Complement System Research Articles

From Teeth to Body: The Complex Role of Streptococcus mutans in Systemic Diseases.

Streptococcus mutans, the principal pathogen associated with dental caries, impacts individuals across all age groups and geographic regions. Beyond its role in compromising oral health, a growing body of research has established a link between S. mutans and various systemic diseases, including immunoglobulin A nephropathy (IgAN), nonalcoholic steatohepatitis (NASH), infective endocarditis (IE), ulcerative colitis (UC), cerebral hemorrhage, and tumors. The pathogenic mechanisms associated with S. mutans frequently involve collagen-binding proteins (CBPs) and protein antigens (PA) present on the bacterial surface. These components facilitate intricate interactions with the host immune system, thereby potentially contributing to various pathological processes. Specifically, CBP is implicated in the deposition of IgA and complement component C3, which exhibits characteristics reminiscent of IgAN-like lesions through animal models, recent clinical studies suggest a potential involvement of S. mutans in IgAN. In addition, CBP binds to complement component C1q, effectively inhibiting the classical activation pathway of the complement system. In addition, CBP promotes the induction of host cells to produce interferon-gamma (IFN-γ). Furthermore, CBP leads to direct inhibitory effects on platelets and the activation of matrix metalloproteinase-9 (MMP-9) at sites of vascular injury.Moreover, PA enhances the ability of S. mutans to invade hepatic tissue. Through utilization of its PAc, S. mutans excessively produces kynurenine (KYNA), which promotes the development and progression of oral squamous cell carcinoma (OSCC). This article synthesizes the latest advancements in understanding the mechanisms of intricate interactions between S. mutans and various systemic conditions in humans, expanding our perspective beyond the traditional focus on dental caries.

Unveiling the omics tapestry of B-acute lymphoblastic leukemia: bridging genomics, metabolomics, and immunomics

Acute B-lymphoblastic leukemia (B-ALL) is a highly heterogeneous hematologic malignancy, characterized by significant molecular differences among patients as the disease progresses. While the PI3K-Akt signaling pathway and metabolic reprogramming are known to play crucial roles in B-ALL, the interactions between lipid metabolism, immune pathways, and drug resistance remain unclear. In this study, we performed multi-omics analysis on different patient cohorts (newly diagnosed, relapsed, standard-risk, and poor-risk) to investigate the molecular characteristics associated with metabolism, signaling pathways, and immune regulation in B-ALL. Our findings indicate that the PI3K-Akt signaling pathway is significantly enriched across all groups, highlighting its critical role in B-ALL pathogenesis and progression. Furthermore, metabolomic analysis revealed that lipid metabolism, ferroptosis, and glutathione metabolism are closely linked to disease progression. Notably, in relapsed patients, dysregulated lipid metabolism and the activation of antioxidant mechanisms may contribute to treatment resistance. Immune-related pathways, such as the complement system and coagulation cascade, were also significantly enriched in patients with B-ALL. This suggests that these pathways, alongside the PI3K-Akt pathway, play a role in forming the tumor microenvironment, thereby promoting disease progression and relapse. Based on these findings, this study provides novel potential therapeutic targets for the personalized treatment of B-ALL and lays the foundation for further development of PI3K-Akt pathway inhibitors and immunometabolism-targeted therapies.

Candidiasis: Insights into Virulence Factors, Complement Evasion and Antifungal Drug Resistance

Invasive fungal infections constitute a substantial global health burden, with invasive candidiasis representing approximately 70% of reported cases worldwide. The emergence of antifungal resistance among Candida species has further exacerbated this challenge to healthcare systems. Recent epidemiological studies have documented a concerning shift towards non-albicans Candida species, exhibiting reduced antifungal susceptibility, in invasive candidiasis cases. The complement system serves as a crucial first-line defence mechanism against Candida infections. These fungal pathogens can activate the complement cascade through three conventional pathways—classical, lectin, and alternative—in addition to activation through the coagulation system. While these pathways are initiated by distinct molecular triggers, they converge at C3 convertase formation, ultimately generating biologically active products and the membrane attack complex. Candida species have evolved sophisticated mechanisms to evade complement-mediated host defence, including the masking of cell wall components, proteolytic cleavage and inhibition of complement proteins, recruitment of complement regulators, and acquisition of host proteins. This review examines the intricate interplay between Candida species and the host complement system, with emphasis on complement evasion strategies. Furthermore, we highlight the importance of exploring the crosstalk between antifungal resistance and immune evasion strategies employed by Candida species. Understanding these interactions may facilitate the development of novel therapeutic approaches and strategies to overcome treatment failures in Candida species infections.

Renal implications of systemic lupus erythematosus pathogenesis and treatment

Lupus nephritis (LN) is a severe complication of systemic lupus erythematosus (SLE) that significantly contributes to morbidity and mortality. Its pathogenesis involves complex interactions between immune dysregulation, genetic susceptibility, and environmental factors, resulting in immune complex deposition and subsequent renal inflammation. Advances in understanding these mechanisms have highlighted the role of B cells, cytokines, and the complement system in disease progression. Current therapeutic strategies rely on immunosuppressants such as glucocorticoids, cyclophosphamide, and mycophenolate mofetil, which have proven effective in managing renal inflammation but carry risks of significant adverse effects. Biologic agents targeting B cells and complement components, including belimumab and eculizumab, have demonstrated promise in improving outcomes and reducing disease activity in refractory cases. The discovery of novel biomarkers is transforming the diagnosis and management of LN. Urinary markers like MCP-1 and complement activation products offer non-invasive tools for monitoring disease activity and predicting relapses. Molecular studies have identified microRNAs and genetic variants as potential indicators of disease susceptibility and therapeutic response. Advances in metabolomics and proteomics have revealed metabolic and protein profiles unique to LN, offering insights into disease mechanisms and new targets for intervention. Emerging technologies such as artificial intelligence are revolutionizing the analysis of complex biomarker data, enabling personalized treatment approaches. These advances highlight the importance of integrating multidisciplinary research efforts to optimize patient care. While challenges remain, including the heterogeneity of LN and disparities in access to care, ongoing research is paving the way for improved therapeutic options and outcomes. Precision medicine, driven by biomarker discovery and innovative therapies, holds the potential to transform the landscape of LN management, offering hope for better renal preservation and quality of life for affected individuals.

Membranous Nephropathy

Membranous nephropathy is a glomerular disease that may be caused by exogenous risk factors in genetically predisposed individuals (primary MN) or may be associated with other autoimmune diseases, drug exposure, or cytotoxic agents (secondary MN). Primary membranous nephropathy (PMN) is an autoimmune disease in which antigens—mainly the phospholipase A2 receptor—are located in the podocytes and are targeted by circulating antibodies, leading to in situ formation of immune complexes that activate the complement system. Clinically, the disease is characterized by nephrotic syndrome (NS) and associated complications. The outcome of PMN can vary, but untreated patients with NS may progress to end-stage kidney disease (ESKD) in 35–40% of cases within 10 years. Treatment primarily aims to prevent NS complications and progression to ESKD. The most commonly used immunosuppressive drugs are rituximab, corticosteroids, cyclophosphamide, and calcineurin inhibitors. Most patients may experience an improvement of proteinuria, which can sometimes be followed by NS relapse. Fewer than 50% of patients with PMN achieve complete and stable remission. In addition to immunosuppressive therapy, antiproteinuric, anti-lipemic, and anticoagulant medicaments are often required.

Cryo-EM analysis of complement C3 reveals a reversible major opening of the macroglobulin ring.

The C3 protein is the central molecule within the complement system and undergoes proteolytic activation to C3b in the presence of pathogens. Pattern-independent activation of C3 also occurs via hydrolysis, resulting in C3(H2O), but the structural details of C3 hydrolysis remain elusive. Here we show that the conformation of the C3(H2O) analog, C3MA, is indistinguishable from C3b. In contrast, the reaction intermediate C3* adopts a conformation dramatically different from both C3 and C3MA. In C3*, unlocking of the macroglobulin (MG) 3 domain creates a large opening in the MG ring through which the anaphylatoxin (ANA) domain translocates through a transient opening. C3MA formation is inhibited by an MG3-specific nanobody and prevented by linking the ANA domain to the C3 β-chain. Our study reveals an unexpected dynamic behavior of C3 and forms the basis for elucidation of the in vivo contribution of C3 hydrolysis and for controlling complement upon intravascular hemolysis and surface-contact-induced activation.

Mitochondrial injury and complement dysregulation are drivers of pathological inflammation in viral myocarditis.

This study sheds light on how enteroviruses, specifically coxsackievirus B3, may contribute to heart failure by triggering harmful immune responses in the heart. We discovered that viral infections in heart cells cause mitochondrial damage, which in turn activates a destructive immune response involving the complement system. This immune activation is one of the significant contributors that lead to further injury of heart tissues, worsening the damage caused by the virus. Additionally, we identified key protective molecules that are targeted and disrupted by the virus, allowing the immune system to attack the heart even more aggressively. Understanding these mechanisms may provide additional insights into how viral infections can lead to chronic heart conditions and suggests potential therapeutic targets to prevent or reduce heart damage in patients affected by viral myocarditis.

Acinetobacter baumannii clinical isolates resist complement-mediated lysis by inhibiting the complement cascade and improperly depositing MAC.

Acinetobacter baumannii is a gram-negative opportunistic bacterium that causes life-threatening infections in immunocompromised hosts. The World Health Organization (WHO) recognizes the high mortality and increasing antimicrobial resistance of A. baumannii and calls for new treatment options. The complement system is a critical mechanism of innate immunity that protects the human body from bacterial infections. Complement activation leads to the deposition of the membrane attack complex (MAC), which can directly lyse gram-negative bacteria. However, A. baumannii has developed evasion mechanisms to protect itself from complement. Here, we examined clinical isolates of A. baumannii and found 11 isolates with MAC deposition and 5 isolates without deposition. Trypsinization of MAC-positive isolates significantly reduced MAC, indicating incorrect insertion, consistent with a lack of lysis of these strains. MAC-negative isolates inhibited alternative pathway activation and were significantly more serum-resistant. These strains were also more virulent in a Galleria mellonella infection model. Whole genome sequencing revealed that MAC-negative isolates carried more virulence genes, and both MAC-negative and MAC-positive A. baumannii significantly differed in capsule type. Importantly, a correlation was observed between complement inhibition and capsule type (e.g., capsule locus KL171) of MAC-negative bacteria, while the capsule type (e.g., KL230) of MAC-positive A. baumannii was associated with increased sensitivity to MAC-mediated lysis. Thus, our findings suggest a relationship between capsule type, complement resistance, and host virulence in A. baumannii.

Targeted Complement Treatments in Glomerulopathies: A Comprehensive Review

The complement system includes soluble and cell surface proteins and is an important arm of the innate immune system. Once activated, the complement system rapidly generates proteins with inflammatory and vasoactive activities. Although complement is crucial to host defense and homeostasis, its inappropriate or uncontrolled activation can also drive tissue injury. Glomerulopathy encompasses a spectrum of diseases with diverse etiologies, clinical presentations, and outcomes. Among the intricate web of factors contributing to glomerulopathies pathogenesis, the role of complement activation has emerged as a focal point of research interest and therapeutic intervention. The pioneer drug was eculizumab, which made it possible to drastically change the prognosis of atypical hemolytic uremic syndrome, an otherwise fatal disease. This comprehensive review aims to elucidate the multifaceted interplay between complement pathways and glomerulopathies, shedding light on potential pathways for targeted therapies and improved patient care.

DNA-loaded targeted nanoparticles as a safe platform to produce exogenous proteins in tumor B cells

IntroductionThe functionalization of nanoparticles (NPs) with an antiCD19 targeting mechanism represents a promising approach for the selective delivery of drugs and nucleic acids into normal and tumor B cells. This strategy has the advantage of minimizing off-target effects by restricting gene delivery to the desired cell population. However, the nanoplatform must guarantee both the local production of the protein and the safety of the treatment to allow an effective therapy with reduced systemic toxicity.MethodsIn order to ensure a selective delivery of nucleic acids, we developed poly(lactic-co-glycolic acid) (PLGA)-poly(vinyl alcohol) (PVA) NPs loaded with an Enhanced Green Fluorescent Protein (EGFP)-coding plasmid and covalently coated with antiCD19 recombinant antibody as a targeting mechanism. To assess the functionality of the NPs, physicochemical characterization, safety tests, and transfection assay were employed to evaluate the NPs’ behavior in vitro and in vivo, in a human/zebrafish lymphoma xenograft model.ResultsThe results demonstrated that the PLGA-PVA nanoplatform was capable of efficiently encapsulating and releasing the payload. These nanostructures demonstrated a favorable safety profile, as evidenced by the absence of significant cell cytotoxicity, coagulation activation, complement system activation, and the slight activation of endothelial cells and leukocytes. The targeting mechanism facilitated the interaction of NPs with target cells, thereby enhancing their internalization and subsequent exogenous plasmid DNA (pDNA) translation and protein expression. In the human/zebrafish lymphoma xenograft model, no evidence of toxicity was observed, and targeted NPs demonstrated the capacity to enhance exogenous pDNA expression.ConclusionOur findings provide a rationale for the use of targeted NPs as a DNA delivery system for the local expression of therapeutic proteins.

Single-cell and spatial transcriptomics illuminate bat immunity and barrier tissue evolution.

Bats have adapted to pathogens through diverse mechanisms, including increased resistance - rapid pathogen elimination, and tolerance - limiting tissue damage following infection. In the Egyptian fruit bat (an important model in comparative immunology) several mechanisms conferring disease tolerance were discovered, but mechanisms underpinning resistance remain poorly understood. Previous studies on other species suggested that elevated basal expression of innate immune genes may lead to increased resistance to infection. Here, we test whether such transcriptional patterns occur in Egyptian fruit bat tissues through single-cell and spatial transcriptomics of gut, lung and blood cells, comparing gene expression between bat, mouse and human. Despite numerous recent loss and expansion events of interferons in the bat genome, interferon expression and induction are remarkably similar to that of mouse. In contrast, central complement system genes are highly and uniquely expressed in key regions in bat lung and gut epithelium, unlike in human and mouse. Interestingly, the unique expression of these genes in the bat gut is strongest in the crypt, where developmental expression programs are highly conserved. The complement system genes also evolve rapidly in their coding sequence across the bat lineage. Finally, the bat complement system displays strong hemolytic activity. Together, these results indicate a distinctive transcriptional divergence of the complement system, which may be linked to bat resistance, and highlight the intricate evolutionary landscape of bat immunity.

Impact of Thrombopoietin Receptor Agonists on Pathophysiology of Pediatric Immune Thrombocytopenia.

Immune thrombocytopenia (ITP) in pediatric patients is a common cause of isolated thrombocytopenia. Various pathophysiological mechanisms are implicated in ITP pathogenesis, including the production of autoantibodies against components of platelets (PLTs) by B-cells, the activation of the complement system, phagocytosis by macrophages mediated by Fcγ receptors, the dysregulation of T cells, and reduced bone marrow megakaryopoiesis. ITP is commonly manifested with skin and mucosal bleeding, and it is a diagnosis of exclusion. In some ITP cases, the disease is self-limiting, and treatment is not required, but chronic-persistent disease can also be developed. In these cases, anti-CD20 monoclonal antibodies, such as rituximab and thrombopoietin (TPO) receptor agonists, can be used. TPO agonists have become standard of care today. It has been reported in the published literature that the efficacy of TPO-RAs can be up to 80% in the achievement of several end goals, such as PLT counts. In the current literature review, the data regarding the impact of TPO agonists in the pathogenesis of ITP and treatment outcomes of the patients are examined. In the era of precision medicine, targeted and individualized therapies are crucial to achieving better outcomes for pediatric patients with ITP, especially when chronic refractory disease is developed.

Complement regulators as novel targets for anti-cancer therapy: A comprehensive review.

Cancer remains a formidable global health challenge requiring the continued exploration of innovative therapeutic approaches. While traditional treatment strategies including surgery, chemotherapy, and radiation therapy have had some success, primarily in early-stage disease, the quest for more targeted, personalized, safer, and effective therapies remains an ongoing pursuit. Over the past decade, significant advances in the field of tumor immunology have dramatically shifted a focus towards immunotherapy, although the ability to harness and coopt the immune system to treat cancer is still just beginning to be realized. One important area that has yet to be fully explored is the complement system, an integral part of innate immunity that has gathered attention recently as a source of potential targets for anti-cancer therapy. The complement system has a complex and context dependent role in cancer biology in that it not only contributes to immune surveillance but also may promote tumor progression. Complement regulators, including CD46, CD55, CD59, and complement factor H, exercise defined control over complement activation, and have also been acknowledged for their role in the tumor microenvironment. This review explores the intricate role of complement regulators in cancer development and progression, examining their potential as therapeutic targets, current strategies, challenges, and the evolving landscape of clinical research.

Dietary rosemary oil with/without zymogen forte improves water quality, growth hormones, immune-physiological response, stress resilience, and health status of Chelon ramada grown in groundwater

With freshwater resources becoming scarce worldwide, mariculture is a promising avenue to sustain aquaculture development, especially by incorporating brackish and saline groundwater (GW) use into fish farming. A 75-day rearing trial was conducted to evaluate fish growth, immune response, overall health, and water quality of Chelon ramada cultured in brackish GW and fed on a basal diet (BD) augmented with rosemary oil (RO) or RO + zymogen forte™ (ZF) as an anti-flatulent. Five treatments were administrated in triplicate: T1: fish-fed BD without additives (control group); T2: fish-fed BD + 0.5 g RO /kg diet; T3: fish-fed BD + 0.5 g RO and 1 g ZF /kg diet; T4: fish-fed BD + 1 g RO /kg diet; T5: fish-fed BD + 1 g RO and 1 g ZF /kg diet. Three hundred fish (8.51 ± 0.01 g/fish) were housed in 15 fiberglass tanks (1500-L tank). The results revealed significant improvements (P < 0.05) in growth performance, survival, growth hormone, and insulin-like growth factor-1. Additionally, there were decreases in the feed conversion ratio (FCR) and the levels of nitrogen by-products (NH4, NH3, and NO2) and pathogenic bacterial counts in the rearing water when fish were fed diets supplemented with RO and RO + ZF. Furthermore, significant reductions in the levels of plasma stress indicators (cortisol, creatinine, and glucose) were detected. In addition, there were significant enhancements observed in the levels of innate immune markers, such as white blood cells, total protein, albumin, and immunoglobulin. The complement system, specifically complement 3 and complement 4, also showed considerable improvements. Furthermore, there were increases in plasma heat shock proteins HSP70 and HSP90, as well as enhanced antioxidant activity. These gains were associated with healthier liver and intestines. The investigation demonstrated that adding 0.5–1 g RO / kg diet or RO + ZF to a C. ramada diet has many benefits, including reducing the levels of nitrogen by-product chemicals and pathogenic bacterial load in GW used in growth tanks. Furthermore, significant improvements were observed in the rates of growth and associated hormones, efficiency of feed utilization, blood indicators, immune function, condition of internal organs (namely the intestine and liver), and overall health of the fish.

Thrombotic Microangiopathy Associated with Systemic Adeno-Associated Virus Gene Transfer: Review of Reported Cases.

Complement-mediated thrombotic microangiopathy (TMA) in the form of atypical hemolytic uremic syndrome (aHUS) has emerged as an immune complication of systemic adeno-associated virus (AAV) gene transfer that was unforeseen based on nonclinical studies. Understanding this phenomenon in the clinical setting has been limited by incomplete data and a lack of uniform diagnostic and reporting criteria. While apparently rare based on available information, AAV-associated TMA/aHUS can pose a substantial risk to patients including one published fatality. Reported cases were originally limited to pediatric Duchenne muscular dystrophy patients receiving micro- or mini-dystrophin transgenes via AAV9 but have subsequently been reported in both pediatric and adult patients across a range of disorders, transgenes, promoters, and AAV capsid types. This article provides an introduction to the complement system, TMA and aHUS, and anticomplement therapies, then presents clinical reviews of AAV-associated TMA/aHUS cases that have been reported publicly. Finally, exploration of risk factors and current and future mitigation approaches are discussed.

Undernutrition affects metabolism and immune response in subcutaneous adipose tissue of pregnant ewes.

Pregnant ewes mobilize body fat to increase energy supply for fetal growth and development upon undernutrition, which disrupts the metabolic homeostasis of the body. However, the comprehensive metabolic changes in subcutaneous adipose tissue upon undernutrition are poorly understood. In this study, an undernutrition sheep model was established to investigate the effects of undernutrition on metabolic changes, immune response, and inflammation in subcutaneous fat through transcriptome, RT-qPCR, and metabolome analysis. Results showed that undernutrition changed the total transcriptional and metabolic profiles of adipose tissue. Compared to the controls, differentially expressed genes (DEGs) involved in fatty acid synthesis, triglyceride genesis, and lipid transport were downregulated in undernourished ewes, while DEGs related to fatty acid and triglyceride degradation were upregulated. Almost all lipid-related differential metabolites (DMs) were downregulated. DEGs and DMs involved in glucose metabolism and glycogen degradation were downregulated, while glycogen synthesis and carbohydrate transport were upregulated. DEGs linked to amino acid degradation were upregulated and some amino acids and derivatives were downregulated. KEGG pathway analysis showed complement and coagulation cascades were enriched significantly by DEGs, and DEGs related to coagulation, macrophage, and inflammation were upregulated while DEGs associated with the complement system were downregulated. Undernutrition during late gestation disrupted the metabolism of lipids, carbohydrates, and amino acids in adipose tissue, which weakened the complement system and immune response and may have ultimately led to inflammation.

Terminal complement complex deposition on chondrocytes promotes premature senescence in age- and trauma-related osteoarthritis.

The complement system is locally activated after joint injuries and leads to the deposition of the terminal complement complex (TCC). Sublytic TCC deposition is associated with phenotypical alterations of human articular chondrocytes (hAC) and enhanced release of inflammatory cytokines. Chronic inflammation is a known driver of chondrosenescence in osteoarthritis (OA). Therefore, we investigated whether TCC deposition contributes to stress-induced premature senescence (SIPS) during aging in vivo and after ex vivo cartilage injury. Femoral condyles of male 13-week-old and 72-week-old CD59-ko (higher TCC deposition), C6-deficient (insufficient TCC formation), and C57BL/6 (WT) mice were collected to assess age-related OA. Furthermore, macroscopically intact human and porcine cartilage explants were traumatized and cultured with/without 30% human serum (HS) to activate the complement system. Explants were additionally treated with clusterin (CLU, TCC inhibitor), N-acetylcysteine (NAC, antioxidant), Sarilumab (IL-6 receptor inhibitor), STAT3-IN-1 (STAT3 inhibitor), or IL-1 receptor antagonist (IL-1RA) in order to investigate the consequences of TCC deposition. Gene and protein expression of senescence-associated markers such as CDKN1A and CDKN2A was determined. In the murine aging model, CD59-ko mice developed after 72 weeks more severe OA compared to C6-deficient and WT mice. mRNA analysis revealed that the expression of Cdkn1a, Cdkn2a, Tp53, Il1b, and Il6 was significantly increased in the cartilage of CD59-ko mice. In human cartilage, trauma and subsequent stimulation with HS increased mRNA levels of CDKN1A, CDKN2A, and IL6, while inhibition of TCC formation by CLU reduced the expression. Antioxidative therapy with NAC had no anti-senescent effect. In porcine tissue, HS exposure and trauma had additive effects on the number of CDKN2A-positive cells, while Sarilumab, STAT-IN-1, and IL-1RA reduced CDKN2A expression by trend. Our results demonstrate that complement activation and consequent TCC deposition is associated with chondrosenescence in age-related and trauma-induced OA. We provided evidence that the SIPS-like phenotype is more likely induced by TCC-mediated cytokine release rather than oxidative stress. Overall, targeting TCC formation could be a future approach to attenuate OA progression.

Ocular Rosacea: An Updated Review.

Ocular rosacea is a chronic inflammatory disorder affecting the ocular surface, often associated with cutaneous rosacea. This review aims to explore its pathogenesis, treatment approaches, and future directions for management. A review of current literature on the pathophysiology, clinical features, and treatment strategies of ocular rosacea in adults and children (pediatric blepharokeratoconjunctivitis) was conducted. Emerging research on immune dysregulation, microbiome alterations, and potential therapeutic targets was analyzed. Ocular rosacea involves dysregulation of the immune and neurovascular systems, with toll-like receptor activation and complement system involvement leading to chronic ocular surface inflammation. Alterations in the ocular microbiome have been implicated in disease progression. Treatment strategies emphasize a stepwise approach, incorporating ocular and skin hygiene, lifestyle modifications, and pharmacological interventions. Recent advancements in understanding the disease mechanisms have led to the exploration of targeted therapies, including biologics and small-molecule inhibitors. Ocular rosacea remains challenging to diagnose and treat, particularly in children (pediatric blepharokeratoconjunctivitis), often leading to delayed intervention and poor outcomes. A multidisciplinary approach, including new therapeutic options, holds promise for improving patient care. Further research into the genetic and molecular basis of ocular rosacea may enable more personalized treatments.

Unravelling the impact of SARS-CoV-2 on hemostatic and complement systems: a systems immunology perspective

The hemostatic system prevents and stops bleeding, maintaining circulatory integrity after injury. It directly interacts with the complement system, which is key to innate immunity. In coronavirus disease 2019 (COVID-19), dysregulation of the hemostatic and complement systems has been associated with several complications. To understand the essential balance between activation and regulation of these systems, a quantitative systems immunology model can be established. The dynamics of the components are examined under three distinct conditions: the disease state representing symptomatic COVID-19 state, an intervened disease state marked by reduced levels of regulators, and drug interventions including heparin, tranexamic acid, avdoralimab, garadacimab, and tocilizumab. Simulation results highlight key components affected, including thrombin, tissue plasminogen activator, plasmin, fibrin degradation products, interleukin 6 (IL-6), the IL-6 and IL-6R complex, and the terminal complement complex (C5b-9). We explored that the decreased levels of complement factor H and C1-inhibitor significantly elevate these components, whereas tissue factor pathway inhibitor and alpha-2-macroglobulin have more modest effects. Furthermore, our analysis reveals that drug interventions have a restorative impact on these factors. Notably, targeting thrombin and plasmin in the early stages of thrombosis and fibrinolysis can improve the overall system. Additionally, the regulation of C5b-9 could aid in lysing the virus and/or infected cells. In conclusion, this study explains the regulatory mechanisms of the hemostatic and complement systems and illustrates how the biopathway machinery sustains the balance between activation and inhibition. The knowledge that we have acquired could contribute to designing therapies that target the hemostatic and complement systems.

Kidney Injury Following Cardiac Surgery: A Review of Our Current Understanding.

Around one-quarter of all patients undergoing cardiac procedures, particularly those on cardiopulmonary bypass, develop cardiac surgery-associated acute kidney injury (CSA-AKI). This complication increases the risk of several serious morbidities and of mortality, representing a significant burden for both patients and the healthcare system. Patients with diminished kidney function before surgery, such as those with chronic kidney disease, are at heightened risk of developing CSA-AKI and have poorer outcomes than patients without preexisting kidney injury who develop CSA-AKI. Several mechanisms are involved in the development of CSA-AKI; injury is primarily thought to result from an amplification loop of inflammation and cell death, with complement and immune system activation, cardiopulmonary bypass, and ischemia-reperfusion injury all contributing to pathogenesis. At present there are no effective, targeted pharmacological therapies for the prevention or treatment of CSA-AKI, although several preclinical trials have shown promise, and clinical trials are under way. Progress in the understanding of the complex pathophysiology of CSA-AKI is needed to improve the development of successful strategies for its prevention, management, and treatment. In this review, we outline our current understanding of CSA-AKI development and management strategies and discuss potential future therapeutic targets under investigation.