Receptor Type Research Articles

Organotypic brain slices as a model to study the neurotropism of the highly pathogenic Nipah and Ebola viruses.

Nipah virus (NiV) and Ebola virus (EBOV) are highly pathogenic zoonotic viruses with case fatality rates of up to 90%. While the brain is a known target organ following NiV infection, involvement of the central nervous system in EBOV-infected patients only became more evident after the West African epidemic in 2013-2016. To gain a deeper comprehension of the neurotropism of NiV and EBOV with respect to target cells, affected brain regions and local inflammatory responses, murine organotypic brain slices (BS) were established and infected. Both NiV and EBOV demonstrated the capacity to infect BS from adult wt mice and mice lacking the receptor for type I IFNs (IFNAR-/-) and targeted various cell types. NiV was observed to replicate in BS derived from both mouse strains, yet no release of infectious particles was detected. In contrast, EBOV replication was limited in both BS models. The release of several pro-inflammatory cytokines and chemokines, including eotaxin, IFN-γ, IL-1α, IL-9, IL-17a and keratinocyte-derived chemokine (KC), was observed in both virus-infected models, suggesting a potential role of the inflammatory response in NiV- or EBOV-induced neuropathology. It is noteworthy that the choroid plexus was identified as a highly susceptible target for EBOV and NiV infection, suggesting that the blood-cerebrospinal fluid barrier may serve as a potential entry point for these viruses.

Corticotropin-Releasing Factor Modulates Binge-Like Ethanol Drinking in a Sex-Dependent Manner: Impact of Amygdala Deletion and Inhibition of a Central Amygdala to Lateral Hypothalamus Circuit

BackgroundBinge alcohol drinking is a dangerous behavior that can contribute to the development of more severe alcohol use disorder. Importantly, the rate and severity of alcohol use disorder has historically differed between men and women, suggesting that there may be sex differences in the central mechanisms that modulate alcohol (ethanol) consumption. Corticotropin-releasing factor (CRF) is a centrally expressed neuropeptide that has been implicated in the modulation of binge-like ethanol intake, and emerging data highlight sex differences in CRF systems. MethodsIn the current report, we characterized CRF+ neurocircuitry arising from the central nucleus of the amygdala (CeA) and innervating the lateral hypothalamus (LH) in the modulation of binge-like ethanol intake in male and female mice. ResultsUsing chemogenetic tools, we found that silencing the CRF+ CeA to LH circuit significantly blunted binge-like ethanol intake in male but not female mice. Consistently, genetic deletion of CRF from neurons of the CeA blunted ethanol intake exclusively in male mice. Furthermore, pharmacological blockade of the CRF type-1 receptor in the LH significantly reduced binge-like ethanol intake in male mice only, while CRF type-2 receptor activation in the LH failed to alter ethanol intake in either sex. Finally, a history of binge-like ethanol drinking reduced CRF messenger RNA levels in the CeA regardless of sex. ConclusionsThese observations provide novel evidence that CRF+ CeA to LH neurocircuitry is more sensitive for modulating binge-like ethanol intake in male mice, which may provide insight into the mechanisms that guide known sex differences in binge-like ethanol intake.

Hydrogen sulfide donor NaHS inhibits formaldehyde-induced epithelial-mesenchymal transition in human lung epithelial cells via activating TGF-β1/Smad2/3 and MAPKs signaling pathways

Formaldehyde (FA) long term exposure leads to abnormal pulmonary function and small airway obstruction of the patients. Hydrogen sulfide (H2S) is one of the recognized gaseous transmitters involved in a wide range of cellular functions. It is unknown the involvement of H2S in FA-induced lung injury. The purpose of this study is to investigate the therapeutic potential and mechanism of H2S on FA-induced epithelial-mesenchymal transition (EMT) of human lung epithelial cells. The cell viability of Beas2B and A549 cells after FA treatment were assessed using MTT assay. The endogenous H2S was visualized by fluorescence microscopy using of the 7-azido-4-methylcoumarin (AzMC). Cell morphology was observed under phase contrast microscope. The mRNAs and proteins level were evaluated by reverse transcription-polymerase chain reaction and western blotting assays. FA treatment downregulated the endogenous H2S levels and the mRNAs and proteins level of H2S synthesizing enzymes, such as cystathionine-β-synthase (CBS), cystathionine-γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3-MST) in Beas2B and A549 cells. FA treatment changed the cell morphology of Beas2B cells from cuboid to a spindle-shape, while declined the protein level of E-cadherin and increased the protein level of Vimentin. Moreover, FA treatment increased the proteins level of transforming growth factor-β1 (TGF-β1), phosphorylated-Smad2 (p-Smad2), phosphorylated-Smad3 (p-Smad3), phosphorylated-extracellular signal-regulated kinase (p-ERK), phosphorylated-c-Jun N-terminal kinase (p-JNK), and phosphorylated-P38 (p-P38). Furthermore, the inhibitors of TGF-β receptor type 1 (TGFβRI) and mitogen-activated protein kinases (MAPKs) signaling pathways reversed FA-induced decrease in E-cadherin expression and increase in Vimentin expression in Beas2B cells. Sodium hydrogen sulfide (NaHS) increased the level of H2S, while reversed FA-induced the low expression of E-cadherin and the high expression of Vimentin, TGF-β1, p-Smad2, p-Smad3, p-ERK, p-JNK, and p-P38. These findings indicates FA treatment downregulating the endogenous H2S in human lung epithelial cells. NaHS may inhibit FA-induced EMT in human lung epithelial cells via modulating TGF-β1/Smad2/3 and MAPKs signaling pathways. Therefore, we demonstrated that supplementation of exogenous H2S may inhibit FA-induced lung injury.

A1 adenosine receptor evoked Ca2+ signals in astrocytes

Abstract In addition to neurons, glial cells make up the nervous system. These glial cells are divided into macroglial cells - including astrocytes - and microglial cells. Astrocytes have several important functions in the central nervous system, such as synthesizing transmitters and releasing them, thereby activating the surrounding neurons and astrocytes. Astrocytes do not generate action potentials, but they can transmit information to neighboring cells and react to external stimuli by employing Ca2+ dynamics. Increased neuronal activity can lead to an increased extracellular level of adenosine, reflected by a change in the metabolic state. Adenosine is a naturally occurring nucleoside distributed throughout the body as a metabolic intermediary. Its action is mediated by binding to adenosine receptors, such as the G-protein coupled receptors (GPCRs) A1 adenosine receptor. The binding of adenosine to the specific receptor type activates different signaling pathways in astrocytes. In our work, we studied Ca2+ signals generated upon adenosine A1 receptor activation by adding the pathway to the computational astrocyte model by Oschmann et.al (2017). We investigated the influence of the high-affinity A1 adenosine receptor in various astrocyte domains on the regulated Ca2+ release from the endoplasmic reticulum (ER) of astrocytes and concluded that the receptor-dependent pathway contributes to Ca2+ signals mainly in the soma.

Impact of neonatal hyperoxia on adult cardiac autonomic function in rats: Role of angiotensin II type 1 receptor activation

Individuals born preterm present altered cardiac autonomic function, a risk factor to heart diseases. Neonatal renin-angiotensin-system activation contributes to adult cardiomyopathy in rats exposed to neonatal hyperoxia, a well-established model of preterm birth-related conditions. Central angiotensin II receptor activation is a key modulator of the autonomic drive to the heart. Whether neonatal hyperoxia leads to alteration of the cardiac autonomic function through activation of the angiotensin II receptor type 1 (AT1) is unknown and was examined in the present study.Sprague-Dawley pups were exposed to hyperoxia or room air from postnatal days 3–10. AT1 antagonist losartan or water was given orally postnatal days 8–10. Blood pressure, autonomic function, left ventricular sympathetic innervation, β-adrenergic-receptors expression, and AT1 expression in the solitary-tract-nucleus were examined in adult rats.Neonatal hyperoxia led to loss of day-night blood pressure variation, decreased heart rate variability, increased sympathovagal balance, increased AT1 expression in the solitary-tract, decreased left ventricle sympathetic innervation, and increased β1-adrenergic-receptor protein expression. Losartan prevented the autonomic changes and AT1 expression in the solitary-tract but did not impact the loss of circadian blood pressure variation nor the changes in sympathetic innervation and in β1-adrenergic-receptor expression.In conclusion, neonatal hyperoxia leads to both central autonomic and cardiac sympathetic changes, partly programmed by neonatal activation of the renin-angiotensin system.

Clinical and Genomic Characterization of ERBB2-Altered Gallbladder Cancer: Exploring Differences Between an American and a Chilean Cohort.

Gallbladder cancer (GBC) is a biliary tract malignancy characterized by its high lethality. Although the incidence of GBC is low in most countries, specific areas such as Chile display a high incidence. Our collaborative study sought to compare clinical and molecular features of GBC cohorts from Chile and the United States with a focus on ERBB2 alterations. Patients were accrued at Memorial Sloan Kettering Cancer Center (MSK) or the Pontificia Universidad Católica de Chile (PUC). Clinical information was retrieved from medical records. Genomic analysis was performed by the next-generation sequencing platform MSK-Integrated Mutation Profiling of Actionable Cancer Targets. A total of 260 patients with GBC were included, 237 from MSK and 23 from PUC. There were no significant differences in the clinical characteristics between the patients identified at MSK and at PUC except in terms of lithiasis prevalence which was significantly higher in the PUC cohort (85% v 44%; P = .0003). The prevalence of ERBB2 alterations was comparable between the two cohorts (15% v 9%; P = .42). Overall, ERBB2 alterations were present in 14% of patients (8% with ERBB2 amplification, 4% ERBB2 mutation, 1.5% concurrent amplification and mutation, and 0.4% ERBB2 fusion). Notably, patients with GBC that harbored ERBB2 alterations had better overall survival (OS) versus their ERBB2-wild type counterparts (22.3 months v 11.8 months; P = .024). The prevalence of lithiasis seems to be higher in Chilean versus US patients with GBC. A similar prevalence of ERBB2 alterations of overall 14% and better OS suggests that a proportion of them could benefit from human epidermal growth factor receptor type 2-targeted therapies. The smaller cohort of Chile, where the disease prevalence is higher, is a reminder and invitation for the need of more robust next-generation sequencing analyses globally.

The endocannabinoid system in appetite regulation and treatment of obesity.

The endocannabinoid system (ECS) is a complex cell-signaling system that is responsible for maintaining homeostasis by modulating various regulatory reactions in response to internal and environmental changes. The influence of ECS on appetite regulation has been a subject of much recent research, however, the full extent of its impact remains unknown. Current evidence links human obesity to ECS activation, increased endocannabinoid levels in both central and peripheral tissues, along with cannabinoid receptor type 1 (CBR1) up-regulation. These findings imply the potential pharmacological use of the ECS in the treatment of obesity. Here, we present various pathophysiological processes in obesity involving the ECS, highlighting different pharmacological options for modulating endocannabinoid activity to treat obesity. However, the potential of those pharmacological possibilities remains under investigation and requires further research.

Combination of the chemokine receptor type 2 (CCR2) antagonist DMX-200 and candesartan for COVID-19: a randomised controlled trial

ObjectiveTo determine whether a chemokine receptor type 2 antagonist, DMX-200 (repagermanium), in combination with an angiotensin receptor blocker, candesartan, improves clinical outcomes in people with COVID-19.DesignProspective, multicentre, double-blind, placebo-controlled trial.SettingTen...

Taste receptor T1R3 regulates testosterone synthesis via the cAMP-PKA-SP1 pathway in testicular Leydig cells

Taste receptor type 1 subunit 3 (T1R3) is a G protein-coupled receptor encoded by the TAS1R3 gene that can be specifically activated by certain sweeteners or umami agents for sweet/umami recognition. T1R3 is a potential target for regulating male reproduction. However, studies on the impact of non-nutritive sweeteners on reproduction are limited. In the present study, we evaluated the impact of the non-nutritive sweeteners (saccharin sodium, sucralose and acesulfame-K) on testosterone synthesis in testicular Leydig cells of Xiang pigs by comparing the relative abundance of mRNA transcripts and protein expression of T1R3, steroidogenic related factors, and intracellular cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), as well as testosterone levels using Western blotting, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA). To clarify the specific mechanism, a dual luciferase assay was used to uncover the relationship between the transcription factors and steroidogenic enzyme. The acute intratesticular injection of a typical non-nutritive sweeteners was conducted to verify this impact in mouse. The results showed that saccharin sodium not only enhanced T1R3 expression in Leydig cells of Xiang pigs, but also caused significant increases in testosterone, cAMP, PKA, phosphorylation of specificity protein 1 (p-SP1), total protein of specificity protein 1 (SP1), steroidogenic acute regulatory protein (StAR), and 3β-hydroxysteroid dehydrogenase type 1 (3β-HSD1) (P<0.05). Similarly, treatment of Leydig cells with sucralose and acesulfame-K also increased testosterone level, protein expression of T1R3, 17-α-hydroxylase/17, 20-lyase (CYP17A1), and 3β-HSD1 (P<0.05). Treatment with SQ22536 (an adenylate cyclas inhibitor) or H89 (a PKA inhibitor) significantly reduced saccharin sodium-induced protein levels of p-SP1, StAR, CYP17A1, and 3β-HSD1 (P<0.05). In addition, a dual luciferase assay further demonstrated that SP1 significantly increased the promoter activity of CYP17A1 (P<0.05). When mouse testes were injected with saccharin sodium, T1R3, p-SP1, CYP17A1, and 3β-HSD1 were upregulated, leading to a significant testicular increase in testosterone and cAMP levels (P<0.05). These results suggest a mechanism by which the taste receptor T1R3 regulates testosterone production, and this mechanism may be linked to the cAMP-PKA pathway. Understanding the interrelationship between T1R3 and the cAMP-PKA-SP1 pathway contributes to clarify the regulatory mechanisms of male reproduction.

The chemokine receptor type 5 inhibitor maraviroc alleviates sepsis-associated liver injury by regulating MAPK/NF-κB signaling.

Sepsis-related organ damage, as the most intractable problem in intensive care units (ICUs), receives a great deal of attention from healthcare professionals. Sepsis-associated liver injury (SALI) often leads to poor clinical outcomes due to its complex physiological mechanism. In previous studies, chemokine receptor 5 (CCR5) inhibitors were shown to exert unique anti-inflammatory effects. As the therapeutic effect of maraviroc (MVC) on SALI is still unclear, we aimed to explore whether MVC is effective in treating SALI. We established a model of SALI by cecal ligation and puncture (CLP) and intraperitoneally injected 20mg/kg MVC 2h after CLP. The results showed that MVC could significantly ameliorate liver injury after CLP. Furthermore, we demonstrated that MVC reduced inflammatory infiltration and apoptosis after SALI. In addition, we found that the function of MVC in reducing inflammation was obtained through the inhibition of the two inflammatory signaling pathways mentioned above. Finally, the JNK agonist AN was chosen for reverse research. As shown by the results, the therapeutic effects of MVC disappeared after AN treatment, indicating that MVC exerted anti-inflammatory and antiapoptotic effects through JNK. Our study revealed that MVC could reduce liver injury after SALI by inhibiting liver inflammation and hepatocyte apoptosis induced by CLP and that MVC exerted diminish inflammatory effects by inhibiting the NF-κB and MAPK signaling pathways.

Omeprazole affects the expression of serotonin-1A in the brain regions and alleviates anxiety in rat model of immobilization-induced stress.

Omeprazole, a drug of choice for the management of gastric hyperacidity, influences serotonergic neurotransmission in brain regions and its long-term use is known to cause stress-related behavioral deficits including anxiety. Aim of the current study was to explore the effects of omeprazole treatment on immobilization-induced anxiety in rats, specifically on the role of serotonin (5-HT). In view of the role of serotonin-1A (5-HT1A) autoreceptor in the availability of 5-HT in brain regions, mRNA expression of this autoreceptor was performed in raphe nuclei. Similarly, because of the role of hippocampal 5-HT neurotransmission in anxiety-like disorders, expression of the 5-HT1A heteroreceptors was determined in this region. We found that the treatment with omeprazole reduces anxiety-like behavior in rats, increases the expression of 5-HT1A autoreceptor in the raphe and decreases the hippocampal expression of 5-HT1A heteroreceptor. This suggests a role of 5-HT1A receptor types in omeprazole-induced behavioral changes. It also indicates a potential role of omeprazole in the management of serotonergic disorders.

Ovalbumin-induced food allergy suppression via regulatory T cell expansion mediated by a TNFR2 agonist in mice

Food allergies represent a growing health concern worldwide, characterized by abnormal immune responses to specific dietary antigens. This condition is often associated with a dysregulation of immune tolerance, especially within the intestinal mucosa. Regulatory T cells (Tregs), a crucial subset of lymphocytes, play a central role in maintaining peripheral immune tolerance and are abundant in the intestinal lamina propria. Recent studies have highlighted Treg dysfunction in patients with food allergies, suggesting a potential connection between impaired Treg function and allergy onset. Therefore, strategies to adequately control and activate Tregs could offer new avenues for the prevention and treatment of food allergies. Our research focuses on targeting the regulatory molecule, tumor necrosis factor receptor type 2 (TNFR2), a key modulator of Treg function. We have developed a TNFR2 agonist, scR2agoTNF-Fc, characterized by high TNFR2-stimulating activity and enhanced blood retention in vivo for Treg expansion. In this study, we utilized an ovalbumin (OVA)-induced food allergy mouse model to verify the therapeutic potential of scR2agoTNF-Fc in modulating allergic responses and restoring immune balance. The results showed that scR2agoTNF-Fc promoted the expansion of Treg population in vivo in mice. In addition, scR2agoTNF-Fc reduced diarrhea caused by the food allergy. This was consistent with the molecular mechanisms of suppression of blood immunoglobulins and Th2 cells. Therefore, it was shown that quantitative and functional enhancement of Tregs by the TNFR2 agonist, scR2agoTNF-Fc, may be effective in treating food allergies.

Structure-activity optimization of ryanodine receptor modulators for the treatment of catecholaminergic polymorphic ventricular tachycardia

BackgroundCatecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia disorder associated with potentially lethal arrhythmias. Most CPVT cases are caused by inherited variants in the gene encoding ryanodine receptor type 2 (RYR2). ObjectiveThe goal of this study was to investigate the structure-activity relationship of tetracaine derivatives and to test a lead compound in a mouse model of CPVT. MethodsWe synthesized >200 tetracaine derivatives and characterized 11 of those. The effects of these compounds on Ca2+ handling in cardiomyocytes from R176Q/+ mice was tested with confocal microscopy. The effects of lead compound MSV1302 on arrhythmia inducibility and cardiac contractility were tested by programmed electrical stimulation and echocardiography, respectively. Plasma and microsomal stability and cytotoxicity assays were also performed. ResultsCa2+ imaging revealed that 4 of 11 compounds suppressed sarcoplasmic reticulum Ca2+ leak through mutant RyR2. Two compounds selected for further testing exhibited a half-maximal effective concentration of 146 nM (MSV1302) and 49 nM (MSV1406). Whereas neither compound altered baseline electrocardiogram intervals, only MSV1302 suppressed stress- and pacing-induced ventricular tachycardia in vivo in R176Q/+ mice. Echocardiography revealed that the lead compound MSV1302 did not negatively affect cardiac inotropy and chronotropy. Finally, compound MSV1302 did not block INa, ICa,L, or IKr; it exhibited excellent stability in plasma and microsomes, and it was not cytotoxic. ConclusionStructure-activity relationship studies of second-generation tetracaine derivatives identified lead compound MSV1302 with a favorable pharmacokinetic profile. MSV1302 normalized aberrant RyR2 activity in vitro and in vivo, without altering cardiac inotropy, chronotropy, or off-target effects on other ion channels. This compound may be a strong candidate for future clinical studies to determine its efficacy in CPVT patients.

BNST CRF receptor type 1 modulates mechanical hypersensitivity induced by adolescent alcohol exposure in adult female mice.

Alcohol exposure during adolescence has been linked to long-lasting behavioral consequences, contributing to the development of alcohol use disorder. Negative affect and chronic pain during alcohol withdrawal are critical factors influencing problematic alcohol use and relapse. Our previous research demonstrated that adolescent intermittent ethanol (AIE) vapor exposure elicits sex-specific negative affect-like behavior in adult mice following stress exposure. Additionally, AIE induces persistent mechanical hypersensitivity, which is accompanied by increased activation of corticotropin-releasing factor receptor type 1 (CRFR1) neurons in the dorsolateral bed nucleus of the stria terminalis (dlBNST). This study extends previous work by investigating plasma corticosterone levels and CRFR1 protein expression in the dlBNST following restraint stress exposure in adult mice with an AIE history. We also aim to explore the role of dlBNST CRFR1 signaling in mediating negative affect-like behavior and mechanical hypersensitivity. Female mice exhibited elevated plasma corticosterone levels compared to males following restraint stress. Moreover, females with AIE history showed higher expression of CRFR1 protein in the dlBNST compared to air controls. Antagonism of CRFR1 in the dlBNST blocked AIE-induced mechanical hypersensitivity in adult females but did not affect stress-induced negative affect-like behavior. In alcohol-naïve females, intra-dlBNST administration of a CRFR1 agonist induced mechanical hypersensitivity. These findings provide new insights into the neurobiological mechanisms underlying stress-induced negative affect and pain-related behavior, both influenced by a history of adolescent alcohol exposure. The results suggest that CRFR1 antagonists warrant further investigation for their potential in addressing alcohol-related chronic pain.

Stress triggers gut dysbiosis via CRH-CRHR1-mitochondria pathway.

Stress can lead to gut dysbiosis in brain-gut axis disordered diseases as irritable bowel syndrome (IBS), yet the mechanisms how stress transfer from the brain to the gut and disrupt gut microbiota remain elusive. Here we describe a stress-responsive brain-to-gut axis which impairs colonocytes' mitochondria to trigger gut dysbiosis. Patients with IBS exhibit significantly increased facultative anaerobes and decreased obligate anaerobes, related to increased serum corticotropin-releasing hormone (CRH) level and defected colonocytes' mitochondria ultrastructure. Mice exposed to acute stress experienced enhanced CRH-CRH receptor type 1 (CRHR1) signaling, which impaired mitochondria and epithelium hypoxia in the colon, subsequently triggered gut dysbiosis. Antagonizing CRHR1 expression to inhibit cAMP/Ras/MAPK signaling or activating mitochondria respiration conferred resilience against stress-induced mitochondria damaging and epithelium hypoxia impairment, ultimately improving gut dysbiosis. These results suggest that the CRH-CRHR1-mitochondria pathway plays a pivotal role in stress-induced gut dysbiosis that could be therapeutically targeted for stress-induced gastrointestinal diseases. Yiming Zhang et.al report that psychological stress activated Corticotropin-releasing hormone (CRH)-CRH receptor type 1 (CRHR1)-mitochondria pathway to trigger gut dysbiosis and reveal CRHR1 upregulation damages mitochondria via cAMP/Ras/MAPK signaling in colonocytes.

Distinct Non-Human Leukocyte Antigen Antibody Signatures Correlate with Endothelial Crossmatch Status in Lung and Renal Transplant Recipients

Non-HLA antibodies against heterogeneous targets on endothelial cells have been associated with allograft injuries. The endothelial cell crossmatch (ECXM) is used in the detection of non-HLA antibodies but remains non-discriminatory for specific antibody identification. The primary objective of this study was to delineate the specific non-HLA antibody signatures associated with ECXM positivity and to determine the correlation of ECXM status and non-HLA antibody signatures on allograft health. Serum specimens from 25 lung transplant recipients (LTRs) and 13 renal transplant recipients (RTRs) were collected as part of clinical evaluation, and testing for angiotensin II receptor type 1 (AT1R) and donor-specific MHC class I chain-related gene A (MICA) antibodies and ECXM was performed. Remnant sera were tested for non-HLA antibodies using the LABScreen™ Autoantibody (LSAUT) Group 1, 2, and 3 kits (One Lambda, Inc., Los Angeles, CA, USA). In both cohorts, the concordance of AT1R and MICA together or individually with ECXM+ status was poor (&lt;0.7), suggesting the presence of other unaccounted antibodies. Autoantibody profiling revealed three distinct clusters targeting fibrotic products, cytoskeletal proteins, and cell signaling molecules. A comparative analysis of ECXM+ and ECXM− specimens identified nine and five differentially expressed antibodies in the LTR and RTR cohorts, respectively. Employing machine learning techniques (variable importance, feature selection, ROC-AUC), we derived a five-antibody panel (TNFα, collagen V, CXCL11, GDNF, GAPDH) and a two-antibody panel (TNFα, CXCL9) that effectively discriminated between ECXM+ and ECXM− status in the LTR and RTR cohorts, respectively. Distinct antibody signatures were identified in LTR and RTR cohorts that correlated with ECXM+ status and were associated with allograft dysfunction.

An iron-rich subset of macrophages promotes tumor growth through a Bach1-Ednrb axis.

We define a subset of macrophages in the tumor microenvironment characterized by high intracellular iron and enrichment of heme and iron metabolism genes. These iron-rich tumor-associated macrophages (iTAMs) supported angiogenesis and immunosuppression in the tumor microenvironment and were conserved between mice and humans. iTAMs comprise two additional subsets based on gene expression profile and location-perivascular (pviTAM) and stromal (stiTAM). We identified the endothelin receptor type B (Ednrb) as a specific marker of iTAMs and found myeloid-specific deletion of Ednrb to reduce tumor growth and vascular density. Further studies identified the transcription factor Bach1 as a repressor of the iTAM transcriptional program, including Ednrb expression. Heme is a known inhibitor of Bach1, and, correspondingly, heme exposure induced Ednrb and iTAM signature genes in macrophages. Thus, iTAMs are a distinct macrophage subset regulated by the transcription factor Bach1 and characterized by Ednrb-mediated immunosuppressive and angiogenic functions.

Sphingosine-1-phosphate receptor type 4 is critically involved in the regulation of peritoneal B-1 cell trafficking and distribution in vivo.

B-1 cells are crucially involved in immune defense and regulation of inflammation and autoimmunity. B-1 cells are predominantly located in the peritoneal and pleural cavities, although body cavity B-1 cells recirculate systemically under steady-state conditions. The chemokines CXCL12 and CXCL13 have been identified as the main regulators of peritoneal B-cell trafficking. In mice deficient for sphingosine-1-phosphate receptor 4 (S1PR4), B-1a and B-1b cell numbers are reduced in the peritoneal cavity by an unknown mechanism. In this study, we show that S1PR4-mediated S1P signaling modifies the chemotactic response of peritoneal B cells to CXCL13 and CXCL12 in vitro. In vivo, S1PR4-mediated S1P signaling affects both immigration into and emigration from the peritoneal cavity. Long-term reconstitution experiments of scid mice with wt or s1pr4 -/- peritoneal B cells revealed a distinct distributional pattern in secondary lymphoid organs. As a functional consequence, both plasmatic and mucosal IgM levels, the main product of B-1a cells, are reduced in mice reconstituted with s1pr4 -/- peritoneal cells. In summary, our data identify S1PR4 as the second S1P receptor (besides S1PR1), which is critically involved in the regulation of peritoneal B-1 cell function.

Targeting the autoreactive CD8+ T-cell receptor in type 1 diabetes: Insights from scRNA-seq for immunotherapy

Type 1 Diabetes (T1D) is an autoimmune disease characterized by the attack and destruction of Pancreatic islet beta cells by T cells. Understanding the role of T-cell receptor (TCR) in the development of T1D is of paramount importance. This study employs single-cell RNA sequencing (scRNA-seq) to delve into the mechanistic actions and potential therapeutic applications of autoreactive stem cell-like CD8 TCR in T1D. By retrieving T-cell data from non-obese diabetic (NOD) mice via the GEO database, it was revealed that CD8+ T cells are the predominant T-cell subset in the pancreatic tissue of T1D mice, along with the identification of T-cell marker genes closely associated with T1D. Moreover, the gene TRAJ23 exhibits a preference for T1D, and its knockout alleviates T1D symptoms and adverse reactions in NOD mice. Additionally, engineered TCR-T cells demonstrate significant cytotoxicity towards β cells in T1D.

Prevalence of genetically diagnosed familial hypercholesterolemia in Vietnamese patients with premature acute myocardial infarction.

Familial hypercholesterolemia (FH) is a genetic disorder that results in elevated low-density lipoprotein cholesterol (LDL-C) levels, which manifest early in the first decades of life. It is a major cause of premature coronary artery disease worldwide, leading to significant public health challenges. The prevalence of genetically determined FH in patients with premature coronary artery disease remains underestimated, particularly in developing countries. This study aimed to assess the prevalence of genetically defined FH in Vietnamese patients with premature acute myocardial infarction (AMI) in the Vietnamese population. This cross-sectional study enrolled 218 consecutive patients diagnosed with premature AMI who underwent coronary angiography. The low-density lipoprotein receptor (LDLR), apolipoprotein B, and proprotein convertase subtilisin-kexin type 9 genes were analyzed by next-generation sequencing. FH was diagnosed according to Dutch Lipid Clinic Network criteria. Among the patients with premature AMI who underwent coronary angiography, the mean age was 46.9 ± 6.1 years, with a predominance of males (83.9%). The prevalence of potential FH diagnosed using Dutch Lipid Clinic Network criteria was 14.7% (definite FH, 6.0%; probable FH, 8.7%). Pathogenic or likely pathogenic variants in LDLR, apolipoprotein B, and proprotein convertase subtilisin-kexin type 9 were found in 9 of 218 patients (4.1%), all of which were causative mutations in LDLR. Patients with premature AMI and FH had significantly greater LDL-C levels (217.6 vs 125.7 mg/dL) and more severe coronary artery lesions, as assessed by the Gensini score (100.3 vs 60.5), than did those in the No FH group. The prevalence of genetically determined FH among Vietnamese patients with premature AMI is relatively high. Screening and diagnosis of hereditary conditions in patients with premature AMI are essential to improve early detection and management and reduce the burden of coronary artery disease in this population.