Complement activation in obesity, insulin resistance, and type 2 diabetes mellitus

Amplified inflammatory reaction has been observed to be involved in cardiometabolic diseases such as obesity,insulin resistance,diabetes,dyslipidemia,and atherosclerosis.The complement system was originally viewed as a supportive first line of defense against microbial invaders,and research over the past decade has come to appreciate that the functions of the complement system extend beyond the defense and elimination of microbes,involving in such diverse processes as clearance of the immune complexes,complementing T and B cell immune functions,tissue regeneration,and metabolism.The focus of this review is to summarize the role of the activation of complement system and the initiation and progression of metabolic disorders including obesity,insulin resistance and diabetes mellitus.In addition,we briefly describe the interaction of the activation of the complement system with diabetic complications such as diabetic retinopathy,nephropathy and neuropathy,highlighting that targeting complement system therapeutics could be one of possible routes to slow down those aforementioned diabetic complications.

Association of secretory IgA with clinical pathological characteristics and complement activation in IgA nephropathy

Objective To further investigate the association among clinical pathology,complement activation and renal secretory IgA(SIgA)deposition in patients with IgA nephropathy(IgAN).Methods The activation of serum complements was detected by immunoturbidimetry and ELISA.Renal deposition of SIgA and activation of complements were detected by immunofluorescence.

Activated complement classical pathway in a murine model of oxygen-induced retinopathy

AIM: To investigate whether the complement system is involved in a murine model of oxygen-induced retinopathy(OIR).METHODS: Forty C57BL/6J newborn mice were divided randomly into OIR group and control group. OIR was induced by exposing mice to 75% ±2% oxygen from postnatal 7d(P7) to P12 and then recovered in room air.For the control group, the litters were raised in room air.At the postnatal 17d(P17), gene expressions of the complement components of the classical pathway(CP),the mannose-binding lectin(MBL) pathway and the alternative pathway(AP) in the retina were determined by quantitative real-time polymerase chain reaction(RT-PCR). Retinal protein expressions of the key components in the CP were examined by Western blotting.· RESULTS: Whole mounted retina in the OIR mice showed area of central hypoperfusion in both superficial and deep layers and neovascular tufts in the periphery.The expressions of C1 qb and C4 b genes in the OIR retina were significantly higher than those of the controls. The expression of retinal complement factor B(CFB) gene in OIR mice was significantly lower than those of the controls. However, the expressions of C3 and complement factor H(CFH) genes were higher. The protein synthesis of the key components involved in the CP(C1q, C4 and C3) were also significantly higher in OIR mouse retina. Although MBL-associated serine protease 1(MASP1) and MASP2 were detected in both the OIR and the control groups, the expressions were weak and the difference between the two groups was not significant.CONCLUSION: Our data suggest that the complement system CP is activated during the pathogenesis of murine model of OIR.

Activation of mitogen activated protein kinases via complement receptor type 2

Background Complement receptor type 2 (CR2) is the receptor for C3d and C3dg and for Epstein Barr virus The aim of our study was to explore whether CR2 can independently mediate the activation of mitogen activated protein kinases (MAPKs, including ERK, JNK, and p38MAPK), and to highlight the molecular mechanism of CD 4 + cell deletion in AIDS Methods HOS cells (HOS CR2) and HOS CD4 cells (HOS CD4CR2) stably expressing CR2 were established and then identified by FACS and Western blotting Activation and blocking tests of MAPKs were assessed by Western blot Cell proliferation was determined using Cell Titer 96 Aqueous One Solution Reagent Results FACS results showed that the positive rates of HOS CR2 and HOS CD4CR2 cells were greater than 96%, and Western blot showed that the CR2 expression levels on HOS CR2 and HOS CD4CR2 cells were high Activation and blocking tests of MAPKs (ERK, JNK, and p38MAPK) were carried out in HOS CR2, HOS CD4, and HOS CD4CR2 cells The activation of MAPKs in HOS CR2 cells stimulated with PMA (100 ng/ml) and NHS (10%) was identical The activation of MAPKs increased at 5 minutes, reached a peak at 10 minutes, and decreased to baseline within 30 minutes, all in a time dependent manner; the activation of MAPKs was blocked by anti CR2 McAb, PD98059 (inhibitor of ERK), and Wortmanin (inhibitor of PI 3K), respectively In HOS CD4 cells, MAPKs were activated by HIV gp160 In HOS CD4CR2 cells, MAPK activation was induced by HIV gp160, 10% NHS, and HIV gp160+10%NHS; phosphorylation of p38MAPK was dramatically induced by HIV gp160+NHS, and lasted for 1 hour The cell proliferation results showed that HIV gp160 inhibited the proliferation of HOS CD4 and HOS CD4CR2 cells ( P <0 01) and that NHS enhanced the effect of HIV gp160 ( P <0 01) Conclusions The activation of MAPKs is independently mediated by CR2 and that anti CR2 McAb, PD98059, and Wortmanin block the activation of MAPKs, respectively The results of the signal transduction and cell proliferation assays of HOS CD4CR2 cells show that CR2 plays a role in the pathogenesis of HIV infection, especially in the inhibition of CD 4 + cell proliferation

Effects of Chinese Medicine Shen-Fu Injection(参附注射液)on the Expression of Inflammatory Cytokines and Complements during Post-Resuscitation Immune Dysfunction in A Porcine Model

Objective：To investigate the action of Shen-Fu Injection（参附注射液,SFI） in regulating the expression of the serum complements and inflammatory cytokines synthesized and released in response to the stress of global ischemia accompanying cardiac arrest（CA） and resuscitation.Methods：Thirty pigs were randomly divided into the sham（n=6） and 3 returns of spontaneous circulation（ROSC） groups（n=24）.After 8-min untreated ventricular fibrillation and 2-min basic life support,24 pigs of the ROSC groups were randomized into three groups（n=8 per group）,which received central venous injection of SFI（SFI group）,epinephrine（EP group）,or saline（SA group）.Hemodynamic status and blood samples were obtained at 0,0.5,1,2,4,6,12,and 24 h after ROSC.Results：Serum concentrations of specific activation markers of the complement system C3,C4 and C5b-9 were increased during cardiopulmonary resuscitation th rough1 24 h after ROSC.There were intense changes of various pro-inflammatory cytokines and anti-inflammatory cytokines as early as 0.5 h after CA.Compared with the EP and SA groups,SFI treatment reduced the proinflammatory cytokines levels of interleukin（IL）-6,IL-8and tumor necrosis factor α（TNF-α,P〈0.05）,and increased the anti-inflammatory cytokine levels of IL-4 and IL-10（P〈0.05）.Further,SFI treatment decreased the values of C3,C4 and C5b-9 compared with the EP and SA groups.Conclusions：SFI,derived from the ancient Chinese medicine,has significant effects in attenuating post-resuscitation immune dysfunction by modulating the expression of complements and cytokines levels.The current study provided an experimental basis for the clinical application of a potential pharmacologic target for post resuscitation immune dysfunction.

Innate and adaptive immune responses toward nanomedicines

Since the commercialization of the frst liposomes used for drug delivery,Doxil/Caelyx® and Myocet®,tremendous progress has been made in understanding interactions between nanomedicines and biological systems.Fundamental work at the interface of engineering and medicine has allowed nanomedicines to deliver therapeutic small molecules and nucleic acids more effciently.While nanomedicines are used in oncology for immunotherapy or to deliver combinations of cytotoxics,the clinical successes of gene silencing approaches like patisiran lipid complexes(Onpattro®)have paved the way for a variety of therapies beyond cancer.In parallel,the global severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)pandemic has highlighted the potential of mR NA vaccines to develop immunization strategies at unprecedented speed.To rationally design therapeutic and vaccines,chemists,materials scientists,and drug delivery experts need to better understand how nanotechnologies interact with the immune system.This review presents a comprehensive overview of the innate and adaptative immune systems and emphasizes the intricate mechanisms through which nanomedicines interact with these biological functions.

Multi-organ protection during open heart surgery

PURPOSE AND METHODS: Open-heart surgery with the use of cardiopulmonary bypass (CPB) is associated with an inflammatory cascade which contributes to the development of postoperative complications including multiple organ failure. To provide an update on the subject, we briefly review the recent English-language literature. RESULTS: During CPB, various factors have been recognized to induce a complex inflammatory response. Based on an enhanced understanding of the underlying mechanisms, therapeutic strategies have been developed to reduce this inflammatory reaction and its subsequent damaging effects. Off-pump coronary artery bypass grafting may result in less inflammatory injury as compared with the conventional maneuver, which can in turn, diminish the incidence of cardiac, renal, or neurological dysfunction. It is also clear that improving the biocompatibility of CPB materials can lead to a better patient recovery. Inasmuch as the pathophysiology involved appears to be multifactorial, it is unlikely that a single intervention could achieve the desired goal. Both pharmacologic strategies, such as steroid pretreatment, and modification of mechanical devices, such as the use of heparin-coated CPB circuits, could have important clinical implications. The balance pro- and anti-inflammatory responses may be crucial in limiting the extent of inflammatory injury. CONCLUSIONS: To date, the concept of organ protection should no longer be limited to the individual organ. Instead, investigations must be extended to focus on a systemic level.