Role In Defense Research Articles

Microfiber-Based Triboelectric Acoustic Sensors Enable Self-Powered Ultrasonic Localization and Tracking Underwater.

Underwater ultrasonic detection is critical for marine security, playing a vital role in resource development, environmental protection, and national defense. However, existing detection systems, which primarily rely on active scanning technologies, are hindered by high costs, significant energy demands, and challenges in achieving large-scale deployment. Here, we introduce a microfiber-based triboelectric acoustic sensor (MTAS) featuring a core-shell hierarchical structure, offering a self-powered solution for precise measurement of underwater ultrasound source distance. By leveraging the principles of contact electrification/triboelectrification and electrostatic induction, the MTAS efficiently converts complex ultrasonic vibrations into real-time electrical signals. The MTAS demonstrates rapid response times as low as 8.6 μs, a high signal-to-noise ratio of 29.8 dB, and the capability to detect ultrasonic sources with power levels above 1.6 W via time-difference-of-arrival analysis. To address large-scale sea applications, we further propose a distributed network that integrates multiple MTAS units capable of precise ultrasonic source localization and real-time motion trajectory visualization. This innovation represents a transformative approach, combining self-powered operation, ease of deployment, and high imperceptibility, paving the way for large-area, energy-efficient submarine security systems. Such advancements redefine the paradigm of underwater target detection, aligning technological innovation with the pressing demands of marine safety and environmental sustainability.

Adaptable Alchemy: Exploring the Flexibility of Specialized Metabolites to Environmental Perturbations Through Post-Translational Modifications (PTMs)

Plants are subjected to various stresses during the growth process, including biotic stresses, as well as abiotic stresses such as temperature, drought, salt, and heavy metals. To cope with these biotic and abiotic adversities, plants have evolved complex regulatory mechanisms during their long-term environmental adaptations. In a suddenly changing environment, protein modifiers target other proteins to induce post-translational modification (PTM) in order to maintain cell homeostasis and protein biological activity in plants. PTMs modulate the activity of enzymes and transcription factors in their respective metabolic pathways, enabling plants to produce essential compounds for their survival under stress conditions. Examples of post-translational mechanisms include phosphorylation, ubiquitination, glycosylation, acetylation, protein–protein interactions, and targeted protein degradation. Furthermore, the role of histone modifications in regulating secondary metabolism deserves attention due to its potential impact on heritability and its contribution to stress tolerance. Understanding the epigenetic aspect of these modifications can provide valuable insights into the mechanisms underlying stress response. In this context, also examining PTMs that impact the biosynthesis of secondary metabolites is meaningful. Secondary metabolites encompass a wide range of compounds such as flavonoids, alkaloids, and terpenoids. These secondary metabolites play a crucial role in plant defense against herbivores, pathogens, and oxidative stress. In this context, it is imperative to understand the contribution of secondary metabolism to plant tolerance to abiotic stresses and how this understanding can be leveraged to improve long-term survival. While many studies have focused on the transcriptional regulation of these metabolites, there is a growing interest in understanding various changes in PTMs, such as acetylation, glycosylation, and phosphorylation, that are able to modulate plants’ response to environmental conditions. In conclusion, a comprehensive exploration of post-translational mechanisms in secondary metabolism can enhance our understanding of plant responses to abiotic stress. This knowledge holds promise for future applications in genetic improvement and breeding strategies aimed at increasing plant resilience to environmental challenges.

Evaluation of serum and peritoneal fluid mannose-binding lectin associated serine protease-3, adipsin, properdin, and complement factor-H levels in endometriosis patients.

Endometriosis is a chronic disease which has been reported to be associated with distorted immune mechanisms. The alternative pathway is a complement system which plays a role in immune defense. The present study aimed to evaluate whether the level of alternative complement molecules differ in women with endometriosis compared to heathy individuals. A total of 58 women participated in this prospective research. Women with a diagnosis of endometriosis confirmed by laparoscopy (n = 32) were compared to healthy women (n = 26) in terms of serum adipsin, properdin, mannose-binding lectin-associated serine protease-3 and complement factor-H (CFH) levels. The peritoneal fluid samples which were taken during the endometriosis surgery were also analyzed in terms of the complement levels. The clinical and demographic data including the serum CA-125 level and pelvic pain were also analyzed. SPSS version 23.0 was used in statistical analysis. The serum levels of adipsin and CFH were found to be significantly increased in women with endometriosis (P = 0.027 and P = 0.040, respectively). Serum adipsin level was found to significantly correlate with serum CA-125 level (r = 0.320, P = 0.015), serum CFH level (r = 0.705, P < 0.001), and degree of the pelvic pain complaint (r = 0.326, P = 0.013). A strong, positive correlation was also observed between peritoneal fluid levels of adipsin, and CFH (r = 0.593; P < 0.001). To the best of our knowledge, the present study is the first to evaluate the alternative complement system in women with endometriosis. The current findings may be noteworthy to elucidate the possible role of the key molecules of the alternative pathway in endometriosis pathogenesis.

Genome-wide identification and characterization of transcription factors involved in defense responses against Sclerotinia sclerotiorum in Brassica juncea

Sclerotinia sclerotiorum could cause significant yield losses of up to 70% in rapeseed cultivation. Nevertheless, the availability of immune or highly resistant germplasm and mechanisms to combat S. sclerotiorum, particularly in B. juncea, remains insufficient. Transcription factors (TFs) are recognized for their critical role in plant defense against S. sclerotiorum. In the present study, a total of 4807 TFs from 48 families were expressed and identified at 12, 24, and 36 h after inoculation (HAI) in two B. juncea lines: G21-912, exhibiting higher S. sclerotiorum resistance (HR), and G21-853, displaying lower S. sclerotiorum resistance (LR). The number of differentially expressed TFs (DETs) between the HR and the LR lines peaked at 24 HAI, with 202 upregulated and 105 downregulated TFs. Through expression and subcellular localization analyses, three candidate DETs, namely BjuA037408 (ETHYLENE RESPONSIVE FACTOR 59, ERF59), BjuB028842 (RELATED TO ABI3/VP1 1, RAV1), and BjuA016484 (WRKY25), were identified as the primary TFs in defense against S. sclerotiorum inoculation. The expression of these three genes was validated in the double haploid lines of BC3 (the third backcrossing generation) derived from the HR×LR cross. This study serves as a valuable case study for the characterization of TFs associated with defense mechanisms against S. sclerotiorum in B. juncea. The confirmed resistant B. juncea line of HR, along with the three key DETs, is expected to significantly contribute to future breeding efforts aimed at developing Sclerotinia-resistant varieties.

Manipulation of the brown glume and internode 1 gene leads to alterations in the colouration of lignified tissues, lignin content and pathogen resistance in wheat.

Lignin is a crucial component of the cell wall, providing mechanical support and protection against biotic and abiotic stresses. However, little is known about wheat lignin-related mutants and their roles in pathogen defence. Here, we identified an ethyl methanesulfonate (EMS)-derived Aegilops tauschii mutant named brown glume and internode 1 (bgi1), which exhibits reddish-brown pigmentation in various tissues, including internodes, spikes and glumes. Using map-based cloning and single nucleotide polymorphism (SNP) analysis, we identified AET6Gv20438400 (BGI1) as the leading candidate gene, encoding the TaCAD1 protein. The mutation occurred in the splice acceptor site of the first intron, resulting in a premature stop codon in BGI1. We validated the function of BGI1 using loss-of-function EMS and gene editing knockout mutants, both of which displayed reddish-brown pigmentation in lignified tissues. BGI1 knockout mutants exhibited reduced lignin content and shearing force relative to wild type, while BGI1 overexpression transgenic plants showed increased lignin content and enhanced disease resistance against common root rot and Fusarium crown rot. We confirmed that BGI1 exhibits CAD activity both in vitro and in vivo, playing an important role in lignin biosynthesis. BGI1 was highly expressed in the stem and spike, with its localisation observed in the cytoplasm. Transcriptome analysis revealed the regulatory networks associated with BGI1. Finally, we demonstrated that BGI1 interacts with TaPYL-1D, potentially involved in the abscisic acid signalling pathway. The identification and functional characterisation of BGI1 significantly advance our understanding of CAD proteins in lignin biosynthesis and plant defence against pathogen infection in wheat.

Mechanisms and effects of activation of innate immunity by mitochondrial nucleic acids.

In recent years, a growing number of roles have been identified for mitochondria in innate immunity. One principal mechanism is that the translocation of mitochondrial nucleic acid species from the mitochondrial matrix to the cytosol and endolysosomal lumen in response to an array of microbial and non-microbial environmental stressors has been found to serve as a second messenger event in the cell signaling of the innate immune response. Thus, mitochondrial DNA and RNA have been shown to access the cytosol through several regulated mechanisms involving remodeling of the mitochondrial inner and outer membranes and to access lysosomes via vesicular transport, thereby activating cytosolic [e.g. cyclic GMP-AMP synthase (cGAS), retinoic acid-inducible gene I (RIG-I)-like receptors], and endolysosomal (Toll-like receptor 7, 9) nucleic acid receptors that induce type I interferons and pro-inflammatory cytokines. In this mini-review, we discuss these molecular mechanisms of mitochondrial nucleic acid mislocalization and their roles in host defense, autoimmunity, and auto-inflammatory disorders. The emergent paradigm is one in which host-derived DNA interestingly serves as a signal amplifier in the innate immune response and also as an alarm signal for disturbances in organellar homeostasis. The apparent vast excess of mitochondria and mitochondrial DNA nucleoids per cell may thus serve to sensitize the cell response to stressors while ensuring an underlying reserve of intact mitochondria to sustain cellular metabolism. An improved understanding of these molecular mechanisms will hopefully afford future opportunities for therapeutic intervention in human disease.

Evolutionary-Distinct Viral Proteins Subvert Rice Broad-Spectrum Antiviral Immunity Mediated by the RAV15-MYC2 Module.

A variety of plant viruses employ different virulence strategies to achieve successful infection, resulting in abnormal plant development. However, the common pathogenicity of distinct viruses has rarely been studied. Here, it is shown that a plant-specific RAV-type transcription factor, OsRAV15, is specifically targeted by several distinct viral proteins for facilitating viral infection. OsRAV15 is found to activate jasmonic acid (JA)-mediated broad-spectrum antiviral immunity by physically associating with JA signaling essential components OsMYC2-OsJAZ complex. To facilitate viral infection, evolutionarily distinct viral proteins encoded by diverse rice viruses generally disrupt the OsRAV15-OsMYC2 complex to attenuate activation of JA signaling. Together, the results reveal a common counter-defense strategy used by different viruses to suppress the OsRAV15-OsMYC2 module that plays a vital role in fine-tuning JA-mediated antiviral defense.

Hypoxia-driven mobilization of altruistic cancer stem cells in platinum-treated head and neck cancer

BackgroundHead and neck cancers harbor dormant cancer stem cells (CSCs). This study explores how platinum therapy impacts these cells in a non-genetic manner and the role of hypoxia in this process. Previously, we identified a novel population of CSCs exhibiting an “altruistic” phenotype, sacrificing self-renewal to promote niche defense (tumor stemness defense, TSD), potentially protecting a dormant subpopulation of CSCs, the reawakening CSC (R-CSC) retaining stress memory. This TSD phenotype involves the activation of the MYC-HIF2α pathway and, importantly, is linked to a hypoxic tumor microenvironment. We termed these TSD+ CSCs “altruistic cancer stem cells” (A-CSCs). Here we investigated the potential role of tumor hypoxia in the mobilization of TSD+ CSCs to the circulation as a part of niche defense against platinum therapy.MethodsWe isolated CTCs and primary tumor cells from head and neck squamous cell carcinoma (HNSCC) patients undergoing platinum therapy (n = 14). We analyzed the TSD phenotype and markers of hypoxia in these cells. Additionally, we further characterized a previously reported pre-clinical model of platinum-induced tumor stemness to study the link between hypoxia, TSD+ CSC emergence, and mobilization to the circulation and bone marrow.ResultsWe isolated TSD+ CTCs with a hypoxic signature from eight out of 14 HNSCC patients. These cells displayed increased proliferation and invasion upon cisplatin treatment, suggesting a role in niche defense. Our pre-clinical model confirmed that hypoxia directly correlates with the expansion of TSD+ CSCs and their mobilization into the circulation and bone marrow following cisplatin treatment. We demonstrated the protection of R-CSCs by TSD+ CSCs. Notably, inhibiting hypoxia alone with tirapazamine did not reduce TSD+ CSCs, CTCs, or R-CSCs. However, combining tirapazamine with FM19G11, a MYC-HIF2α pathway inhibitor, significantly reduced the platinum-induced expansion of both TSD+ CSCs, CTCs, and the presence of R-CSCs in the bone marrow.ConclusionsThis study reveals that HNSCC patients undergoing platinum therapy can harbor TSD+ CTCs exhibiting an altruistic phenotype and a hypoxic signature. Additionally, the pre-clinical study provides a novel non-genetic mechanism of therapy resistance-the altruistic tumor self-defense. The tumor microenvironment, through the emergence of TSD+ CSCs, appears to act collectively to defend the tumor self-identity by hijacking an altruistic stem cell niche defense mechanism.

Unlocking Gut Health: The Potent Role of Stilbenoids in Intestinal Homeostasis

Stilbenoids are a class of naturally occurring phenolic compounds found in various plant species, characterized by a stilbene backbone with diverse substituents that confer a range of biological activities. These compounds exhibit antioxidant, anti-inflammatory, and antimicrobial properties, making them promising candidates for improving intestinal health. The intestinal tract plays a critical role in nutrient digestion, absorption, and immune defense, and maintaining its integrity is vital for animal growth. Stilbenoids contribute to gut health by enhancing intestinal morphology, supporting mucosal immune responses, regulating gut microbiota composition, modulating metabolic pathways, and maintaining mitochondrial health. This review provides a comprehensive analysis of key stilbenoids, including resveratrol, pterostilbene, piceatannol, and oxyresveratrol, focusing on their biological effects and regulatory mechanisms. By highlighting their roles in mitigating intestinal inflammation and promoting gut function, this review provides a basis for the practical application of stilbenoids in animal health and husbandry.

The Origin, Intricate Nature, and Role of the Skin Surface pH (pHSS) in Barrier Integrity, Eczema, and Psoriasis

The inherent acidic nature of the stratum corneum (SC), the so-called “acid mantle”, has a multitude of effects on skin barrier integrity owing to its (patho)physiological role in skin homeostasis, antimicrobial defense, and inflammation. Several salient SC acidifying mechanisms, including the breakdown of FLG (filaggrin) protein, lipid processing, and the activity of the sodium proton pump SLC9A1/NHE1, are indispensable for the structural and functional integrity and cohesion of the SC as they contribute immensely to the origin, generation, maintenance, and overall SC acidification of the skin surface pH (pHss). As many endogenous and exogenous factors can affect the pHss, the pHss can inevitably deviate from its optimum. The elevation of the pHss is often accompanied by abnormalities in SC lipid metabolism and organization, SC cohesion, and SC integrity and is commonly observed in eczema, which is associated with symptoms of dry skin, inflammation, pruritus, and infection. In psoriasis, it seems that the pHss is altered as well; however, in this case, it is likely to be lower than the physiological pHss. Due to the negative effects of an altered pHss in both eczema and psoriasis, it has been suggested to maintain the pHss at physiological levels by utilizing pH-balanced topical cleansers and moisturizers that can improve the skin’s structural and functional integrity by benefiting skin moisturization and the regeneration and organization of the SC barrier. The principal aim of this review is to gather an understanding of the existing research and to stimulate critical thinking and inspire innovative ideas about ‘known unknowns’, considering the origin, intricate nature, and prime role of the pHss in human skin health, as well as the pathogenesis of eczema and psoriasis.

Mining of Candidate Novel Alleles Using GWAS and Haplotype Identification for Rice Blast Resistance

ABSTRACTBlast caused by Pyricularia oryzae (synonym Magnaporthe oryzae) is a major fungal disease affecting productivity and quality in rice‐growing areas globally. A genome‐wide association study (GWAS) was performed using the blast score(s) and whole‐genome sequence data pertaining to a subset of 280 diverse accessions of the IRRI 3 K Rice Genome panel. Continuous variation was observed, with 8.9% of the total accessions resistant, 39.6% moderately resistant, 37.2% moderately susceptible and 14.2% susceptible, with average disease severity ratings of 0 to 3, &gt; 3 to 5, &gt; 5 to 7 and &gt; 7 to 9, respectively, indicating the polygenic inheritance of the trait. We identified potential accessions in different subpopulations with a resistance disease reaction (IRGC 127151 [subtrop], 127738 [ind2], 132245 [aro] and 127130 [aus]), having the lowest average disease ratings of &lt; 2. GWAS revealed the significant association of 22 quantitative trait nucleotides (QTNs)—20 main effect and two interaction effect—linked to blast resistance that led to the identification of 43 plant defence‐related candidate genes. The haplo‐pheno association analysis of the candidate genes (LOC_Os02g06470, LOC_Os02g06510, LOC_Os07g34370, LOC_Os08g29760, LOC_Os10g07470 and LOC_Os12g34290) associated with the superior haplotypes were identified and play a critical role in defence mechanisms. The identified resistant sources hold promise for stacking the superior haplotypes into an elite genetic background using a haplotype‐based breeding approach for the development of cultivars with blast resistance to a wide range of pathotypes.

Exceptionally Preserved Setae: A Possible Morphological Synapomorphy of Cambrian Lophotrochozoans.

Cambrian Lagerstätten yield exceptionally preserved fossils that have greatly improved our understanding of the origin and evolution of animal groups. Brachiopoda, a phylum of bivalved marine invertebrates nested firmly within the lophotrochozoan protostomes, are widely recovered in such Lagerstätten. The marginal chitinous setae (or chaetae) of brachiopods are the most commonly described soft tissue and have been interpreted as performing a defensive and/or sensory role. Despite their relatively common appearance in Cambrian Lagerstätten, the origin, function, and evolution of setae in the Brachiopoda is poorly known. Here, we document exquisitely preserved setal structures from South China and Laurentia paleocontinents giving new insights into their formation, microstructure and preservation mode. New setae typically make their appearance within the follicle of a neighbouring older seta and then branches off laterally forming its own follicle. Setal microstructure is likely to be composed of many canals, highly comparable to setae of their recent counterparts. Moreover, setae recovered from these palaeo-continents present different preservation: aside from the normal preservation of iron oxides and carbonaceous ingredients, some compositions of calcium are also detected in this originally chitinous organization. Investigating the evolutionary origins of chitinous setae, a specialized type found notably in lophotrochozoans such as brachiopods and annelids, reveals its presence in early Cambrian stem groups. This character likely serves as a morphological synapomorphy in lophotrochozoan evolution. However, the dearth of morpho-ultrastructure and comparative studies in Cambrian fossils presents a challenge in fully understanding this evolutionary development.

Exotic cuticular specializations in a Cambrian scalidophoran.

Scalidophora, the ecdysozoan group including priapulids, kinorhynchs and loriciferans, comprises some of the most abundant and ecologically important Cambrian animals. However, reconstructions of the morphology and lifestyles of fossil scalidophorans are often hampered by poor preservation of their submillimetre-scale cuticular specializations. Based on exceptionally preserved small carbonaceous fossils (SCFs), we describe a new scalidophoran-grade animal, Scalidodendron crypticum gen. et sp. nov., from the Early to Middle Cambrian Hess River Formation of northern Canada. The Hess River SCFs comprise pharyngeal teeth, coniform sclerites and hook-like sclerites, all closely comparable to known scalidophoran counterparts. The coniform and hook-like sclerites recurrently associate with arborescent cuticular projections that show multiple orders of branching, morphologically unlike those of any known living or fossil scalidophoran. The fine splintering and inferred post-pharyngeal position of these structures argue against locomotory, feeding and defensive roles with direct analogues in extant counterparts. As such, the arborescent structures of Scalidodendron denote a previously cryptic range of morphological variation in Cambrian scalidophorans, paralleling that of coeval panarthropods but expressed at a fundamentally different level of anatomical organization.

Identification and functional analysis of a novel L-type lectin (NdLTL1) from Neocaridina denticulata sinensis.

This study investigates an L-type lectin, NdLTL1, derived from Neocaridina denticulata sinensis, emphasizing its role in immune defense through carbohydrate binding and bacterial agglutination. Bioinformatics analysis identified 179 lectin sequences, leading to subsequent investigations into the structure and function of NdLTL1. The open reading frame (ORF) of NdLTL1 spans 966 bp and encodes a protein consisting of 321amino acids (36.25kDa), which features a signal peptide, a transmembrane domain and Lectin_leg-like domain. Three-dimensional modeling revealed three antiparallel β-sheets characteristic of Lectin_leg-like domain, confirming evolutionary links with proteins such as VIP36. Protein-carbohydrate and protein-protein interaction studies showed that NdLTL1 binds to both carbohydrates like N-acetylglucosamine, peptidoglycan, lipopolysaccharides (LPS), and mannose, as well as sorting proteins (COPI/COPII). Gene expression analyses indicated that NdLTL1 exhibits the highest expression levels in cardiac tissues and significant upregulation in gills following exposure to Vibrio parahaemolyticus. Recombinant NdLTL1 expressed in Escherichia coli was shown to bind multiple bacterial strains and exhibit calcium-dependent agglutination properties. Enzyme-linked immunosorbent assay (ELISA) confirmed concentration-dependent carbohydrate binding, particularly rapid for LPS. In vitro experiments suggested that recombinant NdLTL1 may promote bacterial growth under nutrient-limited conditions while potentially triggering immune defenses indirectly.

Chimeric cytokine receptor TGF-β RⅡ/IL-21R improves CAR-NK cell function by reversing the immunosuppressive tumor microenvironment of gastric cancer.

Gastric cancer remains a significant global health burden, characterized by regional variations in incidence and poor survival prospects in advanced stages. Natural killer (NK) cells play a crucial role in the body's anti-cancer defense, and chimeric antigen receptor (CAR)-NK cell therapy is gaining attention as a cutting-edge and promising treatment method. This study aims to tackle the challenge of TGF-β-mediated tumor immune evasion within the immunosuppressive tumor microenvironment by designing a novel chimeric cytokine receptor TRII/21 R, which consists of extracellular domains of TGF-β receptor II (TRII) and transmembrane and intracellular domains of IL-21 receptor (21 R) and can convert the immunosuppressive signal from TGF-β in the tumor microenvironment (TME) into an NK cell activation signal through the IL-21R-STAT3 pathway. We successfully constructed NKG2D-CAR-NK cells expressing TRII/21 R and demonstrated strong anti-tumor activity against cancer cells both in vitro and in vivo. The co-expression of TRII/21 R in CAR-NK cells enhanced the cytotoxicity, promoted proliferation and survival capabilities, and reduced the expression of exhaustion markers. In the xenograft mouse model, TRII/21R-CAR-NK cells significantly inhibited tumor growth and improved the survival rate of tumor-bearing mice compared to the mice receiving control CAR-NK cells. Additionally, TRII/21 R co-expression enhanced NK cells' infiltration, activation, and persistence within the tumor, indicating a robust anti-tumor response mediated by the JAK-STAT3 signaling pathway. This study underscores the therapeutic potential of TRII/21R-modified CAR-NK cells as a breakthrough strategy for combating cancer.

The Role of Immune Defense in Serratia marcescens Nosocomial Infections

Developing resistance mechanisms leads to various nosocomial infections caused by opportunistic bacteria. Serratia marcescens are well known to be opportunistic and are equipped with an armory of virulence factors against host immune response. The study aims to detect the immune defense in patients infected with multidrug-resistant S. marcescens. The study includes 132 clinical samples, including burn, wound, otitis media, and urinary tract infection (UTI) at several hospitals in Baghdad, Iraq. All isolates are identified by cultivation on MacConkey agar, nutrient agar, and blood agar, followed by biochemical tests and assessment with the VITEK 2 compact system. The isolates are tested for antibiotic susceptibility tests, interleukin-12 (IL12) levels, neutrophil ability to phagocytosis, and complement C3 and C4 levels. Out of 120 positive cultures, six isolates are identified as S. marcescens. The urine samples are the most isolated source and a higher level of antibiotic resistance was noticed in ampicillin and cefotaxime (100%), whereas a lower level is in imipenem. Stimulation (p ꞊ 0.005) provided a significant increase in IL-12 production. The infection with the S. marcescens stimulated the neutrophil’s phagocytosis process compared with the control. The interplay role of virulence factors in S. marcescens influences its pathogenesis, antibiotic resistance, and immune response, particularly involving neutrophils and IL-12. Understanding these interactions is crucial for developing effective therapeutic strategies.

Modulating the complement system through epitope-specific inhibition by complement C3 inhibitors.

As an integral part of the innate immune system, the complement system is a tightly regulated proteolytic cascade, playing a critical role in microbial defense, inflammation activation, and dying host cell clearance. Complement proteins are now emerging as subjects of intense research and drug development, since dysregulation of the complement system plays a critical role in several diseases and disorders, such as Paroxysmal Nocturnal Hemoglobinuria (PNH) and Geographic Atrophy (GA). Within the complement cascade, complement C3 is the central component, situated at the convergence of all complement activation pathways, rendering it an attractive target for complement-related diseases. However, due to the complicated Structure-Activity Relationship (SAR) of C3, elucidating the mechanisms of C3 inhibition on diverse epitopes is the basis for the rational design of C3-targeted therapeutics. Here, we have developed a set of comprehensive biochemical assays that are tailored to the specific steps within the complement cascade, allowing for a thorough understanding of the pharmacological consequences of different C3 inhibitors at each stage. Utilizing three Model Inhibitors (MIs) with different epitopes, we found that inhibition of MG4/MG5 domains has potent inhibition efficacy across all the complement activation pathways by interrupting C3-C3 convertase interaction, while inhibition of C345C domain displays a bias over the Alternative Pathway (AP) inhibition by impairing AP C3 proconvertase formation. This study elucidates the intricate impact of C3 inhibition by targeting different epitopes, offering valuable insights into understanding the mechanism and facilitating the rational design of C3-targeted therapeutics.

Melatonin biosynthesis, signaling regulation, crosstalk with phytohormones and its role in defence mechanism and ROS scavenging

Melatonin biosynthesis, signaling regulation, crosstalk with phytohormones and its role in defence mechanism and ROS scavenging

Coumarins: Chemical Synthesis, Properties and Applications

Coumarins are compounds characterized by a benzopyrone structure resulting from the condensation of pyrone and a benzene ring. They are commonly found as secondary metabolites in various plants, microorganisms, and sponges. These metabolites play a crucial role in defence mechanisms, and extensive research has revealed numerous biological activities associated with these compounds. Coumarin and its derivatives show significant potential as candidates for new drugs due to their exceptional biocompatibility and a wide range of biological activities, including antimicrobial, anticancer, antimitotic, antioxidant, anti-inflammatory, and anticoagulant properties. Beyond medicinal applications, the simple and versatile scaffold structures of coumarins have found use in fields such as food production, agriculture, cosmetics, and textiles. This review covers the classification of coumarin and its derivatives, as well as various chemical synthesis methods. Furthermore, it delves into the properties, biological activities, and diverse application areas of coumarins.

Advances in the Regulation of Inflammatory Mediators in Nitric Oxide Synthase: Implications for Disease Modulation and Therapeutic Approaches

Nitric oxide synthases (NOS) are crucial enzymes responsible for the production of nitric oxide (NO), a signaling molecule with essential roles in vascular regulation, immune defense, and neurotransmission. The three NOS isoforms, endothelial NOS (eNOS), neuronal NOS (nNOS), and inducible NOS (iNOS), are tightly regulated by inflammatory mediators and cellular signaling pathways. While physiological NO production is vital for maintaining homeostasis, dysregulated NOS activity contributes to the pathogenesis of numerous diseases, including cardiovascular disorders, neurodegenerative conditions, and cancer. Recent advances in understanding the molecular mechanisms of NOS regulation have unveiled novel therapeutic opportunities, including isoform-specific modulators, upstream pathways, and nanotechnology-enhanced delivery systems. This review highlights these advancements, offering insights into how targeting NOS and its regulatory network can enable precise and effective therapeutic strategies for managing inflammation-driven pathologies.