Receptor Family Research Articles

A Novel TEK::GAB2 Gene Fusion in Pediatric Angiosarcoma of Pelvic soft Tissue: A Case Report and Literature Review.

Pediatric angiosarcoma of soft tissue, an extremely rare entity, remains poorly understood from a genetic standpoint. Herein, we present the case of a previously healthy 17-year-old girl with acute left hip pain. Subsequent magnetic resonance imaging revealed a 21.8 cm left pelvic sidewall mass with heterogeneous enhancement and multiple lung nodules. Biopsy of the tumor showed an infiltrative, hemorrhagic neoplasm composed primarily of atypical spindle to epithelioid cells. Focal vasoformative architecture was appreciated. Immunohistochemically, the tumor cells were strongly positive for CD31, ERG, and FLI-1, supporting the diagnosis of angiosarcoma. Genetic analysis identified a novel TEK::GAB2 gene fusion. TEK belongs to the angiopoietin receptor family, and its fusion with GAB2 is predicted to mediate tumorigenesis. This report expands the current knowledge on the spectrum of gene rearrangements of angiosarcoma.

NLRC5 exerts anti-endometriosis effects through inhibiting ERβ-mediated inflammatory response

BackgroundEndometriosis is well known as a chronic inflammatory disease. The development of endometriosis is heavily influenced by the estrogen receptor β (ERβ), while NOD-like receptors (NLRs) family CARD domain-containing 5 (NLRC5) exhibits anti-inflammatory properties during endometriosis. However, whether NLRC5-mediated anti-inflammation is involved in the ERβ-mediated endometriosis is still uncertain. This study aimed to assess that relation.MethodsNine cases of eutopic endometrial tissue and ten cases of ectopic endometrial tissue were collected from patients with endometriosis, and endometrial samples from ten healthy fertile women were analyzed, and the expression levels of ERβ were quantified using immunohistochemistry (IHC). Subsequently, we constructed mouse model of endometriosis by intraperitoneal injection. We detected the expression of ERβ, NLRC5, tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, and IL-10 and measured the volume of ectopic lesions in mice with endometriosis. In vitro, human endometrial stromal cells (hESCs) were transfected respectively with ERβ-overexpressing and NLRC5-overexpressing plasmids. We then assessed the expression of ERβ and NLRC5 using quantitative real-time PCR (qRT-PCR) and western blot analysis. Furthermore, we measured the concentrations of TNF-α, IL-6, and IL-10 in the cell culture supernatant through enzyme-linked immunosorbent assay (ELISA). Additionally, we evaluated the migration and invasion ability of hESCs using transwell and wound healing assays.ResultsInhibition of NLRC5 expression promotes the development of ectopic lesions in mice with endometriosis, upregulates the expression of pro-inflammatory factors TNF-α and IL-6, and downregulates the expression of anti-inflammatory factor IL-10. The high expression of NLRC5 in endometriosis depended on the ERβ overexpression. And ERβ promoted the migration of hESCs partially depend on inflammatory microenvironment. Lastly, NLRC5 overexpression inhibited ERβ-mediated development and inflammatory response of endometriosis.ConclusionsOur results suggest that the innate immune molecule NLRC5-mediated anti-inflammation participates in ERβ-mediated endometriosis development, and partly clarifies the pathological mechanism of endometriosis, expanding our knowledge of the specific molecules related to the inflammatory response involved in endometriosis and potentially providing a new therapeutic target for endometriosis.

The Roles of Proton-Sensing G-Protein-Coupled Receptors in Inflammation and Cancer.

The precise regulation of pH homeostasis is crucial for normal physiology. However, in tissue microenvironments, it can be impacted by pathological conditions such as inflammation and cancer. Due to the overproduction and accumulation of acids (protons), the extracellular pH is characteristically more acidic in inflamed tissues and tumors in comparison to normal tissues. A family of proton-sensing G-protein-coupled receptors (GPCRs) has been identified as molecular sensors for cells responding to acidic tissue microenvironments. Herein, we review the current research progress pertaining to these proton-sensing GPCRs, including GPR4, GPR65 (TDAG8), and GPR68 (OGR1), in inflammation and cancer. Growing evidence suggests that GPR4 and GPR68 are mainly pro-inflammatory, whereas GPR65 is primarily anti-inflammatory, in various inflammatory disorders. Both anti- and pro-tumorigenic effects have been reported for this family of receptors. Moreover, antagonists and agonists targeting proton-sensing GPCRs have been developed and evaluated in preclinical models. Further research is warranted to better understand the roles of these proton-sensing GPCRs in pathophysiology and is required in order to exploit them as potential therapeutic targets for disease treatment.

The role of receptor activity-modifying proteins in obesity and diabetes mellitus.

Receptor activity-modifying proteins (RAMPs) modulate the expression and activity of numerous G protein-coupled receptors, primarily those within class B1. These receptors have important physiological roles, including in the regulation of food intake, energy metabolism, and glucose homeostasis. Dysregulation of these pathways can lead to obesity and diabetes mellitus, which present an ever-expanding global challenge. Whilst the roles of class B1 receptors and their peptide agonists in obesity and diabetes have been investigated, the contribution of RAMPs is less well understood. This review summarises the results of RAMP knockout studies, highlighting the involvement of these proteins in the incidence of disease. It then moves to discuss how receptor, RAMP, and agonist expression changes in disease states, and the benefits (or detriments) of these agonists to the pathways implicated in disease pathophysiology. Whilst much of the data centres around the calcitonin family of receptors, as their interactions with RAMPs are well established, this review then discusses receptors whose role in obesity and diabetes is well founded, but the significance of whose interactions with RAMPs is more recently emerging. The conclusion of this study of the literature is, however, that the information surrounding RAMPs is conflicting and multifaceted, and more research is required to fully understand their contribution to obesity and diabetes.

Targeting RAC1 reactivates pyroptosis to reverse paclitaxel resistance in ovarian cancer by suppressing P21-activated kinase 4.

Pyroptosis may play an important role in the resistance of ovarian cancer (OC) to chemotherapy. However, the mechanism by which pyroptosis modulation can attenuate chemotherapy resistance has not been comprehensively studied in OC. Here, we demonstrated that RAS-associated C3 botulinum toxin substrate 1 (RAC1) is highly expressed in OC and is negatively correlated with patient outcomes. Through cell function tests and in vivo tumor formation tests, we found that RAC1 can promote tumor growth by mediating paclitaxel (PTX) resistance. RAC1 can mediate OC progression by inhibiting pyroptosis, as evidenced by high-throughput automated confocal imaging, the release of lactate dehydrogenase (LDH), the expression of the inflammatory cytokines IL-1β/IL-18 and the nucleotide oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome. Mechanically, RNA-seq, gene set enrichment analysis (GSEA), coimmunoprecipitation (Co-IP), mass spectrometry (MS), and ubiquitination tests further confirmed that RAC1 inhibits caspase-1/gasdermin D (GSDMD)-mediated canonical pyroptosis through the P21-activated kinase 4 (PAK4)/mitogen-activated protein kinase (MAPK) pathway, thereby promoting PTX resistance in OC cells. Finally, the whole molecular pathway was verified by the results of in vivo drug combination tests, clinical specimen detection and the prognosis. In summary, our results suggest that the combination of RAC1 inhibitors with PTX can reverse PTX resistance by inducing pyroptosis through the PAK4/MAPK pathway.

Evaluation of glycyrrhetinic acid in attenuating adverse effects of a high-fat diet in largemouth bass (Micropterus salmoides)

Glycyrrhetinic acid (GA) has been shown to promote growth characteristics and play a crucial role in anti-inflammatory responses in animals. To investigate the effects of dietary GA supplementation on growth performance, intestinal inflammation, and intestinal barrier protection in largemouth bass (Micropterus salmoides) fed a high-fat diet (HFD), a 77-day feeding experiment was conducted. A total of 750 largemouth bass, initially averaging 17.39 ± 0.09 g in body weight, were randomly allocated to five experimental groups and fed a control diet, a HFD, and the HFD diet supplemented with GA at either 0.5, 1.0, or 1.5 mg/kg, named as control, HDF, HFD+GA 0.5, HFD+GA 1.0, and 1.5 HFD+GA 1.5, respectively. Each group contained three replicates. The study revealed that dietary GA improved final body weight (P < 0.001), percent weight gain (P = 0.041), and feed intake (P < 0.001), all of which had been affected by a HFD in largemouth bass (P < 0.05). Supplementation of HFD with 1.0 mg/kg GA increased the mRNA expressions and protein levels of corresponding tight junctions, occludin, zonula occluden-1 (ZO-1) and claudin-1 in the intestines of largemouth bass. Furthermore, the addition of HFD with both of 0.5 and 1.0 mg/kg GA decreased the mRNA expressions of pro-inflammatory genes such as interleukin-1β (IL-1β), IL-18, and cysteinyl aspartate specific proteinase 1 (caspase-1), as well as proteins associated with pyroptosis-induced inflammation, including NOD-like receptor family and pyrin domain contain 3 (NLRP3), apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC), gasdermin E (GSDME), and N-terminal domain of GSDME (GSDME-N) (P < 0.05). Finally, dietary GA supplementation alleviated mitochondrial damage and reduced reactive oxygen species (ROS) production induced by the HFD. It is concluded that GA supplementation in HFD enhances growth performance, increases mRNA expression and protein levels of tight junction-related parameters, decreases mRNA expression and protein levels of pyroptosis-related genes, and alleviates intestinal mitochondrial injury and inflammation induced by HFD.

NLRP3 Inflammasome Inhibition After Pilocarpine-Induced Status Epilepticus Attenuates Chronic Inflammation in Epileptic Mice.

To investigate the effects of inhibiting the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome on neuronal damage and chronic pro-inflammatory responses during epileptogenesis in a mouse model of pilocarpine-induced status epilepticus (SE). Mice were randomly allocated into three groups: control, SE, and SE + MCC 950. The expression patterns of M1 and M2 microglial biomarkers in the hippocampus were quantified using Western blotting, quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and immunofluorescence staining. Additionally, seizure susceptibility, video-electroencephalography recording, Morris water maze test, and brain immunofluorescence staining were performed to evaluate the epileptic brain 4 weeks post-SE. Within 72 hours post-SE, hippocampal microglia demonstrated a preferential polarization towards the M1 phenotype, a trend that was mitigated by NLRP3 inflammasome inhibition. During epileptogenesis, SE mice treated with NLRP3 inflammasome inhibition exhibited reduced neuronal damage, improved cognitive function, decreased seizure susceptibility, and attenuated chronic pro-inflammatory responses. Inhibition of NLRP3 inflammasome post-SE effectively ameliorates neuronal loss, seizure susceptibility, and cognitive dysfunction during epileptogenesis. This neuroprotective effect may be mediated through the mitigation of chronic pro-inflammatory responses within the epileptic brain.

NOX2 mediates NLRP3/ROS facilitating nasal mucosal epithelial inflammation in chronic rhinosinusitis with nasal polyps

BackgroundPrevious investigations have provided limited insight into the role of oxidative stress in nasal mucosa inflammation. The aim of this study was to investigate the mechanism of oxidative stress in the epithelial cells of chronic rhinosinusitis with nasal polyps CRSwNP utilizing single-cell RNA sequencing data. MethodsSingle-cell RNA sequencing data from HRA000772 were used to assess oxidative stress, inflammasome activation, and nicotinamide adenine dinucleotide phosphate oxidases (NOXs) expression in epithelial cells via integrative rank-based gene set enrichment analysis. The localization of reactive oxygen species (ROS) and NOX2 in nasal mucosa and cell models was visualized using fluorescent probes and immunohistochemistry, respectively. Functional studies on NOX2 involved siRNA and plasmid transfections in vitro, while Nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activity was examined using the inducer TMAO and the inhibitor MCC950. ResultsSingle-cell RNA sequencing data suggested an increase of oxidative stress score and NLRP3 inflammasome score in CRSwNP epithelial cells. Vitro experiments demonstrated that lipopolysaccharide could induce ROS accumulation, NLRP3 inflammasome activation and epithelial alarmin expression. MCC950 inhibited the expression of epithelia alarmin in vitro. Elevated NOX2 in CRSwNP epithelial cells was associated with increased ROS, NLRP3 inflammasome activation, and epithelial alarmin expression. NOX2-targeted siRNA inhibited these effects in vitro. Moreover, TMAO reversed the downregulation of epithelial alarmins without impacting ROS levels. ConclusionThis study highlights the crucial role of NOX2 as a key regulator of ROS accumulation and NLRP3 inflammasome activation in CRSwNP, underscoring its potential as a valuable therapeutic target for CRSwNP.

Increased nuclear receptor subfamily 2, group E, member 1 (NR2E1) concentrations of PBMCs are associated with chronic inflammation in overweight/obesity

BackgroundChronic inflammation plays a crucial role in the pathogenesis of overweight/obesity. Nuclear receptor subfamily 2, group E, member 1 (NR2E1) is one of the nuclear receptor family proteins that play crucial roles in regulating numerous life processes. In this study, we attempted to detect NR2E1 levels in peripheral blood mononuclear cells (PBMCs) of overweight/obese people and preliminarily elucidate the regulatory role of NR2E1 in obesity-related chronic inflammation. MethodsWe conducted a cross-sectional analysis of the clinical and biochemical data from 62 overweight/obese people and 70 control subjects. PBMCs of the participants were collected for detection of NR2E1 levels. PBMCs isolated from the control subjects were treated with different concentrations of palmitic acid (PA). We also transfected p-EGFP-N1-NR2E1 plasmids into PBMCs and treated them with PA, then detected TNF-α and IL-6 concentrations in the supernatant of PBMCs. ResultsThe NR2E1 mRNA and protein levels in overweight/obese people were both significantly higher than those in normal-BMI people (p < 0.01). NR2E1 mRNA levels in PBMCs of overweight/obese people were positively related with TC, FFA, IL-6, TNF-α (r = 0.387, 0.440, 0.610, 0.530, p < 0.01) and LDL-c (r = 0.290, p < 0.05). A similar correlation was also found between NR2E1 protein levels and these parameters. The expression of NR2E1 in PBMCs from the control subjects increased apparently with the treatment of PA in a concentration-depend manner in vitro. Overexpression of NR2E1 in PBMCs decreased TNF-α and IL-6 expression induced by PA (p < 0.01). ConclusionNR2E1 levels are increased in overweight/obese people and have a positive relationship with TC, FFA, LDL-C, TNF-α and IL-6. Overexpression of NR2E1 could alleviate PA-induced chronic inflammation. NR2E1 may be a potential target for regulating chronic inflammation in obesity.

Abstract P166: Genetic Ablation of the Bile Acid Receptor- Takeda G-protein Coupled Receptor 5 (TGR5) Promotes Weight Gain but Lowers Hypertension

Introduction: TGR5 belongs to G-protein coupled receptor family, that mediates bile acid signaling. Activation of TGR5 by bile acids triggers intestinal glucagon-like peptide-1 secretion, whereby pharmacological activation of TGR5 constitutes a promising incretin-based strategy for the treatment of metabolic disorders. Hypertension is one of the hallmark features of metabolic disorders. We previously reported that hypertension is associated with lower conjugated bile acids, which are ligands for TGR5. Therefore, we hypothesized that lack of activation of TGR5-mediated bile acid signaling promotes not only body weight gain, but also hypertension. Methods: CRISPR/Cas9 technology was used to generate Tgr5 -/- rats from hypertensive Dahl Salt-sensitive (S) rats. Twenty-four-hour blood pressure (BP) readings of 8-weeks-old control female Tgr5 +/+ S rats and age-matched female Tgr5 -/- S rats (n=7/group) were monitored by radiotelemetry for 4 weeks. Body weight, food intake, and water intake were recorded every week. At the end of the study, vascular function was examined using wire myography of dorsal and mesenteric resistance arteries, cardiac function was assessed by echocardiography, and microbiota profiling was conducted via fecal 16S rRNA gene sequencing using Miseq. Results: In support of our hypothesis, despite no difference in food and water intake, at 4 weeks, the body weights of Tgr5 -/- S rats were significantly higher compared to Tgr5 +/+ S rats (236.3gm vs. 225.4gm; p&lt;0.01). Surprisingly, in contrast to our hypothesis, at 4 weeks, Tgr5 -/- S rats had significantly lower systolic BP (151.8mmHg vs. 156.9mmHg, p&lt;0.0001), diastolic BP (107.9mmHg vs. 115.5mmHg, p&lt;0.0001), and mean arterial BP (128.8mmHg vs. 134.9mmHg, p&lt;0.0001) compared to Tgr5 +/+ S rats. However, no significant differences were observed either in vascular reactivity or cardiac function between the groups. Interestingly, fecal microbiota analysis revealed that Tgr5 -/- S rats presented with significant remodeling of gut microbiota with lower α-diversity (observed features; p=0.05), b-diversity (Bray-Curtis; p&lt;0.05, Jaccard; p&lt;0.01), and higher relative abundance of the BP-lowering genera Akkermansia . Conclusion: Our study revealed that deletion of TGR5 resulted in weight gain but lowered BP. It implies that activation of TGR5 may be a risk factor for raising BP. The mechanism by which TGR5 regulates BP seem independent of changes in vascular or cardiac function but is likely mediated by gut microbiota.

Neuregulin 1 (NRG1) and its receptors in the enteric nervous system and other parts of the gastrointestinal wall.

Neuregulin 1 (NRG1) belonging to the transmembrane growth factors family is widespread in living organisms. It acts through ErbB family receptors and first of all takes part in embryogenesis, as well as in developmental, regenerative and adaptive processes occurring in various internal organs and systems. It is known that NRG1 and its receptors are present in various parts of the gastrointestinal (GI) tract. First of all NRG1 and ErbB receptors have been detected in the enteric nervous system (ENS) localized in the wall of the esophagus, stomach and intestine and regulating the majority of the GI tract functions, but also in the mucosal and muscular layers of the GI tract. The NRG1/ErbB pathway is involved in the development and differentiation of the ENS and regulation of the intestinal epithelium functions. Moreover, dysregulation of this pathway results in a wide range of gastrointestinal diseases. However, till now there are no summarizations of previous studies concerning distribution and functions of NRG1 and its receptors in the GI tract. The present review fills this gap.

The Role of Cornichons in the Biogenesis and Functioning of Monovalent-Cation Transport Systems.

Monovalent-cation homeostasis, crucial for all living cells, is ensured by the activity of various types of ion transport systems located either in the plasma membrane or in the membranes of organelles. A key prerequisite for the functioning of ion-transporting proteins is their proper trafficking to the target membrane. The cornichon family of COPII cargo receptors is highly conserved in eukaryotic cells. By simultaneously binding their cargoes and a COPII-coat subunit, cornichons promote the incorporation of cargo proteins into the COPII vesicles and, consequently, the efficient trafficking of cargoes via the secretory pathway. In this review, we summarize current knowledge about cornichon proteins (CNIH/Erv14), with an emphasis on yeast and mammalian cornichons and their role in monovalent-cation homeostasis. Saccharomyces cerevisiae cornichon Erv14 serves as a cargo receptor of a large portion of plasma-membrane proteins, including several monovalent-cation transporters. By promoting the proper targeting of at least three housekeeping ion transport systems, Na+, K+/H+ antiporter Nha1, K+ importer Trk1 and K+ channel Tok1, Erv14 appears to play a complex role in the maintenance of alkali-metal-cation homeostasis. Despite their connection to serious human diseases, the repertoire of identified cargoes of mammalian cornichons is much more limited. The majority of current information is about the structure and functioning of CNIH2 and CNIH3 as auxiliary subunits of AMPAR multi-protein complexes. Based on their unique properties and easy genetic manipulation, we propose yeast cells to be a useful tool for uncovering a broader spectrum of human cornichons´ cargoes.

Unveiling the role of RARs in stomach adenocarcinoma: clinical implications and prognostic biomarkers.

Retinoic acid receptors (RARs) family are known to play a significant role in the occurrence and development of tumors. However, the relationship between RARs and stomach adenocarcinoma (STAD) has not yet been clearly identified. The aim of this study is to evaluate the expression profile and clinical value of the RARs family in STAD. The expression level, clinical characteristics, prognostic value, immunity-related evaluations, genetic alteration and methylation site of RARs in STAD were explored using a series of online databases including gene expression profiling interactive analysis (GEPIA), tumor immune estimation resource (TIMER), University of Alabama at Birmingham cancer data (UALCAN), Human Protein Atlas (HPA), Kaplan-Meier plotter, gene set cancer analysis (GSCA), cBioPortal, MethSurv, GeneMANIA, LinkedOmics, Metascape, Search tool for the retrieval of interacting genes (STRING), tumor immune single-cell hub (TISCH) and cancer cell line encyclopedia (CCLE). We discovered dramatically increased expression of RARA and decreased expression of RARB in STAD tissues, and many clinical variables were closely related to RARs. Notably, higher expressions of RARA and RARB as well as lower expression of RARG correlated with worse overall survival (OS) for STAD patients. The clinical value of prognostic model indicated that RARs were identified to be potential prognostic biomarkers for STAD patients. Moreover, RARB was closely related to immune cell infiltration, which had effect on the role of RARB in STAD prognosis. And the genetic alteration of RARB was significantly associated with the longer disease-free survival (DFS) of STAD patients. Additionally, some CpG sites of the RARs family were related with the prognosis of STAD patients. Functional enrichment analyses indicated that several pathways in STAD might be pivotal pathways regulated by RARs. At the single-cell level, there was some extent of infiltration of tumor microenvironment-related cells in the RARs expression in STAD. Our results evaluated the expression profile and clinical values of RARs in patients with STAD, which provided a basis for future in-depth exploration of the specific mechanisms of each member of RARs in STAD.

The consistently up-regulated expression of NLRP3 in severe asthma patients from mRNA microarray and ovalbumin-induced mouse model of asthma.

Severe asthma (SA) is a chronic lung disease, resistant to current treatments, symbolized by repeated symptoms of reversible airflow obstruction, airway hyper-responsiveness, and inflammation. The aim of this study was to identify genes exhibiting differential expression in individuals without asthma and SA patients. We aimed to pinpoint hub differentially expressed genes (DEGs) by utilizing a mouse model of asthma sensitized to ovalbumin (OVA). Microarray data for SA were acquired from the Gene Expression Omnibus (GEO) databases. DEGs were identified, and functional enrichment analyses were carried out. STRING and Cytoscape were utilized to design a protein-protein interaction (PPI) network and conduct module analysis. An OVA-induced asthma mice model was established. Lung tissue from the mice was collected for quantitative reverse transcription polymerase chain reaction (qRT-PCR), Western blot, and immunohistochemistry (IHC) to assess the expression of DEGs. A total of 545 DEGs were identified, among which 172 genes were upregulated in SA patients compared to healthy controls. The nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) was significantly up-regulated in SA patients [adjusted P value (Padj) =0.001]. Analysis of lung tissue using qRT-PCR, western blot, and IHC revealed higher expression of NLRP3 in OVA-induced asthma mice compared to the control group. Enrichment analysis suggests the involvement of NLRP3 in pathways related to pyroptosis, c-type lectin receptor signaling, and NOD-like receptor signaling. Through bioinformatics analysis, we identified a multitude of DEGs that could potentially contribute significantly to the development of SA. Notably, our findings highlight NLRP3 as a potential pivotal player in asthma pathogenesis, underscoring its prospective utility as a biomarker for SA.

MCC950 promotes diabetic wound healing through modulating macrophage polarization in an MDSC-dependent manner

Diabetic foot ulcers (DFUs) are serious skin injuries whereby the wound healing process is frequently stalled in the inflammatory phase. Currently, there is a lack of effective therapeutic strategies. MCC950, a highly selective nod-like receptor family pyrin domain containing 3 (NLRP3) inhibitor, has been reported to show strong anti-inflammation effects in many diseases. In this study, we unveiled the role of MCC950 in DFU mice model and its underlying molecular mechanisms. MCC950 could significantly accelerate diabetic wound healing, as shown by shortened healing time and better healing quality. Moreover, increased M2 phenotype macrophages and decreased pro-inflammatory genes were observed in MCC950-treated DFU mice. Additionally, myeloid-derived suppressor cells (MDSCs) were significantly increased in blood, spleen and wound tissues at different time courses. Specifically, MCC950 could recruit more MDSCs in an early phase in DFU mice, exerting an anti-inflammation effect. We identified the cell crosstalk between macrophages and MDSCs with MCC950 treatment process. Depleting MDSCs in vivo could eliminate the therapeutic effect of MCC950 on diabetic wound healing through inhibiting M2 macrophage polarization. Besides, MDSCs isolated from the wounds of MCC950 or saline treated mice were cocultured with bone marrow derived macrophage (BMDM) in a transwell system. Results confirmed that MDSCs sorted from MCC950 treated mice caused a significant increased percentage of M2 macrophages. Collectively, our findings suggest that the administration of MCC950 has the potential to accelerate diabetic wound healing by promoting M2 macrophage polarization in an MDSC-dependent manner. This study provides valuable insights into the utilization of pharmacological agents for DFU treatment.

Amiloride Sensitizes Prostate Cancer Cells to the Reversible Tyrosine Kinase Inhibitor Lapatinib by Modulating ERBB3 Subcellular Localization.

Neoadjuvant therapy (NAT) has been studied in clinically localized prostate cancer (PCa) to improve the outcomes from radical prostatectomy (RP) by 'debulking' of high-risk PCa; however, using androgen deprivation at this point risks castration resistant PCa (CRPC) clonal proliferation with potentially profound side effects such as fatigue, loss of libido, hot flashes, loss of muscle mass, and weight gain. Our goal is to identify alternative NAT that reduce hormone sensitive PCa (HSPC) without affecting androgen receptor (AR) transcriptional activity. PCa is associated with increased expression and activation of the epidermal growth factor receptor (EGFR) family, including HER2 and ErbB3. Dimerization between these receptors is required for activation of downstream targets involved in tumor progression. The FDA-approved HER2 inhibitor lapatinib has been tested in PCa but was ineffective due to continued activation of ErbB3. We now demonstrate that this is due to ErbB3 being localized to the nucleus in HSPC and thus protected from lapatinib which affect membrane localized HER2/ErbB3 dimers. Here, we show that the well-established, well-tolerated diuretic amiloride hydrochloride dose dependently prevented ErbB3 nuclear localization via formation of plasma membrane localized HER2/ErbB3 dimers. This in turn allowed lapatinib inactivation of these dimers via inhibition of its target HER2, which dephosphorylated downstream survival and proliferation regulators AKT and ERK1/2. Amiloride combined with lapatinib significantly increased apoptosis but did not affect AR transcriptional activity. Thus, our data indicate that a combination of amiloride and lapatinib could target HSPC tumors without problems associated with androgen deprivation therapy in localized PCa.

Like Father like Daughter: Surgical Redo Thoracoabdominal Aneurysm Repairs in a Family With Loeys-Dietz Syndrome.

Loeys Dietz Syndrome (LDS) is an autosomal dominant connective tissue disorder resulting from a mutation in the transforming growth factor beta receptor (TGFBR) family of genes. It is commonly associated with the development of aortic aneurysms and dissections. We report the successful open surgical management of thoracoabdominal aneurysms in a father and daughter with Loeys-Dietz Syndrome after failed endovascular repair. The daughter required stent graft explantation, while the stent graft remained in the father. These cases highlight the importance of early genetic testing of both patients and first-degree family members in those with a strong history of aortic disease, even when there is a lack of typical connective tissue disorder associated physical exam findings and open surgical index operations.

An improved understanding of pediatric chronic nonbacterial osteomyelitis pathophysiology informs current and future treatment.

Chronic nonbacterial osteomyelitis (CNO) is an autoinflammatory bone disease that primarily affects children and young people. It can cause significant pain, reduced function, bone swelling, and even (vertebral body) fractures. Because of a limited understanding of its pathophysiology, the treatment of CNO remains empiric and is based on relatively small case series, expert opinion, and personal experience. Several studies have linked pathological NOD-kike receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome activation and the resulting imbalance between pro- and anti-inflammatory cytokine expression with CNO. This agrees with elevated pro-inflammatory (mostly) monocyte-derived protein signatures in the blood of CNO patients that may be used as future diagnostic and/or prognostic biomarkers. Recently, rare variants in the P2RX7 gene, encoding for an ATP-dependent transmembrane channel, were linked with increased NLRP3 inflammasome assembly and prolonged monocyte/macrophage survival in CNO. Although the exact molecular mechanisms remain unclear, this will inform future target-directed and individualized treatment. This manuscript reviews most recent developments and their impact on diagnostic and therapeutic strategies in CNO.

A2AR regulate inflammation through PKA/NF-κB signaling pathways in intervertebral disc degeneration

BackgroundReduction of inflammatory damage and inhibition of nucleus pulposus (NP) apoptosis are considered to be the main effective therapy idea to reverse the intervertebral disc degeneration (IDD) and alleviate the chronic low back pain. The adenosine A2A receptor (A2AR), as a member of G protein-coupled receptor families, plays an important role in the anti-inflammation and relieving pain. So far, the impact of A2AR on IDD therapy is unclear. The aim of this study was to explore the role of Adenosine A2A receptor (A2AR) in the intervertebral disc degeneration (IDD) and clarify potential mechanism.Materials and methodsIL-1β and acupuncture was used to establish IDD model rats. A2AR agonist CGS-21680 and A2AR antagonist SCH442416 were used to investigate the therapeutical effects for IDD. Histological examination, western blotting analysis and RT-PCR were employed to evaluate the the association between A2AR and cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway.ResultsA2AR activity of the intervertebral disc tissues was up-regulated in feedback way, and cAMP, PKA and CREB expression were also increased. But in general, IL-1β-induced IDD promoted the significant up-regulation the expression of inflammatory factors. The nucleus pulposus (NP) inflammation was exacerbated in result of MMP3 and Col-II decline through activating NF-κB signaling pathway. A2AR agonist CGS-21680 exhibited a disc protective effect through significantly increasing A2AR activity, then further activated cAMP/PKA signaling pathway with attenuating the release of TNF-α and IL-6 via down-regulating NF-κB. In contrast, SCH442416 inhibited A2AR activation, consistent with lower expression levels of cAMP and PKA, further leading to the acceleration of IDD.ConclusionsThe activation of A2AR can prevent inflammatory responses and mitigates degradation of IDD thus suggest a potential novel therapeutic strategy of IDD.

Targeting Androgen, Thyroid Hormone, and Vitamin A and D Receptors to Treat Prostate Cancer.

The nuclear hormone family of receptors regulates gene expression. The androgen receptor (AR), upon ligand binding and homodimerization, shuttles from the cytosol into the nucleus to activate gene expression. Thyroid hormone receptors (TRs), retinoic acid receptors (RARs), and the vitamin D receptor (VDR) are present in the nucleus bound to chromatin as a heterodimer with the retinoid X receptors (RXRs) and repress gene expression. Ligand binding leads to transcription activation. The hormonal ligands for these receptors play crucial roles to ensure the proper conduct of very many tissues and exert effects on prostate cancer (PCa) cells. Androgens support PCa proliferation and androgen deprivation alone or with chemotherapy is the standard therapy for PCa. RARγ activation and 3,5,3'-triiodo-L-thyronine (T3) stimulation of TRβ support the growth of PCa cells. Ligand stimulation of VDR drives growth arrest, differentiation, and apoptosis of PCa cells. Often these receptors are explored as separate avenues to find treatments for PCa and other cancers. However, there is accumulating evidence to support receptor interactions and crosstalk of regulatory events whereby a better understanding might lead to new combinatorial treatments.