Scavenger Receptor Research Articles

A comparative study of the hypolipidemic effects and mechanisms of action of Laminaria japonica- and Ascophyllum nodosum-derived fucoidans in apolipoprotein E-deficient mice.

The structural characteristics of fucoidans exhibit species and regional diversity. Previous studies have demonstrated that Laminaria japonica- and Ascophyllum nodosum-derived fucoidans have type I and type II fucosyl chains, respectively. These chemical differences may contribute to distinct hypolipidemic effects and mechanisms of action. Chemical analysis demonstrated that the percentage contents of sulfate, glucuronic acid, and galactose were higher in L. japonica-derived fucoidans than those of A. nodosum-derived fucoidans. In hyperlipidemic apolipoprotein E-deficient mice, both A. nodosum- and L. japonica-derived fucoidans significantly decreased the plasma and hepatic levels of total cholesterol and triglyceride, leading to the reduction of atherosclerotic plaques. Western blotting experiments demonstrated that these fucoidans significantly enhanced the expression and levels of scavenger receptor B type 1, cholesterol 7 alpha-hydroxylase A1, and peroxisome proliferator-activated receptor (PPAR)-α, contributing to circulating lipoprotein clearance and fatty acid degradation, respectively. Differentially, L. japonica-derived fucoidan significantly increased the LXR/ATP-binding cassette G8 signaling pathway in the small intestine, as revealed by real-time quantitative PCR, which may lead to further cholesterol and other lipid excretion. Collectively, these data are useful for understanding the hypolipidemic mechanisms of action of seaweed-derived fucoidans, and their potential application for the prevention and/or treatment of atherosclerotic cardiovascular diseases.

The atypical chemokine receptor 2 reduces T cell expansion and tertiary lymphoid tissue but does not limit autoimmune organ injury in lupus-prone B6lpr mice

IntroductionThe atypical chemokine receptor 2 (ACKR2) is a chemokine scavenger receptor, which limits inflammation and organ damage in several experimental disease models including kidney diseases. However, potential roles of ACKR2 in reducing inflammation and tissue injury in autoimmune disorders like systemic lupus erythematosus (SLE) and lupus nephritis are unknown, as well as its effects on systemic autoimmunity. MethodsTo characterize functional roles of ACKR2 in SLE, genetic Ackr2 deficiency was introduced into lupus-prone C57BL/6lpr (Ackr2-/- B6lpr) mice. ResultsUpon inflammatory stimulation in vitro, secreted chemokine levels increased in Ackr2 deficient tubulointerstitial tissue but not glomeruli. Moreover, Ackr2 expression was induced in kidneys and lungs of female C57BL/6lpr mice developing SLE. However, female Ackr2-/- B6lpr mice at 28 weeks of age showed similar renal functional parameters as wildtype (WT)-B6lpr mice. Consistently, assessment of activity and chronicity indices for lupus nephritis revealed comparable renal injury. Interestingly, Ackr2-/- B6lpr mice showed significantly increased renal infiltrates of CD3+ T and B cells, but not neutrophils, macrophages or dendritic cells, with T cells predominantly accumulating in the tubulointerstitial compartment of Ackr2-/- B6lpr mice. In addition, histology demonstrated significantly increased peribronchial lung infiltrates of CD3+ T cells in Ackr2-/- B6lpr mice. Despite this, protein levels of pro-inflammatory chemokines and mRNA expression of inflammatory mediators were not different in kidneys and lungs of WT- and Ackr2-/- B6lpr mice. This data suggests compensatory mechanisms for sufficient chemokine clearance in Ackr2-deficient B6lpr mice in vivo. Analysis of systemic autoimmune responses revealed comparable levels of circulating lupus-associated autoantibodies and glomerular immunoglobulin deposition in the two genotypes. Interestingly, similar to kidney and lung CD4+ T cell numbers and activation were significantly increased in spleens of Ackr2-deficient B6lpr mice. In lymph nodes of Ackr2-/- B6lpr mice abundance of activated dendritic cells decreased, but CD4+ T cell numbers were comparable to WT. Moreover, increased plasma levels of CCL2 were present in Ackr2-/- B6lpr mice, which may facilitate T cell mobilization into spleens and peripheral organs. DiscussionIn summary, we show that ACKR2 prevents expansion of T cells and formation of tertiary lymphoid tissue, but is not essential to limit autoimmune tissue injury in lupus-prone B6lpr mice.

Celastrol nano-emulsions selectively regulate apoptosis of synovial macrophage for alleviating rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune inflammation. Excessive proliferation and inadequate apoptosis of synovial macrophages are the crucial events of RA. Therefore, delivering therapeutic molecules to synovial macrophages specifically to tackle apoptotic insufficiency probably be an efficient way to reduce joint inflammation and bone erosion. Based on the characteristics of dextran sulfate (DS) specifically binding scavenger receptor A (SR-A) on macrophage and celastrol (CLT) inducing apoptosis, we designed synovial macrophage-targeted nano-emulsions encapsulated with CLT (SR-CLTNEs) and explored their anti-RA effect. After intravenous injection, fluorescence-labeled SR-CLTNEs successfully targeted inflammatory joints and synovial macrophages in a mouse model of RA, with the macrophage targeting efficiency of SR-CLTNEs, CLTNEs, and Free DID was 20.53%, 13.93%, and 9.8%, respectively. In vivo and in vitro studies showed that SR-CLTNEs effectively promoted the apoptosis of macrophages, reshaped the balance between apoptosis and proliferation, and ultimately treated RA in a high efficiency and low toxicity manner. Overall, our work demonstrates the efficacy of using SR-CLTNEs as a novel nanotherapeutic approach for RA therapy and the great translational potential of SR-CLTNEs.

Platelets as an inter-player between hyperlipidaemia and atherosclerosis.

Platelet hyperreactivity and hyperlipidaemia contribute significantly to atherosclerosis. Thus, it is desirable to review the platelet-hyperlipidaemia interplay and its impact on atherogenesis. Native low-density lipoprotein (nLDL) and oxidized LDL (oxLDL) are the key proatherosclerotic components of hyperlipidaemia. nLDL binds to the platelet-specific LDL receptor (LDLR) ApoE-R2', whereas oxLDL binds to the platelet-expressed scavenger receptor CD36, lectin-type oxidized LDLR 1 and scavenger receptor class A 1. Ligation of nLDL/oxLDL induces mild platelet activation and may prime platelets for other platelet agonists. Platelets, in turn, can modulate lipoprotein metabolisms. Platelets contribute to LDL oxidation by enhancing the production of reactive oxygen species and LDLR degradation via proprotein convertase subtilisin/kexin type 9 release. Platelet-released platelet factor 4 and transforming growth factor β modulate LDL uptake and foam cell formation. Thus, platelet dysfunction and hyperlipidaemia work in concert to aggravate atherogenesis. Hypolipidemic drugs modulate platelet function, whereas antiplatelet drugs influence lipid metabolism. The research prospects of the platelet-hyperlipidaemia interplay in atherosclerosis are also discussed.

Curcumin Equipped Nanozyme-Like Metal-Organic Framework Platform for the Targeted Atherosclerosis Treatment with Lipid Regulation and Enhanced Magnetic Resonance Imaging Capability.

Atherosclerotic cardiovascular disease (ASCVD) has become the leading cause of death worldwide, and early diagnosis and treatment of atherosclerosis (AS) are crucial for reducing the occurrence of acute cardiovascular events. However, early diagnosis of AS is challenging, and oral anti-AS drugs suffer from limitations like imprecise targeting and low bioavailability. To overcome the aforementioned shortcomings, Cur/MOF@DS is developed, a nanoplatform integrating diagnosis and treatment by loading curcumin (Cur) into metal-organic frameworks with nanozymes and magnetic resonance imaging (MRI) properties. In addition, the surface-modification of dextran sulfate (DS) enables PCN-222(Mn) effectively target scavenger receptor class A in macrophages or foam cells within the plaque region. This nanoplatform employs mechanisms that effectively scavenge excessive reactive oxygen species in the plaque microenvironment, promote macrophage autophagy and regulate macrophage polarization to realize lipid regulation. In vivo and in vitro experiments confirm that this nanoplatform has outstanding MRI performance and anti-AS effects, which may provide a new option for early diagnosis and treatment of AS.

The people behind the papers - Margret Bülow and Pilar Carrera.

Bez is a Class B scavenger receptor in Drosophila that is yet to be characterised. In a new study, Margret Bülow and colleagues uncover a role for Bez in mobilising lipids from Drosophila adipocytes into the ovary for oocyte maturation. To find out more about the people behind the paper, we caught up with first author, Pilar Carrera, and corresponding author, Margret Bülow, Group Leader at the University of Bonn.

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.

Hemoglobin scavenger receptor CD163 as a potential biomarker of hemolysis induced hepatobiliary injury in sickle cell disease.

Sickle cell disease (SCD) associated chronic hemolysis promotes oxidative stress, inflammation and thrombosis leading to organ damage, including liver damage. Hemoglobin scavenger receptor CD163 plays a protective role in SCD by scavenging both hemoglobin-haptoglobin complexes and cell free hemoglobin. A limited number of studies in the past have shown a positive correlation of CD163 expression with poor disease outcomes in patients with SCD. However, the role and regulation of CD163 in SCD related hepatobiliary injury has not been fully elucidated yet. Here, we show that chronic liver injury in SCD patients is associated with elevated levels of hepatic membrane bound CD163. Hemolysis and increase in hepatic heme, hemoglobin and iron levels elevate CD163 expression in the SCD mouse liver. Mechanistically we show that HO-1 positively regulates membrane bound CD163 expression independent of NRF2 signaling in SCD liver. We further demonstrate that of the interaction between CD163 and HO-1 is not dependent on CD163-hemoglobin binding. These findings indicate that CD163 is a potential biomarker of SCD associated hepatobiliary injury. Understanding the role of HO-1 in membrane bound CD163 regulation may help identify novel therapeutic targets for hemolysis induced chronic liver injury.

Immune-Related Gene Profiles and Differential Expression in the Grey Garden Slug Deroceras reticulatum Infected with the Parasitic Nematode Phasmarhabditis hermaphrodita

The grey garden slug (Deroceras reticulatum), a common terrestrial slug native to Europe with a global distribution including North America, is commonly considered the most severe slug pest in agriculture. The nematode Phasmarhabditis hermaphrodita, which has been used in the U.K. and Europe as a commercial biocontrol agent since 1994, has also recently been collected in Oregon and California and has long been considered a candidate biocontrol agent for slug management in the U.S. In this study, we report differential gene expressions in nematode-infected slugs using RNA-seq to identify slug immune-related genes against nematodes. Comparison of gene expression levels between the whole bodies of a nematode-infected slug (N-S) and an uninfected control slug (C-S) revealed that there were a total of 39,380 regulated unigenes, of which 3084 (3%) were upregulated and 6761 (6%) were downregulated at greater than 2-fold change (FC > 2) in the nematode-infected slug. To further investigate the biological functions of differentially expressed genes (DEGs), gene ontology (GO) and functional enrichment analysis were performed to map the DEGs to terms in the GO, eukaryotic ortholog groups of proteins (KOG) and Kyoto Encyclopedia of Genes and Genome Pathway (KEGG) databases. Among these DEGs, approximately 228 genes associated with immunity or immune-related pathways were upregulated 2-fold or more in the N-S compared to C-S. These genes include toll, Imd, JNK, scavenger receptors (SCRs), C-type lectins (CTLs), immunoglobulin-like domains, and JAK/STAT63 signaling pathways. From the RNA-seq results, we selected 18 genes and confirmed their expression levels by qRT-PCR. Our findings provide insights into the immune response of slugs during nematode infection. These studies provide fundamental information that will be valuable for the development of new methods of pest slug control using pathogenic nematodes in the field.

Periportal macrophages protect against commensal-driven liver inflammation.

The liver is the main gateway from the gut, and the unidirectional sinusoidal flow from portal to central veins constitutes heterogenous zones, including the periportal vein (PV) and the pericentral vein zones1-5. However, functional differences in the immune system in each zone remain poorly understood. Here intravital imaging revealed that inflammatory responses are suppressed in PV zones. Zone-specific single-cell transcriptomics detected a subset of immunosuppressive macrophages enriched in PV zones that express high levels of interleukin-10 and Marco, a scavenger receptor that sequesters pro-inflammatory pathogen-associated molecular patterns and damage-associated molecular patterns, and consequently suppress immune responses. Induction of Marco+ immunosuppressive macrophages depended on gut microbiota. In particular, a specific bacterial family, Odoribacteraceae, was identified to induce this macrophage subset through its postbiotic isoallolithocholic acid. Intestinal barrier leakage resulted in inflammation in PV zones, which was markedly augmented in Marco-deficient conditions. Chronic liver inflammatory diseases such as primary sclerosing cholangitis (PSC) and non-alcoholic steatohepatitis (NASH) showed decreased numbers of Marco+ macrophages. Functional ablation of Marco+ macrophages led to PSC-like inflammatory phenotypes related to colitis and exacerbated steatosis in NASH in animal experimental models. Collectively, commensal bacteria induce Marco+ immunosuppressive macrophages, which consequently limit excessive inflammationat the gateway of the liver. Failure of this self-limiting system promotes hepatic inflammatory disorders such as PSC and NASH.

GPR1 and CMKLR1 control lipid metabolism to support development of clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC), the most common type of kidney cancer, is largely incurable in the metastatic setting. ccRCC is characterized by excessive lipid accumulation that protects cells from stress and promotes tumor growth, suggesting that the underlying regulators of lipid storage could represent potential therapeutic targets. Here, we evaluated the regulatory roles of GPR1 and CMKLR1, two G-protein coupled receptors of the pro-tumorigenic adipokine chemerin that is involved in ccRCC lipid metabolism. Both genetic and pharmacological suppression of either receptor suppressed lipid formation and induced multiple forms of cell death, including apoptosis, ferroptosis and autophagy, significantly impeding ccRCC growth in cell lines and patient derived xenograft (PDX) models. Comprehensive lipidomic and transcriptomic profiling of receptor competent and depleted cells revealed overlapping and unique signaling of the receptors granting control over triglyceride synthesis, ceramide production, and fatty acid saturation and class production. Mechanistically, the receptors both enforced suppression of the triglyceride lipase ATGL but also demonstrated distinct functions, such as the unique ability of CMKLR1 to control lipid uptake through regulation of SREBP1c and the CD36 scavenger receptor. Treating PDX models with the CMKLR1-targeting small molecule α-NETA led to a dramatic reduction of tumor growth, lipid storage, and clear cell morphology. Together, these findings provide mechanistic insight into lipid regulation in ccRCC and identify a targetable axis at the core of the histological definition of this tumor that could be exploited therapeutically.

Gut dysbiosis impairs intestinal renewal and lipid absorption in Scarb2 deficiency-associated neurodegeneration.

Scavenger receptor class B, member 2 (SCARB2) is linked to Gaucher disease (GD) and Parkinson's disease (PD). Deficiency in the SCARB2 gene causes progressive myoclonus epilepsy (PME), a rare group of inherited neurodegenerative diseases characterized by myoclonus. We found that Scarb2 deficiency in mice leads to age-dependent dietary lipid malabsorption, accompanied with vitamin E deficiency. Our investigation revealed that Scarb2 deficiency is associated with gut dysbiosis and an altered bile acid pool, leading to hyperactivation of FXR in intestine. Hyperactivation of FXR impairs epithelium renewal and lipid absorption. Patients with SCARB2 mutations have a severe reduction in their vitamin E levels and cannot absorb dietary vitamin E. Finally, inhibiting FXR or supplementing vitamin E ameliorates the neuromotor impairment and neuropathy in Scarb2 knockout mice. These data indicate that gastrointestinal dysfunction is associated with SCARB2 deficiency-related neurodegeneration, and SCARB2-associated neurodegeneration can be improved by addressing the nutrition deficits and gastrointestinal issues.

Nanoparticles loaded with the DNA methyltransferase inhibitor SGI-1027 decrease murine atherosclerosis and inflammation in cultured human macrophages

Aim: The DNA of the atheroma is hypermethylated relative to adjacent healthy vascular tissue. A significant portion of hypermethylated loci in the atheroma DNA map to genes related to macrophage function. Reversing macrophage DNA methylation to physiological levels by targeting DNA methyltransferase (DNMT) activity may therefore slow atherogenesis. Here, the anti-inflammatory and anti-atherogenic activity of macrophage-targeted DNMT inhibitor SGI-1027 were tested. Methods: SGI-1027 was encapsulated into human serum albumin (HSA) nanoparticle (HSANP) functionalized with the PP1 peptide, a macrophage scavenger receptor 1 ligand, fused to a FLAG epitope (S-HSANP-FLAGPP1). Results: Nanoparticle physico-chemical characteristics predicted good marginalization towards the vascular wall, although SGI-1027 encapsulation efficiency was relatively low (~23%). S-HSANP-FLAGPP1 were rapidly internalized compared to non-functionalized and, surprisingly, functionalized void controls, and induced a shift towards an anti-inflammatory profile of secreted cytokines in human THP-1 macrophages. S-HSANP-FLAGPP1 colonized the atheroma and induced a significant ~44% reduction of atherosclerosis burden in the aortic tree of apolipoprotein E (ApoE)-null mice compared to controls. A reduction in aortic root atherosclerosis was observed, although primarily induced by HSANP irrespective of loading or functionalization. No alteration of body weight, non-vascular tissue gross histology, plasma glucose, triglyceride or cholesterol were observed. HSA whether free or structured in nanoparticles, induced a 3–4-fold increase in high-density lipoprotein (HDL) compared to vehicle. Conclusions: Unexpectedly, effects that were likely non-epigenetic and induced by HSA per se were observed. HSANP loaded with SGI-1027 were anti-atherogenic but in an anatomical location-dependent fashion. SGI-1027 displayed a novel anti-inflammatory activity in non-proliferating THP-1 cells, implying that those effects are likely unrelated to DNMT inhibition. HSA elevated HDL per se, thus underlining a possible additional advantage of HSA-based nanocarriers.

Mechanism and functional verification of genes by virulence factors of P. gingivalis in ferroptosis

ObjectivePorphyromonas gingivalis (P. gingivalis) is a key etiological agent in periodontitis and functions as a facultative intracellular microorganism and involves many virulence factors. These virulence factors participate in multiple intracellular processes, like ferroptosis, the mechanistic underpinnings remain to be elucidated. Aim of this study was to investigate the effects of virulence factors on the host cells. DesignHuman umbilical vein endothelial cells (HUVECs) were treated with 4% paraformaldehyde-fixed P. gingivalis, and subsequent alterations in gene expression were profiled via RNA-seq. Further, the molecules associated with ferroptosis were quantitatively analyzed using qRT-PCR and Western blot. ResultsA total of 1125 differentially expressed genes (DEGs) were identified, encompassing 225 upregulated and 900 downregulated. Ferroptosis was conspicuously represented in the kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis, with notable upregulation of Heme oxygenase 1 (HMOX1), Ferritin light chain (FTL), and Solute carrier family 3 member 2 (SLC3A2) and downregulation of Scavenger receptor class A member 5 (SCARA5) and glutaminase (GLS). Random selection of DEGs for validation through qRT-PCR corroborated the RNA-Seq data (R2 = 0.93). Kelch like ECH associated protein 1 (Keap1) protein expression decreased after 4 and 8 h, while NFE2 like bZIP transcription factor 2 (Nrf2) and HMOX1 were elevated, with significant nuclear translocation of Nrf2. ConclusionsThe virulence factors of P. gingivalis may potentially instigating ferroptosis through activation of the Keap1-Nrf2-HMOX1 signaling cascade, in conjunction with modulating the expression of other ferroptosis-associated elements. Further research is necessary to achieve a thorough comprehension of these complex molecular interactions.

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.

Ligand-based Molecular Modeling of HDL Receptor SR-BI Inhibitors As Potent Anti-Hyperlipidemic Agents

Introduction:: The High-density lipoprotein (HDL) receptor, Scavenger receptor class B, type I (SRBI) plays a crucial role in lipoprotein metabolism, cholesterol homeostasis, and atherosclerosis. In the present study, a quantitative structure-activity relationship study (QSAR) investigation was conducted on a data set of 31 novel indolinyl thiazole-based inhibitors of SR-BI mediated lipid uptake. Method:: To build the QSAR model, Multiple linear regression analysis (MLR), partial least square analysis (PLS), and neural analysis (NN) were performed which were further evaluated internally as well as externally for the prediction of activity. The best QSAR model for MLR was selected with a correlation coefficient (r2) of 0.937, cross-validation r2cv of 0.908, and a standard error (S) value of 0.253. For PLS, r2 was 0.937 and for FFNN r2 was 0.961 (for the training set). This was further evaluated externally by a test set having r2 values 0.870 (MLR), 0.863(PLS), and 0.933(neural network) analysis. Result:: The final model comprised hydrophobic parameters (Lipole Z component) and steric parameters (molar refractivity and K alpha2 index). Conclusion:: All these descriptors generated comparable results which prove that the model generated is sound and has good predictability.

Genetic basis for Rapana venosa with different peristome color based on microsatellite, DNA methylation, and transcriptome analysis

Abstract Rapana venosa, a well-known and economic species mainly distributed in the Asian region, has three distinct color patterns in the peristome: pure orange, pure dark stripes, and part stripes. The present study combined microsatellite, DNA methylation, and transcriptome to assess the genetic basis of three color patterns of R. venosa in the peristome. The different color patterns of R. venosa showed no significant genetic differentiation, and each color group was relatively independent with respect to gene flow. Each color pattern showed a high methylation rate of more than 60%. The full-methylation rates for the three color patterns were 34.47%, 35.67%, and 32.54%, respectively. The Gene Ontology (GO) classification and functional enrichment revealed three ontologies: molecular function, cellular components, and biological processes. The function of translation, ribosomal structure, and biogenesis accounted for the top classification, followed by general function prediction. This study also revealed some functional genes related to color and shell formation, including Scavenger receptor cysteine-rich protein (SRCR), beta-carotene ketolase, tyrosinase proteins, and Lustrin A. These findings suggest that the color polymorphism of R. venosa is possibly attributed to environmental effects. The research is also essential for selecting better germplasm for the breeding of Rapana venosa.

In Silico Transcriptomic Expression of MSR1 in Solid Tumors Is Associated with Responses to Anti-PD1 and Anti-CTLA4 Therapies.

Immuno-oncology has gained momentum with the approval of antibodies with clinical activities in different indications. Unfortunately, for anti-PD (L)1 agents in monotherapy, only half of the treated population achieves a clinical response. For other agents, such as anti-CTLA4 antibodies, no biomarkers exist, and tolerability can limit administration. In this study, using publicly available genomic datasets, we evaluated the expression of the macrophage scavenger receptor-A (SR-A) (MSR1) and its association with a response to check-point inhibitors (CPI). MSR1 was associated with the presence of macrophages, dendritic cells (DCs) and neutrophils in most of the studied indications. The presence of MSR1 was associated with macrophages with a pro-tumoral phenotype and correlated with TIM3 expression. MSR1 predicted favorable overall survival in patients treated with anti-PD1 (HR: 0.56, FDR: 1%, p = 2.6 × 10-5), anti PD-L1 (HR: 0.66, FDR: 20%, p = 0.00098) and anti-CTLA4 (HR: 0.37, FDR: 1%, p = 4.8 × 10-5). When specifically studying skin cutaneous melanoma (SKCM), we observed similar effects for anti-PD1 (HR: 0.65, FDR: 50%, p = 0.0072) and anti-CTLA4 (HR: 0.35, FDR: 1%, p = 4.1 × 10-5). In a different dataset of SKCM patients, the expression of MSR1 predicted a clinical response to anti-CTLA4 (AUC: 0.61, p = 2.9 × 10-2). Here, we describe the expression of MSR1 in some solid tumors and its association with innate cells and M2 phenotype macrophages. Of note, the presence of MSR1 predicted a response to CPI and, particularly, anti-CTLA4 therapies in different cohorts of patients. Future studies should prospectively explore the association of MSR1 expression and the response to anti-CTLA4 strategies in solid tumors.

Air Pollution Drives Macrophage Senescence through a Phagolysosome-15-Lipoxygenase Pathway.

Urban particulate matter (PM; uPM) poses significant health risks, particularly to the respiratory system. Fine particles, such as PM2.5, can penetrate deep into the lungs and exacerbate a range of health problems, including emphysema, asthma, and lung cancer. PM exposure is also linked to extrapulmonary disorders such as heart and neurodegenerative diseases. Moreover, prolonged exposure to elevated PM levels can reduce overall life expectancy. Senescence is a dysfunctional cell state typically associated with age but can also be precipitated by environmental stressors. This study aimed to determine whether uPM could drive senescence in macrophages, an essential cell type involved in particulate phagocytosis-mediated clearance. Although it is known that uPM exposure impairs immune function, this deficit is multifaceted and incompletely understood, partly because of the use of particulates such as diesel exhaust particles as a surrogate for true uPM. uPM was collected from several locations in the United States, including Baltimore, Houston, and Phoenix. Bone marrow-derived macrophages were stimulated with uPM or reference particulates (e.g., diesel exhaust particles) to assess senescence-related parameters. We report that uPM-exposed bone marrow-derived macrophages adopt a senescent phenotype characterized by increased IL-1α secretion, senescence-associated β-galactosidase activity, and diminished proliferation. Exposure to allergens failed to elicit such a response, supporting a distinction between different types of environmental exposure. uPM-induced senescence was independent of key macrophage activation pathways, specifically inflammasome and scavenger receptors. However, inhibition of the phagolysosome pathway abrogated senescence markers, supporting this phenotype's attribution to uPM phagocytosis. These data suggest that uPM exposure leads to macrophage senescence, which may contribute to immunopathology.

Atypical chemokine receptor 4 (ACKR4/CCX-CKR): A comprehensive exploration across physiological and pathological landscapes in contemporary research.

Atypical chemokine receptor 4 (ACKR4), also known as CCX-CKR, is a member of the chemokine receptor family that lacks typical G protein signaling activity. Instead, ACKR4 functions as a scavenger receptor that can bind and internalize a wide range of chemokines, influencing their availability and activity in the body. ACKR4 is involved in various physiological processes, such as immune cell trafficking and the development of thymus, spleen, and lymph nodes. Moreover, ACKR4 has been implicated in several pathological conditions, including cancer, heart and lung diseases. In cancer, ACKR4 plays a complex role, acting as a tumor suppressor or promoter depending on the type of cancer and the stage of the disease. For instance, ACKR4 may inhibit the growth and metastasis of breast cancer, but it may also promote the progression of hepatocellular carcinoma and gastric cancer. In inflammatory situations, ACKR4 has been found to modulate the recruitment and activation of immune cells, contributing to the pathogenesis of diseases such as myocardial infraction and pulmonary sarcoidosis. The study of ACKR4 is still ongoing, and further research is needed to fully understand its role in different physiological and pathological contexts. Nonetheless, ACKR4 represents a promising target for the development of novel therapeutic strategies for various diseases.