Search Results (97)

Background/Objectives: Many parasitic diseases remain without an effective treatment and cause many deaths worldwide. Leishmaniasis is a complex disease that belongs to the category of Neglected Tropical Diseases, as its treatment relies on outdated drugs that also lead to resistance and negative side-effects. To address this problem, two new chemical families have been tested in vitro against three of the most common parasites from the genus Leishmania. Methods: One family is formed by the polyamine tris(2-aminoethyl)amine functionalised either in one or its three primary amines with different aryl group, and the other is a group of azamacrocyclic cyclophanes containing either one or two aromatic spacers. Results: From the first family, only one compound showed activity against Leishmania donovani, and from the second family, three compounds were selective, two of them for Leishmania braziliensis and a different one against L. donovani, another parasite of the studied genus. Conclusions: The anti-Leishmania activity seems to be related to the compounds’ ability to inhibit the iron superoxide dismutase activity and to alter the parasite metabolism by inhibiting glucose intake in L. braziliensis or by accelerating it in L. donovani and by attacking the parasite defences against ROS, both effects triggering a mitochondrial membrane depolarization that enhances damage, leading to cell death. Full article

Background: Crocodilians rarely develop cancer despite long lifespans and continuous exposure to environmental carcinogens, suggesting robust natural anti-tumor defense mechanisms. Methods: We investigated the anti-cancer activity of sera derived from the phylogenetically related species—alligators, crocodiles, and chickens, and studied their underlying immune mechanisms. The anti-tumor activity of alligator serum was tested in murine models of melanoma and lymphoma. Results: Alligator serum (AS) and its (NH₄)₂SO₄-precipitated fraction (ASa) showed rapid and potent cytotoxicity toward multiple murine and human cancer cell lines while sparing non-malignant human cells. Importantly, ASa attenuated melanoma and lymphoma tumor growth in mice. Electrophysiological analyses in PN71 cancer cells treated with ASa revealed rapid membrane depolarization and formation of high-conductance pores consistent with Complement-mediated membrane attack complex (MAC) activity. Proteomic analyses identified the Complement component C5 as a major protein enriched in active fractions, implicating the Complement system in cancer cell killing. Based on phylogenetic similarity of C5, crocodile and chicken sera exhibit alligator-like comparable anti-cancer activity. Mechanistic studies in chicken serum showed that the anti-cancer activity depends on Ca²⁺ and Mg²⁺ ions, terminal Complement components (C5–C8), and IgM antibodies that initiate Complement activation. Immunodepletion of IgM from CSa significantly reduced cytotoxicity, whereas purified chicken IgM activated human Complement to induce cancer cell death. Conclusions: These findings identify a conserved IgM–Complement immune mechanism capable of selectively targeting malignant cells. The evolutionary conservation and cross-species functionality of this pathway highlight its potential as a bio-inspired strategy for developing novel Complement-based cancer immunotherapies. Full article

The complement system is the primary defense mechanism against pathogens, acting through opsonization, the membrane attack complex, and classical, lectin, or alternative pathways. These pathways result in the production of key complement components, including C3a (complement component), C5a, and C3b, which recruit inflammatory cells. Complement dysregulation leads to renal disease through the overproduction of anaphylatoxins or inappropriate formation of the membrane attack complex. The levels of complement components have been shown to be useful as predictive markers in acute kidney injury, especially in conditions of alternative pathway activation, and in diseases of immune complex pathology such as lupus nephritis and IgA nephropathy. Genetic defects in complement regulatory proteins result in diseases such as C3 glomerulopathy or atypical hemolytic uremic syndrome, in which uncontrolled C3 convertase activity results in renal failure. Therapeutic interventions targeting complement components, including eculizumab or pegcetacoplan, improve patient outcomes in atypical hemolytic uremic syndrome and C3 glomerulopathy, respectively, while other interventions improve renal function in IgA nephropathy. These findings underscore the dual role of the complement system, which is not only implicated in the progression of renal diseases but also provides the potential for the development of therapeutic interventions for the treatment of various forms of nephropathy. Full article

Muscle biopsy (MB) is an important tool to help differentiate idiopathic inflammatory myopathies (IIMs) from hereditary muscular diseases (HMDs). The usefulness of immunohistochemical stains of the major histocompatibility complex class I and the membrane attack complex are controversial, as both may be identified in some HMDs. More sensitive markers of IIMs have recently been used, such as myxovirus resistance A (MxA), a type I interferon-inducible protein. We selected skeletal MB samples from 81 patients diagnosed with IIM and HMD harbouring overt inflammatory infiltrates on their MBs in the period between March 2022 and September 2024. Two groups were identified: the IIM group (46 cases) and the HMD group (35 cases). We characterized and compared the patterns of MxA protein expression among the two groups. In the IIM group, positive sarcoplasmic MxA expression was detected on the myofibres of 10 patients (24%), among whom were eight dermatomyositis patients. In the HMD group, we did not identify any sarcoplasmic positivity. However, five patients (14%) showed positive labelling restricted to the sarcolemmal membrane, including non-necrotic or regenerating fibres. Our study demonstrates the value of MxA for increasing dermatomyositis diagnostic accuracy and suggests the potential role of interferon type I in the pathophysiology of HMD. Full article

Parainfluenza virus 5 (PIV5) can establish persistent infections in host cells despite encountering innate immune defenses, including the complement (C′) system. The host determinants that enable persistently infected cells (PI) to evade C’-mediated clearance remain largely undefined. Here, we identify the mitochondrial antiviral signaling (MAVS) protein, a central adaptor in double-stranded RNA-triggered antiviral and pro-survival signaling pathways, as a critical mediator of both PIV5 persistence and acquired resistance to C’ lysis. Wild-type (WT) PIV5-infected A549 cells were initially sensitive to C’-directed killing, but these cells rapidly establish a PI in culture with ~25% of the cell population becoming resistant to C’ lysis by day 2 and ~75% by day 4. In contrast, PIV5-infected A549 MAVS-deficient (MAVS KO) cells exhibited elevated viral gene expression, increased deposition of C3 and the membrane attack complex, and were more susceptible than WT cells to C′ killing. PIV5-infected MAVS KO cells showed rapid cytopathic effects and never established a stable PI. While pharmacological suppression of viral gene expression with ribavirin (RBV) restored the survival of PIV5-infected MAVS KO cells into a long-term PI-like state, these RBV-induced PI cells remained sensitive to C’ lysis. Collectively, these findings demonstrate a role of MAVS in modulating a PIV5 infection in culture, to facilitate both the conversion of a PIV5 acute infection to a PI and development of resistance to C’ killing. Full article

Glaucoma is no longer viewed solely as a pressure-mediated optic neuropathy but as a chronic neurodegenerative disease with a strong immune component. Across experimental models and patient samples, convergent inflammatory circuitry complement activation, NLRP3 inflammasome signaling, and microglial reactivity emerge as a central driver of retinal ganglion cell (RGC) dysfunction and death. Local complement upregulation (C1q, C3, C5) in the retina and optic nerve head (ONH) promotes aberrant synaptic tagging, phagoptosis, and membrane attack complex stress. In parallel, biomechanical strain, ischemia, mitochondrial damage, and danger-associated molecular patterns prime and activate the NLRP3 inflammasome in microglia, astrocytes, and ONH cells, leading to caspase-1 activation, IL-1β/IL-18 maturation, and pyroptotic or apoptotic injury. Microglia integrate these cues, shifting from early protective surveillance to chronic maladaptive states that amplify complement and inflammasome outputs. This review synthesizes mechanistic links within the complement NLRP3 microglia axis, considers systemic and adaptive immune contributions, and proposes a translational framework for immune-based clinical stratification. The literature for this review was identified through searches of PubMed, Web of Science, and Scopus using combinations of the terms ‘glaucoma’, ‘complement’, ‘inflammasome’, ‘NLRP3’, ‘microglia’, and ‘neuroinflammation’. Priority was given to recent experimental, translational, and clinical studies. We then evaluate emerging immunomodulatory therapies, complement inhibitors, inflammasome blockers, microglial state reprogrammers, cytokine biologics, and cell-derived immunoregulatory approaches, highlighting biomarkers and trial design needs. An immune systems view of glaucoma enables precision neuroprotection for patients who progress despite controlled intraocular pressure. Full article

Leptospirosis is a widespread zoonosis of human and veterinary concern. The etiological agent of the disease is the pathogenic bacteria of the genus Leptospira. Transmission typically occurs through mucosal contact and/or injured skin with the urine of infected animals or contaminated environmental sources. Understanding the biology and pathogenesis of leptospires is the main focus of our study. In this work, we characterized a novel protein encoded by the LIC_13056 gene from L. interrogans serovar Copenhageni, having an OmpA-like domain. We show that this coding sequence (CDS), previously assigned as a hypothetical protein with an unknown function, is capable of binding to the cellular receptor α8 integrin subunit, potentially contributing to kidney colonization. Additionally, the protein bound to both purified and normal human serum (NHS) plasminogen (PLG). In both conditions, PLG bound to protein was able to generate plasmin (PLA). Furthermore, rLIC_13056 interacted with the complement system components C4b, C4BP, C8 and C9. The interaction of recombinant protein to the C9 had a negative impact on C9 polymerization. Taken together, the protein LIC_13056, having an OmpA-like domain, appears to be involved in leptospiral pathogenesis via different stages of the infection process; PLA generation together with the inhibition of the membrane attack complex (MAC) may contribute to the immune evasion mechanism of Leptospira, thus facilitating the infection. Full article

Plants secrete a heterogenous population of membrane-enclosed extracellular vesicles that harbour an incredible diversity of molecular cargo. It is the complexity of the molecular cargo encapsulated by plant extracellular vesicles (PEVs) which facilitates the fundamental role PEVs play in mediating communication and signalling. PEV molecular cargo is composed of a diverse mixture of lipids, metabolites, proteins, and nucleic acids. Among the nucleic acids, the microRNA (miRNA) class of small regulatory RNA can be viewed as one of the most biologically relevant. Plant miRNAs regulate the expression of genes essential for all aspects of development as well as to control the gene expression changes required to drive the adaptive and defensive responses of plants to environmental stress and pathogen attack. Furthermore, recent research has shown that specific miRNA cohorts are selectively packaged into PEVs as part of the molecular-level response of a plant to its growth environment. For example, PEVs are loaded with a specific miRNA population for their targeted delivery to sites of pathogen infection in the host plant, or for cross-kingdom delivery of host-plant-encoded miRNAs to the pathogen itself. Here we outline PEV physical properties, compare PEV biogenesis pathways, detail the composition of PEV molecular cargo, and go on to provide detailed commentary on the role of PEV-delivered miRNAs in plant development, environmental stress adaptation, and pathogen defence. We conclude this article with a proposal for the potential future use of PEVs and their miRNA cargo in agriculture and aquaculture. Full article

Vilobelimab, a first-in-class, human–mouse chimeric immunoglobulin G4 (IgG4) kappa monoclonal antibody, targets human complement component 5a (C5a) in plasma. Unlike upstream complement inhibitors, vilobelimab does not inhibit the generation of the membrane attack complex (C5b-9), necessary to mitigate certain infections. C5a is a strong anaphylatoxin and chemotactic agent that plays an essential role in both innate and adaptive immunity. Elevated levels of C5a have been associated with pathologic processes, including sepsis and inflammatory respiratory disorders such as acute respiratory distress syndrome (ARDS). Blocking C5a with vilobelimab has shown therapeutic promise. A randomized, multicenter placebo-controlled Phase III study of vilobelimab in patients with severe COVID-19 (PANAMO) found that patients treated with vilobelimab had a significantly lower risk of death by day 28 and 60. Based on this study, the United States Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for Gohibic^® (vilobelimab) injection for the treatment of COVID-19 in hospitalized adults when initiated within 48 h of receiving invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO). In January 2025, the European Commission (EC) granted marketing authorization for Gohibic^® (vilobelimab) for the treatment of adult patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced ARDS who are receiving systemic corticosteroids as part of standard of care and receiving IMV with or without ECMO. Herein, we review the mechanism of action of vilobelimab in selectively inhibiting C5a-induced inflammation, outlining its bench-to-bedside development from the fundamental biology of the complement system and preclinical evidence through to the clinical data demonstrating its life-saving potential in the management of COVID-19–induced ARDS. Full article

There are many contradictory opinions, and the role of TGF-β1 in the vascular effects of atherosclerosis remains unclear. This study aims to verify whether plasma TGF-β1 concentrations are correlated with changes in echocardiographic and vascular parameters in individuals with early coronary artery disease (CAD), including those with type 2 diabetes mellitus (T2DM). The study group consisted of 100 patients with early-onset CAD. Patients underwent echocardiography and electrocardiography. The thickness of the internal and middle membrane complex of the carotid and brachial arteries, the ankle-brachial index, and the atherosclerotic plaques present were assessed via Doppler ultrasound. No statistically significant correlation of TGF-β1 with diabetes, hypertension, metabolic syndrome, or myocardial infarction was observed, only weak associations with impaired ventricular function. The positive correlations between right and left ventricular parameters and TGF-β1 level, as well as the negative correlations fractional shortening and deceleration time, were found. The last correlation was strong. There is a strong positive correlation between TGF-β1 and QRS II width and QRS V5 width. The positive correlation was found between TGF-β1 and PLA density and thickness of the intima-media. These associations are very weak. In patients with early-onset CAD, high TGF-β1 concentrations are not associated with heart attacks or the associated risk factors. However, these cases are potentially those with stable plaques. Our study indicates a significant association between TGF-β1 levels and left ventricular diastolic dysfunction and arrhythmia risk in these patients. Full article

Background: IgA vasculitis (IgAV) represents the most frequently seen form of vasculitis among children. Although it often resolves without intervention, renal involvement (IgAV nephritis) poses a risk for long-term complications. Although the lectin and alternative complement pathways are possible causes in its development, dependable serum biomarkers for the early identification of nephritis remain unavailable. Methods: In this prospective case-control study, we examined how the serum levels of a membrane attack complex (sC5b-9), complement factor H (CFH), mannose-binding lectin (MBL), and mannose-binding lectin-associated serine protease-1 (MASP-1) relate to renal involvement in IgAV. These complement proteins were measured in children diagnosed with IgAV and compared to levels in healthy controls (HCs) matched for age and sex. Results: The study cohort comprised 44 IgAV patients with a median age of 8 years and 34 HCs. The CFH levels were reduced significantly in the patient group (median: 357.31 ng/mL; IQR: 228.32) relative to the controls (median: 543.08 ng/mL; IQR: 504.05) (p < 0.001). This decrease was observed irrespective of the presence of nephritis. There were no significant differences in serum sC5b-9, MBL, or MASP-1 levels between the patients and controls. Furthermore, no correlation emerged between these complement components and renal involvement. Conclusion: The data suggest that lower CFH levels may signal systemic dysregulation of the alternative pathway in IgAV. In contrast, the serum levels of sC5b-9, MBL, and MASP-1 appear inadequate as markers for predicting renal involvement. Further research with larger cohorts that includes genetic analyses and examination of kidney tissue is needed to better define the contribution of complement activation in IgAV-related nephritis. Full article

Persistent RNA virus infections (PI) are often characterized by extended viral shedding and maintained cycles of inflammation. The innate immune Complement (C′) pathways can recognize acute infected (AI) cells and result in their lysis, but the relative sensitivity of PI cells to C′-directed killing is incompletely understood. Here, we extended our previous studies on the interactions of C′ with parainfluenza virus AI and PI A549 cells to two additional respiratory tract cell lines. AI Hep2 and H1975 cells infected with Parainfluenza virus 5 (PIV5) were found to be highly sensitive to C′ lysis. By contrast, PIV5 PI cells were highly resistant to killing by C″. Surface deposition of membrane attack complex (MAC) and C3 was also greatly reduced on the surface of PI cells compared to AI cells. PI cells had lower levels of surface viral glycoprotein expression compared to AI cells. Treatment of AI cells with ribavirin (RBV) showed a dose-dependent decrease in both viral glycoprotein expression and sensitivity to C′-mediated lysis. When surface viral glycoprotein levels were reduced in AI cells to those in PI cells, AI cells became similarly resistant to C′. While sialic acid levels on PI cell surfaces matched that of naïve cells, enzymatic removal of this sialic acid did not increase sensitivity to C′-mediated lysis. Despite their varying profiles of C′ activation and deposition, these studies indicate downregulation of viral gene expression as a common mechanism of C′ resistance across various parainfluenza virus PI cell lines. Full article

Soybean mosaic virus (SMV) is a major viral pathogen that causes significant yield losses and a reduction in seed quality in susceptible soybean cultivars. Resistance breeding is the most effective, economical, and eco-friendly strategy for prevention of SMV-induced damage. Accurate and convenient assessment of SMV resistance is an essential prerequisite for resistance breeding. In this study, we constructed a green fluorescent protein (GFP)-tagged SMV recombinant virus (SMV-GFP) by yeast homologous recombination technology. It was proved that the recombinant virus can not only be used to track the viral infection process in Nicotiana benthamiana and soybean, but also to quantify the viral load based on relative fluorescence area (RFA) value. Using this recombinant virus, the resistance of 286 soybean germplasms from Northeast China to SMV was evaluated. A genome-wide association study (GWAS) was conducted using the RFA values of the 286 soybean accessions to find possible SMV-resistance genes. The results revealed 72 single nucleotide polymorphism (SNP) loci on chromosome 13 closely associated with SMV resistance, and a total of 40 genes were discovered within the candidate regions. By integrating the results of gene functional annotation and haplotype analysis, Glyma.13g176600 encoding a membrane attack complex/perforin (MACPF) domain-containing protein and Glyma.13g177000 encoding a DUF761-containing protein were identified as the most probable candidate genes associated with SMV resistance. Overall, the GFP-based rapid evaluation system developed in this study will facilitate breeding for resistance to SMV in soybean. Full article

With the in-depth study of the unique flight ability of bats in the field of bionic robots, wind-tunnel experiments have become an important means to verify the feasibility of bat-like flying robot structures. However, due to the complex structure of a bat’s flexible wing membrane and multi-joint linkage, there is still a significant gap in the systematic experimental study of its flightability. In this study, a remote-controlled bionic prototype was designed and manufactured for the bat-like flapping-wing flying robot, and the changes in wing flight performance at different flapping frequencies (1–3.5 Hz) and angles of attack (0–15°) were tested in a low-speed (2–6 m/s) wind tunnel experiment. Six flight parameters were obtained through experiments. It was found that the flight performance of the prototype was successfully verified under a specific flapping frequency, angle of attack, and flight speed. This result not only determines the optimal flight parameter combination under the model, but also reveals the key influence of the flexible deformation of the wing membrane and the flapping frequency on the flight performance, which provides a key experimental basis for the structural optimization and control strategy design of the bat-like flapping-wing robot. Full article

Background/Objectives: The field of nephrology is increasingly embracing advanced treatments and clinical trials that focus on inhibiting specific components of the complement cascade, a key driver in complement-mediated kidney diseases. Materials and Methods: This review aims to summarize innovative therapies targeting various pathways, including the inhibition of the terminal part of the complement pathway (mainly C5), the alternative pathway (factor B inhibitors), and the lectin pathway (MASP inhibitors. C5 inhibitors play a critical role in preventing the formation of the membrane attack complex (MAC), offering effective solutions for conditions like atypical hemolytic uremic syndrome (aHUS) and paroxysmal nocturnal hemoglobinuria (PNH). Meanwhile, avacopan, a C5a receptor antagonist, addresses ANCA-associated vasculitis (AAV) by mitigating inflammation and enabling reduced reliance on corticosteroids. Similarly, narsoplimab, which inhibits MASP-2, targets the lectin pathway implicated in conditions such as aHUS. Iptacopan, a factor B inhibitor, focuses on the alternative pathway and demonstrates efficacy in managing C3 glomerulopathy (C3G). Results: A systematic review of complement-targeted therapies was conducted, analysing studies from 2013 to 2023 that address unmet medical needs in primary and secondary glomerular diseases. Conclusions: Our systematic review of complement-targeted therapies shows that these tailored and innovative treatments may specifically address unmet medical needs in primary and secondary glomerular diseases. Full article