The Activation and Signaling Mechanisms of GPR56/ADGRG1 in Melanoma Cell

Adhesion G protein-coupled receptors (aGPCRs) constitute the second largest GPCR subfamily. GPR56/ADGRG1 is a member of the ADGRG subgroup of aGPCRs. Although GPR56 is best known for its pivotal role in the cerebral cortical development, it is also important for tumor progression. Numerous studies have revealed that GPR56 is expressed in various cancer types with a role in cancer cell adhesion, migration and metastasis. In a recent study, we found that the immobilized GPR56-specific CG4 antibody enhanced IL-6 production and migration ability of melanoma cells. In this review, we will summarize the current understanding of GPR56 function and discuss the activation and signaling mechanisms of GPR56 in melanoma cells

Role of PPARα and Its Agonist in Renal Diseases

Peroxisome proliferator-activated receptor (PPAR)-α, a member of a large nuclear receptor superfamily, plays a major role in the regulation of lipid metabolism. Recently, PPARα activation has been shown to confer additional benefits on endothelial function, kidney function, and anti-inflammation, suggesting that PPARα agonists may be good candidates for treating acute renal failure. In clinical application, PPAR-α activators, such as hypolipidemic drugs in fibric acid class, were proven to have therapeutic effects on metabolic syndrome and cardiovascular disease. This paper focuses on signaling pathways, ligand selectivity, and physio-pathological roles of PPARα in kidney diseases and the therapeutic utility of PPARα modulators in the treatment of diabetes and inflammation-induced nephropathy. Implication of new and more potent PPAR-α activators could provide important insights into the overall benefits of activating PPAR-α clinically for the treatment of dyslipidemia and the prevention of diabetic or inflammation-induced nephropathy in the future

Body mass index and active range of motion exercise treatment after intra-articular injection in adhesive capsulitis

Abstract Background: Adhesive capsulitis is commonly associated with medical diseases such as diabetes mellitus, hyperthyroidism, and obesity. Intraarticular injection has been used to speed recovery and relieve pain associated with frozen shoulder. In this study, we evaluated and compared the effects of an intra-articular injection of corticosteroid and lidocaine in the treatment of primary adhesive capsulitis in overweight and normalweight patients. Methods: This is a prospective clinical study of patients with adhesive capsulitis, in which the main treatment strategy was an intra-articular injection of corticosteroid (3 mL) and lidocaine (3 mL). Active range of motion exercise was initiated immediately after the injection and performed four times daily. The evaluation included the recording of a detailed medical and orthopedic history, and the assessment of pain and function by determining the Constant score at baseline (before injection) and every 2 weeks thereafter. Patients were classified as normal weight (body mass index [BMI] < 25 kg/m 2 ) or overweight (BMI 25 kg/m 2 ). The Constant scores of all patients were compared at 8 weeks after injection. Results: After clinical examinations and radiographic and ultrasonographic studies, 79 patients were treated for adhesive capsulitis between 2010 and 2012. In the normal-weight group, the mean Constant score increased from 35.4 to 74.6 after 8 weeks, whereas in the overweight group, the mean Constant score increased from 32.0 to 47.2. There was a significant difference in the mean Constant score between the normal-weight and overweight groups at 8 weeks. Conclusion: Active range of motion exercise after an intra-articular injection of corticosteroid and lidocaine improved pain and functional outcome at 8 weeks in normal-weight (BMI < 25 kg/m 2 ) patients with primary adhesive capsulitis. Manipulation under anesthesia may be considered a priority in overweight patients

Identification and Characterization of a Novel Human Myeloid Inhibitory C-type Lectin-like Receptor (MICL) That Is Predominantly Expressed on Granulocytes and Monocytes

Inhibitory and activatory C-type lectin-like receptors play an important role in immunity through the regulation of leukocytes. Here, we report the identification and characterization of a novel myeloid inhibitory C-type lectin-like receptor (MICL) whose expression is primarily restricted to granulocytes and monocytes. This receptor, which contains a single C-type lectin-like domain and a cytoplasmic immunoreceptor tyrosine-based inhibitory motif, is related to LOX-1 (lectin-like receptor for oxidized low density lipoprotein-1) and the β-glucan receptor (Dectin-1) and is variably spliced and highly N-glycosylated. We demonstrate that it preferentially associates with the signaling phosphatases SHP-1 and SHP-2, but not with SHIP. Novel chimeric analyses with a construct combining MICL and the β-glucan receptor show that MICL can inhibit cellular activation through its cytoplasmic immunoreceptor tyrosine-based inhibitory motff. These data suggest that MICL is a negative regulator of granulocyte and monocyte function

The Adhesion G Protein-Coupled Receptor GPR97/ADGRG3 Is Expressed in Human Granulocytes and Triggers Antimicrobial Effector Functions

The adhesion family of G protein-coupled receptors (aGPCRs) comprises 33 members in human, several of which are distinctly expressed and functionally involved in polymorphonuclear cells (PMNs). As former work indicated the possible presence of the aGPCR GPR97 in granulocytes, we studied its cellular distribution, molecular structure, signal transduction, and biological function in PMNs. RNA sequencing and mass-spectrometry revealed abundant RNA and protein expression of ADGRG3/GPR97 in granulocyte precursors and terminally differentiated neutrophilic, eosinophilic, and basophilic granulocytes. Using a newly generated GPR97-specific monoclonal antibody, we confirmed that endogenous GPR97 is a proteolytically processed, dichotomous, N-glycosylated receptor. GPR97 was detected in tissue-infiltrating PMNs and upregulated during systemic inflammation. Antibody ligation of GPR97 increased neutrophil reactive oxygen species production and proteolytic enzyme activity, which is accompanied by an increase in mitogen-activated protein kinases and IκBα phosphorylation. In-depth analysis of the GPR97 signaling cascade revealed a possible switch from basal Gαs/cAMP-mediated signal transduction to a Gαi-induced reduction in cAMP levels upon mutation-induced activation of the receptor, in combination with an increase in downstream effectors of Gβγ, such as SRE and NF-κB. Finally, ligation of GPR97 increased the bacteria uptake and killing activity of neutrophils. We conclude that the specific presence of GPR97 regulates antimicrobial activity in human granulocytes

The macrophage F4/80 receptor is required for the induction of antigen-specific efferent regulatory T cells in peripheral tolerance

We show that the mouse macrophage-restricted F4/80 protein is not required for the development and distribution of tissue macrophages but is involved in the generation of antigen-specific efferent regulatory T (T reg) cells that suppress antigen-specific immunity. In the in vivo anterior chamber (a.c.)–associated immune deviation (ACAID) model of peripheral tolerance, a.c. inoculation of antigen into F4/80−/− mice was unable to induce efferent T reg cells and suppress delayed-type hypersensitivity (DTH) responses. Moreover, the use of anti-F4/80 mAb and F4/80−/− APCs in an in vitro ACAID model showed that all APC cells in the culture must be able to express F4/80 protein if efferent T reg cells were to be generated. In a low-dose oral tolerance model, WT but not F4/80−/− mice generated an efferent CD8+ T reg cell population that suppressed an antigen-specific DTH response. Peripheral tolerance was restored in F4/80−/− mice by adoptive transfer of F4/80+ APCs in both peripheral tolerance models, indicating a central role for the F4/80 molecule in the generation of efferent CD8+ T reg cells

Foxp3-positive macrophages display immunosuppressive properties and promote tumor growth

Identification of a population of Foxp3-expressing suppressive macrophages

Correlation of virulence genes to clinical manifestations and outcome in patients with Streptococcus dysgalactiae subspecies equisimilis bacteremia

Background/PurposeStreptococcus dysgalactiae subsp. equisimilis (SDSE) is increasingly recognized as a human pathogen responsible for invasive infection and streptococcal toxic shock syndrome (STSS). The pathogen possesses virulence genes that resemble those found in Streptococcus pyogenes (GAS). We analyzed the association between these specific toxic genes, clinical presentations, and outcome in patients with SDSE infections.MethodsPatients (older than 18 years) with community-acquired invasive bacteremia caused by SDSE bacteremia who were undergoing treatment at China Medical University Hospital from June 2007 to December 2010 were included in this study. Multiplex polymerase chain reaction was performed to identify virulence genes of the SDSE isolates. Demographic data, clinical presentations, and outcome in patients with SDSE infections were reviewed and analyzed.ResultsForty patients with 41 episodes of SDSE bacteremia were reviewed. The median age of the patients with SDSE infection was 69.7 years; 55% were female and 78% had underlying diseases. Malignancy (13, 33%) and diabetes mellitus (13, 33%) were the most common comorbidities. The 30-day mortality rate was 12%. Compared with the survivors, the non-survivors had a higher rate of diabetes mellitus (80% vs. 26%), liver cirrhosis (60% vs.11%), shock (60% vs.17%), STSS (60% vs. 8%), and a high Pittsburgh bacteremia score >4 (40% vs. 6%). Most isolates had scpA, ska, saga, and slo genes, whereas speC, speG, speH, speI, speK, smez, and ssa genes were not detected. speA gene was identified only in one patient with STSS (1/6, 17%). All isolates were susceptible to penicillin, cefotaxime, levofloxacin, moxifloxacin, vancomycin, and linezolid.ConclusionIn invasive SDSE infections, most isolates carry putative virulence genes, such as scpA, ska, saga, and slo. Clinical SDSE isolates in Taiwan remain susceptible to penicillin cefotaxime, and levofloxacin

Recent insights into breast milk microRNA: their role as functional regulators

Breast milk (BM) is a primary biofluid that plays a crucial role in infant development and the regulation of the immune system. As a class of rich biomolecules in BM, microRNAs (miRNAs) are regarded as active factors contributing to infant growth and development. Surprisingly, these molecules exhibit resilience in harsh conditions, providing an opportunity for infants to absorb them. In addition, many studies have shown that miRNAs in breast milk, when absorbed into the gastrointestinal system, can act as a class of functional regulators to effectively regulate gene expression. Understanding the absorption pattern of BM miRNA may facilitate the creation of formula with a more optimal miRNA balance and pave the way for novel drug delivery techniques. In this review, we initially present evidence of BM miRNA absorption. Subsequently, we compile studies that integrate both in vivo and in vitro findings to illustrate the bioavailability and biodistribution of BM miRNAs post-absorption. In addition, we evaluate the strengths and weaknesses of previous studies and discuss potential variables contributing to discrepancies in their outcomes. This literature review indicates that miRNAs can be absorbed and act as regulatory agents