Activation Of Complement Pathway Research Articles

Local complement synthesis-A process with near and far consequences for ischemia reperfusion injury and transplantation.

The model of the solid organ as a target for circulating complement deposited at the site of injury, for many years concealed the broader influence of complement in organ transplantation. The study of locally synthesized complement especially in transplantation cast new light on complement's wider participation in ischaemia-reperfusion injury, the presentation of donor antigen and finally rejection. The lack of clarity, however, has persisted as to which complement activation pathways are involved and how they are triggered, and above all whether the distinction is relevant. In transplantation, the need for clarity is heightened by the quest for precision therapies in patients who are already receiving potent immunosuppressives, and because of the opportunity for well-timed intervention. This review will present new evidence for the emerging role of the lectin pathway, weighed alongside the longer established role of the alternative pathway as an amplifier of the complement system, and against contributions from the classical pathway. It is hoped this understanding will contribute to the debate on precisely targeted versus broadly acting therapeutic innovation within the aim to achieve safe long term graft acceptance.

Complement C1s as a diagnostic marker and therapeutic target: Progress and propective.

The molecules of the complement system connect the effectors of innate and adaptive immunity and play critical roles in maintaining homeostasis. Among them, the C1 complex, composed of C1q, C1r, and C1s (C1qr2s2), is the initiator of the classical complement activation pathway. While deficiency of C1s is associated with early-onset systemic lupus erythematosus and increased susceptibility to bacteria infections, the gain-of- function variants of C1r and C1s may lead to periodontal Ehlers Danlos syndrome. As C1s is activated under various pathological conditions and associated with inflammation, autoimmunity, and cancer development, it is becoming an informative biomarker for the diagnosis and treatment of a variety of diseases. Thus, more sensitive and convenient methods for assessing the level as well as activity of C1s in clinic samples are highly desirable. Meanwhile, a number of small molecules, peptides, and monoclonal antibodies targeting C1s have been developed. Some of them are being evaluated in clinical trials and one of the antibodies has been approved by US FDA for the treatment of cold agglutinin disease, an autoimmune hemolytic anemia. In this review, we will summarize the biological properties of C1s, its association with development and diagnosis of diseases, and recent progress in developing drugs targeting C1s. These progress illustrate that the C1s molecule is an effective biomarker and promising drug target.

A network pharmacology integrated pharmacokinetics strategy to investigate the pharmacological mechanism of absorbed components from crude and processed Zingiberis Rhizoma on deficiency-cold and hemorrhagic syndrome

Ethnopharmacological relevanceZingiberis Rhizoma (ZR) and Zingiberis Rhizoma Carbonisata (ZRC), as two forms of ginger-based herbal drugs used in China for at least 2000 years, have been recorded in Chinese Pharmacopoeia and applied for specific indications in traditional Chinese medicine (TCM). Aim of the studyThe present study aimed to explore the underlying therapeutic and processing mechanism of the absorbed components of ZR and ZRC on deficiency-cold and hemorrhagic syndrome (DCHS) using network pharmacological technique combined with pharmacokinetics strategy. Materials and methodsIn this study, a rapid and sensitive approach was conceived to simultaneously determine the seven components (zingiberone, 6-gingerol, 8-gingerol, 6-shogaol, 6-paradol, diacetyl-6-gingerol and 10-gingerol) in rat serum by HPLC-DAD-MS. The network pharmacological technique was employed to evaluate the effect of the absorbed components of ZR and ZRC on DCHS. Also, the vitro experiments were carried out to validate the functions of the seven compounds on coagulation and other major haematological effects. ResultsThe values of intra-assay and inter-assay precision were determined to be less than 7.44%, with an accuracy value ranging from 83.64% to 107.99%. Analysis of rat plasma revealed that the extraction recoveries and matrix effects of the seven analytes were >85.76%. The method for validation following oral administration of ZR and ZRC to rats was proved to be a success in the pharmacokinetic study of the seven ingredients. Pharmacokinetics showed that ZR processing could enhance the absorption and utilization of 6-shogaol, 6-paradol and diacetyl-6-gingerol, meanwhile reduce the absorption of 6-gingerol, 8-gingerol, and 10-gingerol. Through the pathway enrichment analysis, it was found that the significant biological process of ZR and ZRC on DCHS was primarily associated with complement, coagulation cascades and platelet activation pathways. The vitro experiments indicated that zingiberone, 6-paradol and diacetyl-6-gingerol had a hemostatic effect by upregulating the expression of one or more targets such as TNF-α, FⅩa, FⅫ, FⅧ, ICAM-1, vWF and ITGB3. While 6-gingerol, 6-shogaol, 8-gingerol and 10-gingerol played a critical role in promoting blood circulation by increasing the expression of TM and/or PORC, and/or reducing the expression of ITGB3. ConclusionIn brief, network pharmacological technique in combination with pharmacokinetics strategy provided an applicable method for pharmacological mechanism study of ZR and ZRC, which, also, could be used as reference for quality control of the two drugs. In a broader sense, this combined strategy might even be valuable in uncovering the therapeutic and processing mechanism of Chinese herbs on a systematic level.

The role of complement in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) has become a leading cause of chronic liver diseases globally. NAFLD includes a range of hepatic manifestations, starting with liver steatosis and potentially evolving towards nonalcoholic steatohepatitis, cirrhosis or even hepatocellular carcinoma. Although the pathogenesis of NAFLD is incompletely understood, insulin resistance and lipid metabolism disorder are implicated. The complement system is an essential part of the immune system, but it is also involved in lipid metabolism. In particular, activation of the alternative complement pathway and the production of complement activation products such as C3a, C3adesArg (acylation stimulating protein or ASP) and C5a, are strongly associated with insulin resistance, lipid metabolism disorder, and hepatic inflammation. In this review, we briefly summarize research on the role of the complement system in NAFLD, aiming to provide a basis for the development of novel therapeutic strategies for NAFLD.

In Vitro Modulation of Complement Activation by Therapeutically Prospective Analogues of the Marine Polychaeta Arenicin Peptides.

The widespread resistance to antibiotics in pathogenic bacteria makes the development of a new generation of antimicrobials an urgent task. The development of new antibiotics must be accompanied by a comprehensive study of all of their biological activities in order to avoid adverse side-effects from their application. Some promising antibiotic prototypes derived from the structures of arenicins, antimicrobial peptides from the lugworm Arenicola marina, have been developed. Previously, we described the ability of natural arenicins -1 and -2 to modulate the human complement system activation in vitro. In this regard, it seems important to evaluate the effect of therapeutically promising arenicin analogues on complement activation. Here, we describe the complement-modulating activity of three such analogues, Ar-1[V8R], ALP1, and AA139. We found that the mode of action of Ar-1[V8R] and ALP1 on the complement was similar to that of natural arenicins, which can both activate and inhibit the complement, depending on the concentration. However, Ar-1[V8R] behaved predominantly as an inhibitor, showing only a moderate increase in C3a production in the alternative pathway model and no enhancement at all of the classical pathway of complement activation. In contrast, the action of ALP1 was characterized by a marked increase in the complement activation through the classical pathway in the concentration range of 2.5–20 μg/mL. At the same time, at higher concentrations (80–160 μg/mL), this peptide exhibited a complement inhibitory effect characteristic of the other arenicins. Peptide AA139, like other arenicins, exhibited an inhibitory effect on complement at a concentration of 160 μg/mL, but was much less pronounced. Overall, our results suggest that the effect on the complement system should be taken into account in the development of antibiotics based on arenicins.

With complements: C3 inhibition in the clinic.

C3 is a key complement protein, located at the nexus of all complement activation pathways. Extracellular, tissue, cell-derived, and intracellular C3 plays critical roles in the immune response that is dysregulated in many diseases, making it an attractive therapeutic target. However, challenges such as very high concentration in blood, increased acute expression, and the elevated risk of infections have historically posed significant challenges in the development of C3-targeted therapeutics. This is further complicated because C3 activation fragments and their receptors trigger a complex network of downstream effects; therefore, a clear understanding of these is needed to provide context for a better understanding of the mechanism of action (MoA) of C3 inhibitors, such as pegcetacoplan. Because of C3's differential upstream position to C5 in the complement cascade, there are mechanistic differences between pegcetacoplan and eculizumab that determine their efficacy in patients with paroxysmal nocturnal hemoglobinuria. In this review, we compare the MoA of pegcetacoplan and eculizumab in paroxysmal nocturnal hemoglobinuria and discuss the complement-mediated disease that might be amenable to C3 inhibition. We further discuss the current state and outlook for C3-targeted therapeutics and provide our perspective on which diseases might be the next success stories in the C3 therapeutics journey.

Neutrophils in ANCA-associated vasculitis: Mechanisms and implications for management.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of systemic autoimmune diseases, which is typified by inflammatory necrosis predominantly affecting the small vessels and often accompanied by positive ANCA. Clinically, AAV primarily includes microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), and eosinophilic granulomatosis with polyangiitis (EGPA). It has been found that in AAV pathogenesis, both innate and adaptive immunity are related to neutrophil function mutually. Many proteins, such as myeloperoxidase (MPO) and proteinase 3 (PR3), in neutrophil cytoplasm lead to the production of proteins such as MPO-ANCA and PR3-ANCA by activating adaptive immunity. In addition, through the process of neutrophil extracellular trap (NET) formation, activation of an alternative complement pathway and the respiratory burst can stimulate the neutrophils close to vascular endothelial cells and will participate the vessel inflammation. This review aims to reveal the potential mechanisms regulating the association between the neutrophils and various types of AAVs and to emphasize the results of recent findings on these interactions. Moreover, multiple underlying signaling pathways involved in the regulation of neutrophils during AAV processes have also been discussed. The ultimate goal of this review is to identify novel biomarkers and therapeutic targets for AAV management in the future.

Toxic and bioaccumulative effects of zinc nanoparticle exposure to goldfish, Carassius auratus (Linnaeus, 1758)

The widespread use of produced metal oxide nanoparticles (NPs) has increased major concerns about their impact on human as well as aquatic animal health. The present study shows that exposure to different concentrations of zinc oxide (ZnO) NPs led to high accumulations of Zn ions in the metabolic organs of fish (liver and gills), resulting in severe oxidative stress in Carassius auratus. The goldfish (C. auratus) was chosen as an aquatic species for the evaluation of the potential toxicity of aqueous ZnO-NPs (Treatments of hemoglobin and neutrophils (0, 0.5, 1, and 1.5 mg L− 1) following 14 days of exposure. A range of histological and hematological factors were examined. Exposure to the NPs produced significant reduction of red blood cell and white blood cell counts, hematocrit) were found to produce no significant differences in lymphocyte, monocyte, and eosinophil counts; as well as the mean corpuscular hemoglobin concentrations index (P > 0.05). Moreover, the results revealed significant alterations in serum biochemical parameters, hepatic enzyme levels, and immune and antioxidant responses; except for total protein and superoxide dismutase (SOD) of C. auratus exposed to ZnO-NPs, particularly at the 1 and 1.5 mg L− 1 concentrations. Fish exposed to 1 and 1.5 mg L−1 ZnO-NPs displayed a significant reduction in alternative complement pathway activity, lysozyme, and total protein contents of mucus compared to those in the control group. The results showed that hepatic SOD and catalase, and gill catalase activity were significantly decreased, and their malondialdehyde levels increased at 1 and 1.5 mg L−1 ZnO-NPs compared to the control group (P < 0.05). Significant accumulations of ZnO-NPs were observed in the liver, kidney, and gill tissues of fish leading to severe histopathological alterations in these organs. These results suggest that water-borne ZnO-NPs can easily accumulate in metabolic organs and lead to oxidative stress and destructive effects on the physiological features of C. auratus.

Contributions of animal models to mechanistic understandings of antibody-dependent disease and roles of the amplification loop.

The complement system plays an important pathophysiologic role in human diseases associated with immune or ischemic insults. In addition to understanding the effector mechanisms that are important for the biological effects of the system, substantial efforts have gone into understanding which specific complement activation pathways generate these potent effects. These approaches include the use of gene-targeted mice and specific pathway inhibitors, as well as the integration of human disease genetic and biomarker studies. In some disease states, it is quite clear that the alternate pathway plays a unique role in the initiation of the complement system. However, although initially a widely unexpected finding, it has now been shown in many tissue-based disease models and in initial human studies that engagement of the amplification loop is also essential for tissue injury when the classical and/or lectin pathways initiate pathway activation through pathogenic autoantibodies. This review provides evidence for such a conclusion through animal models, focusing on pathogenic antibody passive transfer models but also other relevant experimental systems. These data, along with initial biomarkers and clinical trial outcomes in human diseases that are associated with pathogenic autoantibodies, suggest that targeting the alternative pathway amplification loop may have near-universal therapeutic utility for tissue-based diseases.

Highly pathogenic coronavirus N protein aggravates inflammation by MASP-2-mediated lectin complement pathway overactivation

Excessive inflammatory responses contribute to the pathogenesis and lethality of highly pathogenic human coronaviruses, but the underlying mechanism remains unclear. In this study, the N proteins of highly pathogenic human coronaviruses, including severe acute respiratory syndrome coronavirus (SARS-CoV), middle east respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), were found to bind MASP-2, a key serine protease in the lectin pathway of complement activation, resulting in excessive complement activation by potentiating MBL-dependent MASP-2 activation, and the deposition of MASP-2, C4b, activated C3 and C5b-9. Aggravated inflammatory lung injury was observed in mice infected with adenovirus expressing the N protein. Complement hyperactivation was also observed in SARS-CoV-2-infected patients. Either blocking the N protein:MASP-2 interaction, MASP-2 depletion or suppressing complement activation can significantly alleviate N protein-induced complement hyperactivation and lung injury in vitro and in vivo. Altogether, these data suggested that complement suppression may represent a novel therapeutic approach for pneumonia induced by these highly pathogenic coronaviruses.

Atypical hemolytic-uremic syndrome: evolution of treatment and impact of clinical and genetic characteristics on possibility of eculizumab withdrawal

Atypical hemolytic uremic syndrome (aHUS) is a rare variant of thrombotic microangiopathy (TMA) associated with uncontrolled activation of alternative complement pathway due to mutations in complement regulatory protein genes or antibodies formation to regulators. Clinical manifestations of aHUS can be triggered by infections, sepsis, pregnancy, autoimmune diseases, organ transplantation, and other complement-activating conditions. Previously, the only treatment option for aHUS was plasma therapy – fresh frozen plasma infusions or plasma exchange, but its effectiveness was insufficient. Currently, targeted treatment available – recombinant monoclonal antibodies against complement C5 protein – eculizumab with high efficiency in achieving aHUS remission, renal function recovery, and preventing TMA at kidney transplantation. For a long time, the question of the optimal duration of treatment and the possibility of eculizumab discontinuing remained unresolved. It was shown that aHUS relapses developed in 20-35 % of patients after discontinuation of complement-blocking therapy. The article presents an overview of a large number of studies of eculizumab treatment outcomes and the possibility of its withdrawal, including a French prospective multicenter study that identified risk factors for aHUS relapse after eculizumab discontinuation: the presence of rare variants of complement genes, female gender, increased soluble C5b-9 plasma level. In patients who did not have rare genetic variants, the risk of relapse was less than 5 %. In general, eculizumab discontinuation after achieving complete remission of aHUS and renal function recovery in patients with low risk of recurrence can provide better tolerability of maintenance treatment, and decrease the incidence of infectious complications and the financial burden on the healthcare system.

Inhibition of macrophage-derived foam cells by Adipsin attenuates progression of atherosclerosis

Phagocytosis of oxidized low-density lipoprotein (OxLDL) by macrophages yields “foam cells” and serves as a hallmark of atherosclerotic lesion. Adipsin is a critical component of the complement activation pathway. Recent evidence has indicated an obligatory role for Adipsin in pathological models including ischemia-reperfusion and sepsis. Adipsin levels are significantly decreased in patients with asymptomatic carotid atherosclerosis, implying the role for Adipsin as a potential marker of asymptomatic carotid atherosclerosis. This study was designed to evaluate the role for Adipsin in atherosclerosis and the mechanisms involved using both in vivo and in vitro experiments. ApoE−/−/AdipsinTg mice were constructed and were fed a high-fat diet for 12 weeks. Compared with ApoE−/− mice, area of the sclerotic plaques was reduced, along with lower macrophage deposition within the plaque in ApoE−/−/AdipsinTg mice. RAW264.7 cells and bone marrow-derived macrophages (BMDMs) were stimulated with oxLDL (50 μg/ml). Adenovirus vectors containing the Adipsin gene were transfected into macrophages. Lipid accumulation was observed by Oil red O staining. Western blot and reverse transcription-polymerase chain reaction data revealed that Adipsin overexpression inhibited oxLDL-induced lipid uptake and foam cell formation and upregulation of CD36 and PPARγ in Ad-Adipsin-transfected macrophages. In addition, the PPARγ-specific agonist GW1929 reversed Adipsin overexpression-evoked inhibitory effect on lipid uptake. These results demonstrate unequivocally that Adipsin inhibits lipid uptake in a PPARγ/CD36-dependent manner and prevents the formation of foam cells, implying that Adipsin may be a potential therapeutic target against atherosclerosis.

P17.10: Effect of Factor H on Complement Alternative Pathway Activation in Human Serum Remains on Porcine Cells Lacking N-Glycolylneuraminic Acid

Background: Triple knockout (TKO) donor pigs lacking alpha-1,3-galactose (Gal), N-glycolylneuraminic acid (Neu5Gc), and Sd(a) expressions were developed to improve the clinical success of xenotransplantation. Neu5Gc, a sialic acid expressed on cell surfaces, recruits factor H to protect cells from attack by the complement system. Lack of Neu5Gc expression may cause unwanted complement activation, abrogating the potential benefit of gene-modified donor pigs. To investigate whether TKO porcine cells display increased susceptibility to complement activation in human serum, pathway-specific complement activation, apoptosis, and human platelet aggregation by porcine cells were compared between alpha-1,3-galactosyltransferase gene-knockout (GTKO) and TKO porcine cells. Methods: Primary porcine peripheral blood mononuclear cells (pPBMCs) and endothelial cells (pECs) from GTKO and TKO pigs were used. Cells were incubated in human serum diluted in gelatin veronal buffer (GVB++) or Mg++-EGTA GVB, and C3 deposition and apoptotic changes in these cells were measured by flow cytometry. C3 deposition levels were also measured after incubating these cells in 10% human serum supplemented with human factor H. Platelet aggregation in human platelet-rich plasma containing GTKO or TKO pECs was analyzed. Results: The C3 deposition level in GTKO pPBMCs or pECs in GVB++ was significantly higher than that of TKO pPBMCs or pECs, respectively, but C3 deposition levels in Mg++-EGTA-GVB were comparable between them. The addition of factor H into the porcine cell suspension in 10% serum in Mg++ -EGTA-GVB inhibited C3 deposition in a dose-dependent manner, and the extent of inhibition by factor H was similar between GTKO and TKO porcine cells. The percentage of late apoptotic cells in porcine cell suspension in GVB++ increased with the addition of human serum, of which the net increase was significantly less in TKO pPBMCs than in GTKO pPBMCs. Finally, the lag time of platelet aggregation in recalcified human plasma was significantly prolonged in the presence of TKO pECs compared to that in the presence of GTKO pECs. Conclusion: TKO genetic modification protects porcine cells from serum-induced complement activation and apoptotic changes, and delays recalcification-induced human platelet aggregation. It does not hamper factor H recruitment on cell surfaces, allowing the suppression of alternative complement pathway activation. This work was carried out with the support of the “Cooperative Research Program for Agriculture Science and Technology Development [Project No. PJ015607 (HK and KO)], Rural Development Administration, Republic of Korea. This research was partly supported by Hallym University Research Fund (HL).

Mannose binding lectin-associated serine protease 2 (MASP2) gene polymorphism and susceptibility to human T-lymphotropic virus type 1 (HTLV-1) infection in blood donors from Mashhad, Iran.

Mannose binding lectin-associated serine protease 2 (MASP2) is the effector part of mannose binding lectin (MBL) that activates the complement system in an antibody-independent manner. We aimed to investigate the role of genetic polymorphisms in the MASP2 gene and susceptibility to HTLV-1 infection. A total of 172 HTLV-1 infected individuals and 170 healthy blood donors were analyzed in this case-control study. Nine single nucleotide polymorphisms (SNPs) encompassing different regions of the MASP2 gene were genotyped with a polymerase chain reaction-sequence-specific primer (PCR-SSP) assay. The relation between the SNPs genotype and the susceptibility to HTLV-1 infection was investigated with a χ2 test considering P < 0.05 as statistically significant. Two of nine tested SNPs were associated with the risk of HTLV-1 infection. The genotype TT at rs17409276 decreased the risk of HTLV-1 (P = 0.005, OR = 0.301, 95% CI = 0.124-0.728). The genotypes CC and CT at rs2273346 were also associated with a higher risk of HTLV-1 acquisition (P = 0.004, OR = 2.225, 95% CI = 1.277-3.877). These findings highlight the importance of MASP2 genetic polymorphisms in the lectin pathway of complement activation and susceptibility to HTLV-1 infection.

Regulation of Conformational Changes in C-reactive Protein Alters its Bioactivity.

The acute phase C-reactive protein (CRP) is mainly synthesized and secreted by the liver in a cytokine-mediated response to infection or inflammation and circulates as a pentamer (pCRP) in plasma. Recent studies indicate that CRP is not only a marker but is directly involved in inflammation. CRP has a vital role in host defense and inflammation, metabolic function and scavenging through its ability for calcium depended binding to exogenous and endogenous molecules having phosphocholine followed by activation of the classical complement pathway. Accumulating evidence indicates that pCRP dissociates into monomeric CRP (mCRP) and most proinflammatory actions of CRP are only expressed following dissociation of its native pentameric assembly into mCRP. The dissociation of CRP into mCRP altogether promotes the ligand-binding capability. mCRP emerges to be the main conformation of CRP that participates in the regulation of local inflammation, however, little is identified concerning what triggers the significantly enhanced actions of mCRP and their binding to diverse ligands. The separation of mCRP from pCRP may be a direct relationship between CRP and inflammation. Here we review the current literature on CRP dissociation and its interaction with different ligands. The possibility to avoid the generation of the proinflammatory potential of mCRP has driven therapeutic approaches by targeting the dissociation mechanism of pCRP or inhibition of mCRP itself during inflammation.

Idiopathic systemic capillary leak syndrome, a unique complement and interferon mediated endotheliopathy syndrome: The role of the normal skin biopsy in establishing the diagnosis and elucidating pathogenetic mechanisms

Idiopathic Systemic Capillary Leak Syndrome (ISCLS), also known as Clarkson's Syndrome, is due to primary fluid and protein leak across capillaries that leads to an accumulation of interstitial fluids and cardiovascular collapse from intravascular hypovolemia. Viral infections are a putative trigger of these episodes. ISCLS is typically associated with a monoclonal gammopathy. Here we present four patients with idiopathic systemic capillary leak syndrome. The cohort consists of three men and one woman who range in age from 55 to 72 years old. All of the patients had a monoclonal gammopathy. Two patients had viral triggers. Biopsies of normal skin were examined throughout all phases of the disease. During an acute attack, we identified perivascular mixed CD4+ and CD8+ T cell lymphocytic infiltrates in the superficial dermis. We observed significant microvascular deposits of C5b-9 and upregulation of type I interferon signaling in endothelium along with reduced serum levels of complement during very active disease. We also identified deposits of immunoglobulin along the dermal epidermal junction mirroring the monoclonal immunoglobulin isotype implicated in each patient. During a post treatment recovery or mild disease phase there was reduced inflammation and decreased amounts of C5b-9 and type I interferon expression. Sudden onset capillary leak syndrome reflects enhanced endothelial cell permeability as a unique form of endothelial injury mediated by the combined effects of complement pathway activation and upregulation of type I interferon signaling on endothelium.

Protective effects of summer savory (Satureja hortensis) oil on growth, biochemical, and immune system performance of common carp exposed to pretilachlor herbicide

There are many reports on the deleterious effects of herbicides on aquatic organisms which lead to tremendous biological, environmental and economical damage. In this regard, in the present study, the protective effect of summer savory (Satureja hortensis) essential oil (SEO) against pretilachlor, one of the most used herbicides was investigated in common carp (Cyprinus carpio). The fish assigned to six treatment groups (T1: control treatment; T2: 25% LC50 pretilachlor herbicide; T3: 50% LC50 pretilachlor herbicide; T4: 1% SEO; T5: 25% LC50 pretilachlor herbicide + 1% SEO; and T6: 25% LC50 pretilachlor herbicide + 1% SEO) for 21 days. The results showed that the SEO-containing treatments significantly increased the survival rate (SR) (P < 0.05). The highest final weight (FW), specific growth rate (SGR), and feed conversion ratio (FCR) were observed in the T4 treatment (P < 0.05). There was a significant increase in glucose (GLU) level in pretilachlor treatments and a significant decrease in SEO-containing treatments compared to the control (P < 0.05). The significantly highest total protein (TP) content was observed in T4 treatment containing SEO. Cholesterol (CHOL) and triglyceride (TRIG) levels decreased in SEO-containing treatments with the lowest level in T4 treatment (P < 0.05). Alternative complement pathway activity (ACH50), activity levels of superoxide dismutase (SOD), and glutathione peroxidase (GPX) showed an increasing trend in SEO-containing treatments with the highest level in T4 treatment (P < 0.05). The activity of liver enzymes showed a significantly lowest level in T4 treatment. To conclude, our findings revealed that the use of SEO in fish exposed to pretilachlor herbicide could improve growth, strengthen the immune system and exert a protective effect on common carp.

Changes in physiological responses and immunity of blunt snout bream Megalobrama amblycephala from transport stress.

This study aimed to investigate the effects of transport stress on the physiological responses and immunity of Megalobrama amblycephala (blunt snout bream). Fish (109.67 ± 1.51g) were sampled at nine time points: before transport (control), at 0h, 1h, 3h, 6h, 12h, 24h, 3days, and 7days after 4h of medium-distance transportation, and four fish were sampled in each time point. The results showed that plasma cortisol, triiodothyronine (T3), complement component 3 (C3), complement component 4 (C4), immunoglobulin M (IgM) and nitrogen monoxide (NO) concentrations, and alternative complement pathway (ACH50), acid phosphatase (ACP), and myeloperoxidase (MPO) activities all reached the peak at 0h after transportation; C4 and NO concentrations as well as ACP and MPO activities returned to the control level after 1h, ACH50 activity as well as cortisol, T3, and IgM concentration returned to the control level after 12h, and C3 concentration returned to the control level after 24h respectively. Plasma glucose and total protein concentrations as well as lysozyme activity all reached the peak at 1h after transportation, total protein concentration and lysozyme activity returned to the control level after 3h, and glucose concentration returned to the control level after 6h (P < 0.05). Liver heat shock protein 70 expression reached the peak at 1h after transportation, and returned to the control level after 24h; liver heat shock protein 90 expression reached the peak at 0h after transportation and returned to the control level after 12h (P < 0.05). Overall, these findings suggested that 4h of medium-distance transportation caused stress response of blunt snout bream, and transport stress had a significant effect on plasma indicators. But the recovery of 24h after transport could return the physiological response, immune indexes, and the expression of heat shock protein to the normal level. This also provided data support for the medium-distance transportation of blunt snout bream in the future.

Development of clinical phenotypes and biological profiles via proteomic analysis of trauma patients

BackgroundTrauma is a heterogeneous condition, and specific clinical phenotypes may identify target populations that could benefit from certain treatment strategies. In this retrospective study, we determined clinical phenotypes and identified new target populations of trauma patients and their treatment strategies.MethodsWe retrospectively analyzed datasets from the Japan Trauma Data Bank and determined trauma death clinical phenotypes using statistical machine learning techniques and evaluation of biological profiles.ResultsThe analysis included 71,038 blunt trauma patients [median age, 63 (interquartile range [IQR], 40–78) years; 45,479 (64.0%) males; median Injury Severity Score, 13 (IQR, 9–20)], and the derivation and validation cohorts included 42,780 (60.2%) and 28,258 (39.8%) patients, respectively. Of eight derived phenotypes (D-1–D-8), D-8 (n = 2178) had the highest mortality (48.6%) with characteristic severely disturbed consciousness and was further divided into four phenotypes: D-8α, multiple trauma in the young (n = 464); D-8β, head trauma with lower body temperature (n = 178); D-8γ, severe head injury in the elderly (n = 957); and D-8δ, multiple trauma, with higher predicted mortality than actual mortality (n = 579). Phenotype distributions were comparable in the validation cohort. Biological profile analysis of 90 trauma patients revealed that D-8 exhibited excessive inflammation, including enhanced acute inflammatory response, dysregulated complement activation pathways, and impaired coagulation, including downregulated coagulation and platelet degranulation pathways, compared with other phenotypes.ConclusionsWe identified clinical phenotypes with high mortality, and the evaluation of the molecular pathogenesis underlying these clinical phenotypes suggests that lethal trauma may involve excessive inflammation and coagulation disorders.

Modern view on the complement system role in membranous nephropathy

Membranous nephropathy (MN), an immune-mediated glomerular disease, is the most common cause of adult nephrotic syndrome. In MN, proteinuria is developed by podocyte damage due to the complement system activation in response to the subepithelial deposition of immune complexes containing various auto- and exogenous antigens. Membrane-attacking complex (MAC) is the terminal product of any complement pathways activation (classical, lectin or alternative) and plays the leading role in the complement-mediated podocytic damage. Thus far, the main pathway of complement activation leading to the formation of MAC in MN has not been established. The review highlights current evidence of various complement pathways activation in the development of MN, as well as recently established new molecular mechanisms of complement-mediated podocyte damage.