascular homeostasis demands re-evaluation of MMP-12 function in diverse settings.

Single or combined consumption of resveratrol and the probiotic, Lactobacillus acidophilus attenuate the effects of crowding stress on growth, immune characteristics, and antioxidant defense in the common carp, (Cyprinus carpio)

In the present study, dietary resveratrol (RE) and Lactobacillus acidophilus (LAB) were individually or combined added to the diet of common carp (Cyprinus carpio) to protect against crowding stress. Fish (30.16 ± 0.7; Mean ± SE) were randomly allocated to seven groups in three replicates, as follows: T1: basic food as control, T2: LAB with a concentration of 1.5 × 107 CFU/g, T3: LAB with a concentration of 3 × 107 CFU/g, T4: 300 mg resveratrol/kg, T5: 600 mg resveratrol/kg, and T6: 1.5 × 107 CFU/g + 300 mg resveratrol/kg and T7: 3 × 107 CFU/g + 600 mg resveratrol/kg. After 60 days feeding, the supplemented fish had the highest final body weight (FBW), weight gain (WG), and specific growth rate (SGR), and the lowest feed conversion ratio (FCR) as compared with the control group (P < 0.05). The activities of amylase, protease and lipase were noticed markedly higher in fish supplemented with 1.5 × 107 CFU/g + 300 mg resveratrol/kg and 1.5 × 107 CFU/g diets compared to the control (P < 0.05). Generally, fish in supplemented diets, particularly T2 and T6 groups, had the highest lysozyme, alternative complement activity (ACH50), total immunoglobulin (Ig), nitroblue tetrazolium test (NBT), myeloperoxidase (MPO), complement component 3 (C3), complement component 4 (C4), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and lower levels of malondialdehyde (MDA), glucose, cortisol, alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH) when were compared with the control before crowding stress (P < 0.05). After crowding stress challenge, fish in the supplemented groups, particularly T2 and T6, generally showed significantly higher values of lysozyme, ACH50, total Ig, NBT, MPO, C3, C4, SOD, CAT, GPx and lower levels of MDA, glucose, cortisol, ALT, ALP, LDH when compared with the control (P < 0.05). Also, recovered fish in the control group demonstrated significantly declined levels of lysozyme, ACH50, total Ig, NBT, MPO, C3, C4, SOD, CAT, GPx and higher levels of MDA, glucose, cortisol, ALT, ALP, LDH as compared to other group (P < 0.05). In conclusion, a combined administration of RE and LAB effectively improved growth performance and health status as well as protected common carp against crowding stress.

Complement C3 Facilitates Stratification of Stages of Chronic Hepatitis B and Signifies Development of Acute-on-Chronic Liver Failure in Acute Decompensated Cirrhosis.

Patients with chronic hepatitis B (CHB) have a dynamic disease process and risk of end-stage liver disease. It is critical to unambiguously differentiate the stages of the disease and focus on therapy prior to onset of an irreversible clinical endpoint. We retrospectively analyzed a wide range of CHB patients at different stages. The predictive power of serum complement component 3 (C3) levels for the development of acute-on-chronic liver failure (ACLF) in patients with decompensated cirrhosis was established and validated. The decrease in serum C3 levels paralleled the severity of diseases related to hepatitis B virus. Patients with decompensated cirrhosis who developed ACLF had significantly lower serum C3 levels than others on admission (0.50 vs. 0.80g/L, P<0.001). Data analysis also revealed that low serum C3 was a significant risk factor for developing ACLF (hazard ratio=0.32, P<0.01). The area under the receiver operating characteristic curve (auROC) for serum C3 levels that predicted the development of ACLF in patients with decompensated cirrhosis was 0.90, which had sensitivity and specificity of 88.2% and 88.7%, respectively. A similar result was observed in the validation set (auROC=0.86 for predicting development of ACLF in patients with decompensated cirrhosis). Serum C3 levels are valuable in assessing the severity of CHB-related stages. Low C3 levels signifies the development of ACLF in patients with decompensated cirrhosis.

Mechanistic insight into female predominance in Alzheimer's disease based on aberrant protein S-nitrosylation of C3.

Protein S-nitros(yl)ation (SNO) is a posttranslational modification involved in diverse processes in health and disease and can contribute to synaptic damage in Alzheimer's disease (AD). To identify SNO proteins in AD brains, we used triaryl phosphine (SNOTRAP) combined with mass spectrometry (MS). We detected 1449 SNO proteins with 2809 SNO sites, representing a wide range of S-nitrosylated proteins in 40 postmortem AD and non-AD human brains from patients of both sexes. Integrative protein ranking revealed the top 10 increased SNO proteins, including complement component 3 (C3), p62 (SQSTM1), and phospholipase D3. Increased levels of S-nitrosylated C3 were present in female over male AD brains. Mechanistically, we show that formation of SNO-C3 is dependent on falling β-estradiol levels, leading to increased synaptic phagocytosis and thus synapse loss and consequent cognitive decline. Collectively, we demonstrate robust alterations in the S-nitrosoproteome that contribute to AD pathogenesis in a sex-dependent manner.

Association of complement components with the risk and severity of NAFLD: A systematic review and meta-analysis.

It is generally believed that complement system is strongly associated with the risk of nonalcoholic fatty liver disease (NAFLD). However, complement system contains a variety of complement components, and the relationship between complement components and the risk and severity of NAFLD is inconsistent. The aim of this meta-analysis was to evaluate the association of complement components with the risk and severity of NAFLD. We searched PubMed, Embase, Cochrane Library, Google Scholar, Scopus, and ZhiWang Chinese databases from inception to May 2022 for observational studies reporting the risk of NAFLD with complement components. Random-effects meta-analysis was used to obtain pooled estimates of the effect due to heterogeneity. We identified 18 studies with a total of 18560 included subjects. According to recent studies, levels of complement component 3 (C3) (mean difference (MD): 0.43, 95% confidence interval (CI) 0.26-0.60), complement component 4 (C4) (MD: 0.04, 95% CI 0.02-0.07), complement component 5(C5) (MD: 34.03, 95% CI 30.80-37.27), complement factor B (CFB) (MD: 0.22, 95% CI 0.13-0.31) and acylation stimulating protein (ASP) (standard mean difference (SMD): 5.17, 95% CI 2.57-7.77) in patients with NAFLD were significantly higher than those in the control group. However, no statistical significance was obtained in complement factor D (CFD) levels between NAFLD and non-NAFLD (MD=156.51, 95% CI -59.38-372.40). Moreover, the levels of C3, C5, CFB, and ASP in patients with moderate and severe NAFLD were significantly higher than those in patients with mild NAFLD. Except for C4 and CFD, the included studies did not explore the changes in the severity of NAFLD according to the concentration of C4 and CFD. This meta-analysis demonstrates that an increase in complement components including C3, C5, CFB, and ASP is associated with an increased risk and severity of NAFLD, indicating that they may be good biomarkers and targets for the diagnosis and treatment of NAFLD. PROSPERO [https://www.crd.york.ac.uk/PROSPERO/], identifier CRD42022348650.

Complement component 3 and complement factor H protein levels are altered in brain tissues from people with human immunodeficiency virus: A pilot study.

People with HIV (PWH) continue to suffer from dysfunction of the central nervous system, as evidenced by HIV-associated neurocognitive disorder (HAND), despite antiretroviral therapy and suppressed viral loads. As PWH live longer they may also be at risk of age-related neurodegenerative diseases such Alzheimer’s disease (AD) and its precursor, amnestic mild cognitive impairment (aMCI). The complement system is associated with deposition of AD-related proteins such as beta amyloid (Aβ), neuroinflammation, and neurological dysfunction in PWH. Complement component 3 (C3) is a key protagonist in the complement cascade and complement factor H (CFH) is an antagonist of C3 activity. We investigated the relationship between C3 and CFH levels in the brain and Aβ plaques and neurological dysfunction in 22 PWH. We analyzed by immunoblot C3 and CFH protein levels in frontal cortex (FC) and cerebellum (CB) brain specimens from PWH previously characterized for Aβ plaque deposition. C3 and CFH protein levels were then correlated with specific cognitive domains. C3 protein levels in the FC were significantly increased in brains with Aβ plaques and in brains with HAND compared to controls. In the CB, C3 levels trended higher in brains with Aβ plaques. Overall C3 protein levels were significantly higher in the FC compared to the CB, but the opposite was true for CFH, having significantly higher levels of CFH protein in the CB compared to the FC. However, only CFH in the FC showed significant correlations with specific domains, executive function and motor performance. These findings corroborate previous results showing that complement system proteins are associated with HAND and AD neuropathogenesis.

Effect of combined use of prednisone and immunosuppressive therapy in patients with systemic lupus erythematosus, and its influence on incidence of adverse reactions

Purpose: To study the effect of combined use of prednisone and immunosuppressive therapy for systemic lupus erythematosus (SLE), and its impact on the incidence of adverse reactions.Methods: In total, 90 SLE patients treated in Longhui People's Hospital between January 2019 and January 2020 were included in this study, and assigned to receive either prednisone (control group) or immunosuppressive therapy and prednisone (study group) via the sealed envelope method. Outcome measures include immunoglobulin measured by enzyme-linked immunosorbent assay (ELISA), complement component 3 (C3) and C4 determined by immunoturbidimetric method, inflammatory factors such as INF-α, IL-10, and IL-6 levels, and the incidence of drug reactions.Results: After treatment, the treatment group had higher levels of immunoglobulin indices and C3 and C4 levels than the control group (p &lt; 0.05). There were lower serum inflammatory factor levels in the treatment group than in the control group (p &lt; 0.05). Prednisone and immunosuppressive therapy resulted in higher treatment effectiveness and lower SLEDAI scores, versus prednisone alone (p &lt; 0.05).Conclusion: Prednisone and immunosuppressive therapy for SLE is safe, enhances treatment effectiveness, and improves clinical indicators in the patients. However, further trials are required prior to its application in clinical practice.

Complement component 3 haplotypes influence serum complement activity and milk production traits in Chinese Holstein cattle.

Complement component 3 (C3) is the key molecule of the three pathways of complement activation (alternative, classical, and lectin pathways), which are involved in phagocytosis, inflammation, and immunoregulation processes to destroy infectious microorganisms. In this study, three novel single-nucleotide polymorphisms (SNPs) (g.-1293C>G located in the 5'-flanking region, g.56T>C in exon I, and g.7017C>T in exon XII) of the C3 gene were detected using created restriction site polymerase chain reaction, restriction fragment length polymorphism, and DNA sequencing in 952 cattle from three Chinese breeds. The genotypes and haplotypes were analyzed to investigate the polymorphisms and their possible implications, with particular investigative focus on their associations with serum C3 level, complement hemolytic activity (CH50 and ACH50), and milk production traits. The g.56T>C SNP in exon I affected the serum ACH50 (P<0.01) and the milk somatic cell score (SCS) (P<0.05), and the g.7017C>T SNP in exon XII significantly affected the serum ACH50 values (P<0.01). Moreover, statistical analyses revealed that individuals with genotypic combination CCC/GCC showed significantly lower SCS and the lowest C3 concentration in serum compared with cows with CCC/GTT (P = 0.0007) and CTT/CTT (P = 0.0021); the individuals with CCC/CCT had significantly higher ACH50 values than those with CCC/CTC (P = 0.0008) and CTC/GTC (P = 0.001); cows with CCT/CTT had higher values of CH50 and 305-day milk yield (P>0.05). The C3 expression levels were significantly increased in lung and mammary tissues (P<0.05), while significantly decreased in heart, spleen, liver, and kidney tissues in mastitis cows compared with those in healthy animals (P<0.01), respectively. Bacterial counts of serum antibacterial activities were also completed to verify the effect of SNPs on resistance to mastitis pathogens. Genetically resistant cows (CCC/GCC) had serum with noticeably higher antibacterial activity against S. aureus and E. coli in vitro than the genetically susceptible CCC/GTT cows (P<0.05). Results from this study imply that the C3 gene plays a role in resistance to bacterial infection and that it can be used as a molecular marker for complement activity and traits related to milk production.

Loperamide-induced Constipation Activates Inflammatory Signaling Pathways in the Mid Colon of SD Rats Via Complement C3 and its Receptors.

Complement component 3 (C3) receptors play an important role as inflammatory mediators in the innate immune system, although their mechanisms were not well studied during constipation. The aim of this study is to investigate the regulatory role of C3 and its receptors' downstream signaling during constipation. Alterations in the C3, C3a receptor (C3aR), and C3b receptor (C3bR) expressions, PI3K/AKT pathway, RhoA/MLC pathway, MAP kinase pathway, and inflammatory cytokine expressions were measured in the mid colon of loperamide (Lop) treated SD rats. Lop treatment successfully induced constipation phenotypes, including decreased stool parameters and histological structure alterations. The expression levels of C3 were significantly increased, whereas expressions of C3aR and C3bR were decreased during Lop-induced constipation. Moreover, significant upregulation was observed in the phosphorylation levels of PI3K, AKT, and GSK3β in mid colons of Lop treated SD rats. The expression of RhoA and phosphorylation of MLC were also enhanced in the Lop treated group. Furthermore, a similar pattern was detected in the MAP kinase pathway and inflammatory cytokine expressions. Subsequent to the Lop treatment, the phosphorylation of ERK and p38, as well as the mRNA levels of NF-κB, TNF-α, IL-6 and IL-1α were remarkably increased in the mid colon. These results indicate that Lop-induced constipation is tightly linked to the downregulation of C3aR and C3bR expressions, and upregulation of the C3 and C3Rs downstream signaling pathway, including PI3K/AKT, RhoA/MLC, and MAP kinase pathways as well as inflammatory cytokine expressions in the mid colon of SD rats.

Effects of heat shock protein inducer on Hsp70 gene expression and immune parameters during Streptococcus iniae infection in a Persian sturgeon fry.

Heat shock proteins (HSPs) as stress-related factors play a fundamental role in innate and adaptive immune responses in fish, which can be considered as strong candidates for the development of new methods for fish disease prevention. It has been proven that Pro-Tex® as a heat shock protein inducer (HSPi) reduces harmful effects of cellular stress by increasing the Hsp70 protein production. We evaluated the effects of Pro-Tex® as an HSPi in a Persian sturgeon, (Acipenser persicus) exposed to a pathogenic bacterium. Therefore, A. persicus fries were pre-treated with 25.00, 50.00 and 100 mg L-1 of Pro-Tex® and then, injected with Streptococcus iniae ATCC29178. The Hsp70 gene expressions were determined in various organs including liver, gill and intestine and lysozyme (LYZ) activities along with supplemental levels of complement component 3 (C3) and immunoglobulin M (IgM) were also determined in sturgeon blood in days 3 and 7 after infection. Expression of Hsp70 gene was increased during the first three days of infection and then, it was found to be down-regulated during the infection process. Also, levels of LYZ activity, C3 and IgM increased in a concentration-dependent manner; but these parameters decreased after 7 days. Our data suggest that induction of Hsp70 is a promising approach in modulation of immune response in A. persicus and it might be employed to confer protection in fish against bacterial infections.