The CD36 scavenger receptor Bez regulates lipid redistribution from fat body to ovaries in Drosophila.

Lipid distribution in an organism is mediated by the interplay between lipoprotein particles, lipoprotein receptors and class B scavenger receptors of the CD36 family. CD36 is a multifunctional protein mediating lipid uptake, mobilization and signaling at the plasma membrane and inside of the cell. The CD36 protein family has 14 members in Drosophila melanogaster, which allows for the differentiated analysis of their functions. Here, we unravel a role for the so far uncharacterized scavenger receptor Bez in lipid export from Drosophila adipocytes. Bez shares the lipid binding residue with CD36 and is expressed at the plasma membrane of the embryonic, larval and adult fat body. Bez loss of function lowers the organismal availability of storage lipids and blocks the maturation of egg chambers in ovaries. We demonstrate that Bez interacts with the APOB homolog Lipophorin at the plasma membrane of adipocytes and trace the Bez-dependent transfer of an alkyne-labeled fatty acid from adipocytes to Lipophorin. Our study demonstrates how lipids are distributed by scavenger receptor-lipoprotein interplay and contribute to the metabolic control of development.

Transfer of Cell-Surface Antigens by Scavenger Receptor CD36 Promotes Thymic Regulatory T Cell Receptor Repertoire Development and Allo-tolerance.

The development of T cell tolerance in the thymus requires the presentation of host proteins by multiple antigen-presenting cell (APC) types. However, the importance of transferring host antigens from transcription factor AIRE-dependent medullary thymic epithelial cells (mTECs) to bone marrow (BM) APCs is unknown. We report that antigen was primarily transferred from mTECs to CD8α+ dendritic cells (DCs) and showed that CD36, a scavenger receptor selectively expressed on CD8α+ DCs, mediated the transfer of cell-surface, but not cytoplasmic, antigens. The absence of CD8α+ DCs or CD36 altered thymic T cell selection, as evidenced by TCR repertoire analysis and the loss of allo-tolerance in murine allogeneic BM transplantation (allo-BMT) studies. Decreases in these DCs and CD36 expression in peripheral blood of human allo-BMT patients correlated with graft-versus-host disease. Our findings suggest that CD36 facilitates transfer of mTEC-derived cell-surface antigen on CD8α+ DCs to promote tolerance to host antigens during homeostasis and allo-BMT.

Scavenger receptor B2, a type III membrane pattern recognition receptor, senses LPS and activates the IMD pathway in crustaceans.

The immune deficiency (IMD) pathway is critical for elevating host immunity in both insects and crustaceans. The IMD pathway activation in insects is mediated by peptidoglycan recognition proteins, which do not exist in crustaceans, suggesting a previously unidentified mechanism involved in crustacean IMD pathway activation. In this study, we identified a Marsupenaeus japonicus B class type III scavenger receptor, SRB2, as a receptor for activation of the IMD pathway. SRB2 is up-regulated upon bacterial challenge, while its depletion exacerbates bacterial proliferation and shrimp mortality via abolishing the expression of antimicrobial peptides. The extracellular domain of SRB2 recognizes bacterial lipopolysaccharide (LPS), while its C-terminal intracellular region containing a cryptic RHIM-like motif interacts with IMD, and activates the pathway by promoting nuclear translocation of RELISH. Overexpressing shrimp SRB2 in Drosophila melanogaster S2 cells potentiates LPS-induced IMD pathway activation and diptericin expression. These results unveil a previously unrecognized SRB2-IMD axis responsible for antimicrobial peptide induction and restriction of bacterial infection in crustaceans and provide evidence of biological diversity of IMD signaling in animals. A better understanding of the innate immunity of crustaceans will permit the optimization of prevention and treatment strategies against the arising shrimp diseases.

Functional role of Ash2l in oxLDL induced endothelial dysfunction and atherosclerosis.

Endothelial injury and dysfunction in the artery wall fuel the process of atherosclerosis. As a key epigenetic regulator, Ash2l (Absent, small, or homeotic-Like 2) is involved in regulating vascular injury and its complications. However, the role of Ash2l in atherosclerosis has not yet been fully elucidated. Here, we found increased Ash2l expression in high-cholesterol diet-fed ApoE-/- mice and oxidized LDL (oxLDL) treated endothelial cells (ECs). Furthermore, Ash2l promoted the scavenger receptors transcription by catalyzing histone H3 lysine 4 (H3K4) trimethylation at the promoter region of transcription factor peroxisome proliferator-activated receptor-γ (PPARγ) and triggered the activation of the pro-inflammatory nuclear factor-kappa B (NF-κB) by enhancing interaction between CD36 and toll-like receptor 4 (TLR4). Meanwhile, enhanced expression of scavenger receptors drove more oxLDL uptake by ECs. In vivo studies revealed that ECs-specific Ash2l knockdown reduced atherosclerotic lesion formation and promoted fibrous cap stability in the aorta of ApoE-/- mice, which was partly associated with a reduced endothelial activation by suppressing scavenger receptors and the uptake of lipids by ECs. Collectively, our findings identify Ash2l as a novel regulator that mediates endothelial injury and atherosclerosis. Targeting Ash2l may provide valuable insights for developing novel therapeutic candidates for atherosclerosis.

Macrophage P2Y6 receptor deletion attenuates atherosclerosis by limiting foam cell formation through phospholipase Cß/store-operated calcium entry/calreticulin/scavenger receptor A pathways.

BACKGROUND AND AIMS: Macrophage-derived foam cells play a causal role during the pathogenesis of atherosclerosis. P2Y6 receptor (P2Y6R) highly expressed has been considered as a disease-causing factor in atherogenesis, but the detailed mechanism remains unknown. This study aims to explore P2Y6R in regulation of macrophage foaming, atherogenesis, and its downstream pathways. Furthermore, the present study sought to find a potent P2Y6R antagonist and investigate the feasibility of P2Y6R-targeting therapy for atherosclerosis. METHODS: The P2Y6R expression was examined in human atherosclerotic plaques and mouse artery. Atherosclerosis animal models were established in whole-body P2Y6R or macrophage-specific P2Y6R knockout mice to evaluate the role of P2Y6R. RNA sequencing, DNA pull-down experiments, and proteomic approaches were performed to investigate the downstream mechanisms. High-throughput Glide docking pipeline from repurposing drug library was performed to find potent P2Y6R antagonists. RESULTS: The P2Y6R deficiency alleviated atherogenesis characterized by decreasing plaque formation and lipid deposition of the aorta. Mechanically, deletion of macrophage P2Y6R significantly inhibited uptake of oxidized low-density lipoprotein through decreasing scavenger receptor A expression mediated by phospholipase Cß/store-operated calcium entry pathways. More importantly, P2Y6R deficiency reduced the binding of scavenger receptor A to CALR, accompanied by dissociation of calreticulin and STIM1. Interestingly, thiamine pyrophosphate was found as a potent P2Y6R antagonist with excellent P2Y6R antagonistic activity and binding affinity, of which the pharmacodynamic effect and mechanism on atherosclerosis were verified. CONCLUSIONS: Macrophage P2Y6R regulates phospholipase Cß/store-operated calcium entry/calreticulin signalling pathway to increase scavenger receptor A protein level, thereby improving foam cell formation and atherosclerosis, indicating that the P2Y6R may be a potential therapeutic target for intervention of atherosclerotic diseases using P2Y6R antagonists including thiamine pyrophosphate.

Nebulized Inhalation of Peptide-Modified DNA Origami To Alleviate Acute Lung Injury.

Acute lung injury (ALI) is a severe inflammatory lung disease, with high mortality rates. Early intervention by reactive oxygen species (ROS) scavengers could reduce ROS accumulation, break the inflammation expansion chain in alveolar macrophages (AMs), and avoid irreversible damage to alveolar epithelial and endothelial cells. Here, we reported cell-penetrating R9 peptide-modified triangular DNA origami nanostructures (tDONs-R9) as a novel nebulizable drug that could reach the deep alveolar regions and exhibit an enhanced uptake preference of macrophages. tDONs-R9 suppressed the expression of pro-inflammatory cytokines and drove polarization toward the anti-inflammatory M2 phenotype in macrophages. In the LPS-induced ALI mouse model, treatment with nebulized tDONs-R9 alleviated the overwhelming ROS, pro-inflammatory cytokines, and neutrophil infiltration in the lungs. Our study demonstrates that tDONs-R9 has the potential for ALI treatment, and the programmable DNA origami nanostructures provide a new drug delivery platform for pulmonary disease treatment with high delivery efficiency and biosecurity.

Relative Adrenal Insufficiency Is a Risk Factor for Pediatric Sepsis: A Proof-of-Concept Study.

Glucocorticoid (GC) therapy had been strongly recommended for pediatric sepsis (grade 1A). However, the recommendation was changed to grade 2C in 2020 due to weak evidence. About 32.8% of patients with pediatric septic develop relative adrenal insufficiency (RAI). But whether GC therapy should be determined by RAI status is controversial. This study utilized 21-day-old SF1CreSRBIfl/fl mice as the first pediatric RAI mouse model to assess the pathogenesis of RAI and evaluate GC therapy. RAI mice exhibited a substantially higher mortality rate in cecal ligation and puncture and cecal slurry-induced sepsis. These mice featured persistent inflammatory responses and were effectively rescued by GC therapy. RNA sequencing analysis revealed persistent inflammatory responses in RAI mice, caused by transcriptional dysregulation of AP-1 and NF-κB, and cytokine-induced secondary inflammatory response. Our findings support a precision medicine approach to guide GC therapy for pediatric patients based on the status of RAI.

Macrophage KLF15 prevents foam cell formation and atherosclerosis via transcriptional suppression of OLR-1.

BACKGROUND: Macrophage-derived foam cells are a hallmark of atherosclerosis. Scavenger receptors, including lectin-like oxidized low-density lipoprotein (LDL) receptor-1 (OLR-1), are the principal receptors responsible for the uptake and modification of LDL, facilitating macrophage lipid load and the uptake of oxidized LDL by arterial wall cells. Krüppel-like factor 15 (KLF15) is a transcription factor that regulates the expression of genes by binding to the promoter during transcription. Therefore, this study aimed to investigate the precise role of macrophage KLF15 in atherogenesis. METHODS: We used two murine models of atherosclerosis: mice injected with an adeno-associated virus (AAV) encoding the Asp374-to-Tyr mutant version of human PCSK9, followed by 12 weeks on a high-fat diet (HFD), and ApoE-/-- mice on a HFD. We subsequently injected mice with AAV-KLF15 and AAV-LacZ to assess the role of KLF15 in the development of atherosclerosis in vivo. Oil Red O, H&E, and Masson's trichome staining were used to evaluate atherosclerotic lesions. Western blots and RT-qPCR were used to assess protein and mRNA levels, respectively. RESULTS: We determined that KLF15 expression was downregulated during atherosclerosis formation, and KLF15 overexpression prevented atherosclerosis progression. KLF15 expression levels did not affect body weight or serum lipid levels in mice. However, KLF15 overexpression in macrophages prevented foam cell formation by reducing OLR-1-meditated lipid uptake. KLF15 directly targeted and transcriptionally downregulated OLR-1 levels. Restoration of OLR-1 reversed the beneficial effects of KLF15 in atherosclerosis. CONCLUSION: Macrophage KLF15 transcriptionally downregulated OLR-1 expression to reduce lipid uptake, thereby preventing foam cell formation and atherosclerosis. Thus, our results suggest that KLF15 is a potential therapeutic target for atherosclerosis.

Ligand-dependent interactions between SR-B1 and S1PR1 in macrophages and atherosclerotic plaques.

HDLs carry sphingosine-1-phosphate (S1P) and stimulate signaling pathways in different cells including macrophages and endothelial cells, involved in atherosclerotic plaque development. HDL signaling via S1P relies on the HDL receptor scavenger receptor class B, type I (SR-B1) and the sphingosine-1-phosphate receptor 1 (S1PR1), which interact when both are heterologously overexpressed in the HEK293 cell line. In this study, we set out to test if SR-B1 and S1PR1 interacted in primary murine macrophages in culture and atherosclerotic plaques. We used knock-in mice that endogenously expressed S1PR1 tagged with eGFP-(S1pr1eGFP/eGFP mice), combined with proximity ligation analysis to demonstrate that HDL stimulates the physical interaction between SR-B1 and S1PR1 in primary macrophages, that this is dependent on HDL-associated S1P and can be blocked by an inhibitor of SR-B1's lipid transfer activity or an antagonist of S1PR1. We also demonstrate that a synthetic S1PR1-selective agonist, SEW2871, stimulates the interaction between SR-B1 and S1PR1 and that this was also blocked by an inhibitor of SR-B1's lipid transport activity. Furthermore, we detected abundant SR-B1/S1PR1 complexes in atherosclerotic plaques of S1pr1eGFP/eGFP mice that also lacked apolipoprotein E. Treatment of mice with the S1PR1 antagonist, Ex26, for 12 h disrupted the SR-B1-S1PR1 interaction in atherosclerotic plaques. These findings demonstrate that SR-B1 and S1PR1 form ligand-dependent complexes both in cultured primary macrophages and within atherosclerotic plaques in mice and provide mechanistic insight into how SR-B1 and S1PR1 participate in mediating HDL signaling to activate atheroprotective responses in macrophages.

Development and validation of a purification system for functional full-length human SR-B1 and CD36.

Scavenger receptor class B type 1 (SR-B1) and CD36 are both members of the class B scavenger receptor family that play important roles in lipoprotein metabolism and atherosclerotic disease. SR-B1 is the primary receptor for high-density lipoproteins, while CD36 is the receptor responsible for the internalization of oxidized low-density lipoproteins. Despite their importance, class B scavenger receptor structure has only been studied by functional domain or peptide fragments-there are currently no reports of utilizing purified full-length protein. Here we report the successful expression and purification of full-length human SR-B1 and CD36 using an Spodoptera frugiperda insect cell system. We demonstrate that both SR-B1 and CD36 retained their normal functions in Spodoptera frugiperda cells, including lipoprotein binding, lipid transport, and the formation of higher order oligomers in the plasma membrane. Purification schemes for both scavenger receptors were optimized and their purity was confirmed by SDS-PAGE. Both purified scavenger receptors were assessed for stability by thermal shift assay and shown to maintain stable melting temperatures up to 6 weeks post-purification. Microscale thermophoresis was used to demonstrate that purified SR-B1 and CD36 were able to bind their native lipoprotein ligands. Further, there was no difference in affinity of SR-B1 for high-density lipoprotein or CD36 for oxidized low-density lipoprotein, when comparing glycosylated and deglycosylated receptors. These studies mark a significant step forward in creating physiologically relevant tools to study scavenger receptor function and lay the groundwork for future functional studies and determination of receptor structure.

"Affimer" synthetic protein scaffolds block oxidized LDL binding to the LOX-1 scavenger receptor and inhibit ERK1/2 activation.

In multicellular organisms, a variety of lipid-protein particles control the systemic flow of triacylglycerides, cholesterol, and fatty acids between cells in different tissues. The chemical modification by oxidation of these particles can trigger pathological responses, mediated by a group of membrane proteins termed scavenger receptors. The lectin-like oxidized low-density lipoprotein (LOX-1) scavenger receptor binds to oxidized low-density lipoprotein (oxLDL) and mediates both signaling and trafficking outcomes. Here, we identified five synthetic proteins termed Affimers from a phage display library, each capable of binding recombinant LOX-1 extracellular (oxLDL-binding) domain with high specificity. These Affimers, based on a phytocystatin scaffold with loop regions of variable sequence, were able to bind to the plasma membrane of HEK293T cells exclusively when human LOX-1 was expressed. Binding and uptake of fluorescently labeled oxLDL by the LOX-1-expressing cell model was inhibited with subnanomolar potency by all 5 Affimers. ERK1/2 activation, stimulated by oxLDL binding to LOX-1, was also significantly inhibited (p < 0.01) by preincubation with LOX-1-specific Affimers, but these Affimers had no direct agonistic effect. Molecular modeling indicated that the LOX-1-specific Affimers bound predominantly via their variable loop regions to the surface of the LOX-1 lectin-like domain that contains a distinctive arrangement of arginine residues previously implicated in oxLDL binding, involving interactions with both subunits of the native, stable scavenger receptor homodimer. These data provide a new class of synthetic tools to probe and potentially modulate the oxLDL/LOX-1 interaction that plays an important role in vascular disease.

Mitochondria-Derived Reactive Oxygen Species Contribute to Synergistic Interaction of Diabetes and Hypertension in Causing Chronic Kidney Injury.

Diabetes (DM) and hypertension (HTN) are major risk factors for chronic kidney injury, together accounting for >70% of end-stage renal disease. The combination of DM and HTN significantly accelerates development of renal injury; however, the underlying mechanisms of this synergy are still poorly understood. This study assessed whether mitochondria (MT) dysfunction is essential in developing renal injury in a rat model with combined DM and HTN. Type 1 DM was induced in Wistar rats by streptozotocin (STZ). HTN was induced six weeks later by inter-renal aorta constriction between the renal arteries, so that right kidneys were exposed to HTN while left kidneys were exposed to normotension. Kidneys exposed to DM or HTN alone had only mild glomerular injury and urinary albumin excretion (UAE). In contrast, kidneys exposed to DM plus 8 weeks HTN had significantly increased UAE and glomerular structural damage with reduced glomerular filtration rate. Marked increases in MT-derived reactive oxygen species (ROS) were also observed in right kidneys exposed to HTN+DM. We further tested whether treatment with MT-targeted antioxidant (MitoTEMPO) after the onset of HTN attenuates renal injury in rats with DM+HTN. Results show that kidneys in DM+AC+MitoTEMPO rats had lower UAE, less glomerular damage, and preserved MT function compared to untreated DM+AC rats. Our studies indicate that MT-derived ROS play a major role in promoting kidney dysfunction when DM is combined with HTN. Preserving MT function might be a potential therapeutic approach to halt the development of renal injury when DM coexists with HTN.

Truncated GPNMB, a microglial transmembrane protein, serves as a scavenger receptor for oligomeric ß-amyloid peptide1-42 in primary type 1 microglia.

Glycoprotein non-metastatic melanoma protein B (GPNMB) is up-regulated in one subtype of microglia (MG) surrounding senile plaque depositions of amyloid-beta (Aß) peptides. However, whether the microglial GPNMB can recognize the fibrous Aß peptides as ligands remains unknown. In this study, we report that the truncated form of GPNMB, the antigen for 9F5, serves as a scavenger receptor for oligomeric Aß1-42 (o-Aß1-42) in rat primary type 1 MG. 125I-labeled o-Aß1-42 exhibited specific and saturable endosomal/lysosomal degradation in primary-cultured type 1 MG from GPNMB-expressing wild-type mice, whereas the degradation activity was markedly reduced in cells from Gpnmb-knockout mice. The Gpnmb-siRNA significantly inhibits the degradation of 125I-o-Aß1-42 by murine microglial MG5 cells. Therefore, GPNMB contributes to mouse MG's o-Aß1-42 clearance. In rat primary type 1 MG, the cell surface expression of truncated GPNMB was confirmed by a flow cytometric analysis using a previously established 9F5 antibody. 125I-labeled o-Aß1-42 underwent endosomal/lysosomal degradation by rat primary type 1 MG in a dose-dependent fashion, while the 9F5 antibody inhibited the degradation. The binding of 125I-o-Aß1-42 to the rat primary type 1 MG was inhibited by 42% by excess unlabeled o-Aß1-42, and by 52% by the 9F5 antibody. Interestingly, the 125I-o-Aß1-42 degradations by MG-like cells from human-induced pluripotent stem cells was inhibited by the 9F5 antibody, suggesting that truncated GPNMB also serve as a scavenger receptor for o-Aß1-42 in human MG. Our study demonstrates that the truncated GPNMB (the antigen for 9F5) binds to oligomeric form of Aß1-42 and functions as a scavenger receptor on MG, and 9F5 antibody can act as a blocking antibody for the truncated GPNMB.

Inhibition of NADPH oxidase 2 enhances resistance to viral neuroinflammation by facilitating M1-polarization of macrophages at the extraneural tissues.

BACKGROUND: Macrophages play a pivotal role in the regulation of Japanese encephalitis (JE), a severe neuroinflammation in the central nervous system (CNS) following infection with JE virus (JEV). Macrophages are known for their heterogeneity, polarizing into M1 or M2 phenotypes in the context of various immunopathological diseases. A comprehensive understanding of macrophage polarization and its relevance to JE progression holds significant promise for advancing JE control and therapeutic strategies. METHODS: To elucidate the role of NADPH oxidase-derived reactive oxygen species (ROS) in JE progression, we assessed viral load, M1 macrophage accumulation, and cytokine production in WT and NADPH oxidase 2 (NOX2)-deficient mice using murine JE model. Additionally, we employed bone marrow (BM) cell-derived macrophages to delineate ROS-mediated regulation of macrophage polarization by ROS following JEV infection. RESULTS: NOX2-deficient mice exhibited increased resistance to JE progression rather than heightened susceptibility, driven by the regulation of macrophage polarization. These mice displayed reduced viral loads in peripheral lymphoid tissues and the CNS, along with diminished infiltration of inflammatory cells into the CNS, thereby resulting in attenuated neuroinflammation. Additionally, NOX2-deficient mice exhibited enhanced JEV-specific Th1 CD4 + and CD8 + T cell responses and increased accumulation of M1 macrophages producing IL-12p40 and iNOS in peripheral lymphoid and inflamed extraneural tissues. Mechanistic investigations revealed that NOX2-deficient macrophages displayed a more pronounced differentiation into M1 phenotypes in response to JEV infection, thereby leading to the suppression of viral replication. Importantly, the administration of H2O2 generated by NOX2 was shown to inhibit M1 macrophage polarization. Finally, oral administration of the ROS scavenger, butylated hydroxyanisole (BHA), bolstered resistance to JE progression and reduced viral loads in both extraneural tissues and the CNS, along with facilitated accumulation of M1 macrophages. CONCLUSION: In light of our results, it is suggested that ROS generated by NOX2 play a role in undermining the control of JEV replication within peripheral extraneural tissues, primarily by suppressing M1 macrophage polarization. Subsequently, this leads to an augmentation in the viral load invading the CNS, thereby facilitating JE progression. Hence, our findings ultimately underscore the significance of ROS-mediated macrophage polarization in the context of JE progression initiated JEV infection.

TiN as Radical Scavenger in Fe─N─C Aerogel Oxygen Reduction Catalyst for Durable Fuel Cell.

Fe─N─C is the most promising alternative to platinum-based catalysts to lower the cost of proton-exchange-membrane fuel cell (PEMFC). However, the deficient durability of Fe─N─C has hindered their application. Herein, a TiN-doped Fe─N─C (Fe─N─C/TiN) is elaborately synthesized via the sol-gel method for the oxygen-reduction reaction (ORR) in PEMFC. The interpenetrating network composed by Fe─N─C and TiN can simultaneously eliminate the free radical intermediates while maintaining the high ORR activity. As a result, the H2O2 yields of Fe─N─C/TiN are suppressed below 4%, ≈4 times lower than the Fe─N─C, and the half-wave potential only lost 15 mV after 30 kilo-cycle accelerated durability test (ADT). In a H2─O2 fuel cell assembled with Fe─N─C/TiN, it presents 980 mA cm-2 current density at 0.6 V, 880 mW cm-2 peak power density, and only 17 mV voltage loss at 0.80 A cm-2 after 10 kilo-cycle ADT. The experiment and calculation results prove that the TiN has a strong adsorption interaction for the free radical intermediates (such as *OH, *OOH, etc.), and the radicals are scavenged subsequently. The rational integration of Fe single-atom, TiN radical scavenger, and highly porous network adequately utilize the intrinsic advantages of composite structure, enabling a durable and active Pt-metal-free catalyst for PEMFC.

Carbonized Polymer Dot-Tannic Acid Nanoglue: Tissue Reinforcement with Concurrent Fluorescent Tracking, Insulin Delivery, and Reactive Oxygen Species Regulation for Normal and Diabetic Wound Healing.

Nanotizing biosealant components offer a multitude of chemical functionalities for superior adhesion-cohesion, delivering unique properties for comprehensive wound healing that are otherwise impossible to achieve using commercial variants. For the first time, a two-step controlled hydrothermal pyrolysis is reported to nanotize dopamine, phloroglucinol, and glutaraldehyde into carbon dot (CD) to be subsequently converted into carbonized polymer dot (CPD) with gelatin as a co-substrate. Chemical crosslinking of CD with gelatin through Schiff base formation before the second pyrolysis step ensures a complex yet porous polymeric network. The retention of chemical functionalities indigenous to CD substrates and gelatin along with the preservation of CD photoluminescence in CPD for optical tracking is achieved. A unique nanoformulation is created with the CPD through tannic acid (TA) grafting evolving CPD-TA nanoglue demonstrating ≈1.32 MPa strength in lap shear tests conducted on porcine skin, surpassing traditional bioadhesives. CPD-TA nanoglue uploaded insulin as chosen cargo disbursal at the wound site for healing normal and in vitro diabetic wound models using HEKa cells with extraordinary biocompatibility. Most importantly, CPD-TA can generate reactive oxygen species (ROS) and scavenge simultaneously under ambient conditions (23 W white LED or dark) for on-demand sterilization or aiding wound recovery through ROS scavenging.

Combination of scavenger receptor-A with anti-cyclic citrullinated peptide antibody for the diagnosis of rheumatoid arthritis.

OBJECTIVES: The routine biomarkers for rheumatoid arthritis (RA), including anticyclic citrullinated peptide antibody (anti-CCP), rheumatoid factor (RF), immunoglobulin M (IgM), erythrocyte sedimentation rate (ESR), and C-reaction protein (CRP) have limited sensitivity and specificity. Scavenger receptor-A (SR-A) is a novel RA biomarker identified by our group recently, especially for seronegative RA. Here, we performed a large-scale multicentre study to further assess the diagnostic value of SR-A in combination with other biomarkers for RA. METHODS: The performance of SR-A in combination with other biomarkers for RA diagnosis was first revealed by a pilot study, and was further elucidated by a large-scale multicentre study. A total of 1129 individuals from 3 cohorts were recruited in the study, including RA patients, healthy controls, and patients with other common rheumatic diseases. Diagnostic properties were evaluated by the covariate-adjusted receiver-operating characteristic (AROC) curve, sensitivity, specificity and clinical association, respectively. RESULTS: Large-scale multicentre analysis showed that SR-A and anti-CCP dual combination was the optimal method for RA diagnosis, increasing the sensitivity of anti-CCP by 13% (87% vs 74%) while maintaining a specificity of 90%. In early RA patients, SR-A and anti-CCP dual combination also showed promising diagnostic value, increasing the sensitivity of anti-CCP by 7% (79% vs 72%) while maintaining a specificity of 94%. Moreover, SR-A and anti-CCP dual combination was correlated with ESR, IgM, and autoantibodies of RA patients, further revealing its clinical significance. CONCLUSION: SR-A and anti-CCP dual combination could potentially improve early diagnosis of RA, thus improving the prognosis and reducing mortality.

Necrophages and necrophiles: a review of their antibacterial defenses and biotechnological potential.

With antibiotic resistance on the rise, there is an urgent need for new antibacterial drugs and products to treat or prevent infection. Many such products in current use, for example human and veterinary antibiotics and antimicrobial food preservatives, were discovered and developed from nature. Natural selection acts on all living organisms and the presence of bacterial competitors or pathogens in an environment can favor the evolution of antibacterial adaptations. In this review, we ask if vultures, blow flies and other carrion users might be a good starting point for antibacterial discovery based on the selection pressure they are under from bacterial disease. Dietary details are catalogued for over 600 of these species, bacterial pathogens associated with the diets are described, and an overview of the antibacterial defenses contributing to disease protection is given. Biotechnological applications for these defenses are then discussed, together with challenges facing developers and possible solutions. Examples include use of (a) the antimicrobial peptide (AMP) gene sarcotoxin IA to improve crop resistance to bacterial disease, (b) peptide antibiotics such as serrawettin W2 as antibacterial drug leads, (c) lectins for targeted drug delivery, (d) bioconversion-generated chitin as an antibacterial biomaterial, (e) bacteriocins as antibacterial food preservatives and (f) mutualistic microbiota bacteria as alternatives to antibiotics in animal feed. We show that carrion users encounter a diverse range of bacterial pathogens through their diets and interactions, have evolved many antibacterial defenses, and are a promising source of genes, molecules, and microbes for medical, agricultural, and food industry product development.

trans-Cyclooctenes as Scavengers of Bromine Involved in Catalytic Bromination.

Scavengers that capture reactive chemical substances are used to prevent the decomposition of materials. However, in the field of catalysis, the development of scavengers that inhibit background pathways has attracted little attention, although the concept will open up an otherwise inaccessible reaction space. In catalytic bromination, fast non-catalyzed background reactions disturb the catalytic control of the selectivity, even when using N-bromoamide reagents, which have a milder reactivity than bromine (Br2 ). Here, we developed a trans-cyclooctene (TCO) bearing a 2-pyridylethyl group to efficiently retard background reactions by capturing Br2 in bromocyclization using N-bromosuccinimide. The use of less than a stoichiometric amount of the TCO was sufficient to inhibit non-catalyzed reactions, and mechanistic studies using the TCO revealed that in situ-generated Br2 provides non-catalyzed reaction pathways based on a chain mechanism. The TCO is useful as an additive for improving enantioselectivity and regioselectivity in catalytic reactions. Cooperative systems using the TCO with selective catalysts offer an alternative strategy for optimizing catalyst-controlled selectivity during bromination. Moreover, it also served as an indicator of Br2 involved in catalytic reaction pathways; thus, the TCO was useful as a probe for mechanistic investigations into the involvement of Br2 in bromination reactions of interest.

Ferritin-mediated neutrophil extracellular traps formation and cytokine storm via macrophage scavenger receptor in sepsis-associated lung injury.

BACKGROUND: Sepsis is a severe systemic inflammatory disorder manifested by a dysregulated immune response to infection and multi-organ failure. Numerous studies have shown that elevated ferritin levels exist as an essential feature during sepsis and are able to suggest patients' prognoses. At the same time, the specific mechanism of ferritin-induced inflammatory injury remains unclear. METHODS: Hyper-ferritin state during inflammation was performed by injecting ferritin into a mouse model and demonstrated that injection of ferritin could induce a systemic inflammatory response and increase neutrophil extracellular trap (NET) formation.Padi4-/-, Elane-/- and Cybb-/- mice were used for the NETs formation experiment. Western blot, immunofluorescence, ELISA, and flow cytometry examined the changes in NETs, inflammation, and related signaling pathways. RESULTS: Ferritin induces NET formation in a peptidylarginine deiminase 4 (PAD4), neutrophil elastase (NE), and reactive oxygen species (ROS)-dependent manner, thereby exacerbating the inflammatory response. Mechanistically, ferritin induces the expression of neutrophil macrophage scavenger receptor (MSR), which promotes the formation of NETs. Clinically, high levels of ferritin in patients with severe sepsis correlate with NETs-mediated cytokines storm and are proportional to the severity of sepsis-induced lung injury. CONCLUSIONS: In conclusion, we demonstrated that hyper-ferritin can induce systemic inflammation and increase NET formation in an MSR-dependent manner. This process relies on PAD4, NE, and ROS, further aggravating acute lung injury. In the clinic, high serum ferritin levels are associated with elevated NETs and worse lung injury, which suggests a poor prognosis for patients with sepsis. Our study indicated that targeting NETs or MSR could be a potential treatment to alleviate lung damage and systemic inflammation during sepsis. Video Abstract.