Search Results (19)

G protein-coupled receptors (GPRs), including pro-inflammatory GPR4 and ovarian cancer GPR1 (OGR1/GPR68), are involved in the pH sensing of the extracellular space and have been implicated in inflammatory bowel disease (IBD). Previous data show that a loss of GPR4 or OGR1 independently is associated with reduced intestinal inflammation in mouse models of experimental colitis. In the present manuscript, we investigated the impact of the simultaneous loss of GPR4 and OGR1 in animal models of IBD. To study the effects of combined loss of Gpr4 Ogr1 in IBD we used the well-established acute dextran sodium sulfate (DSS) and spontaneous Il10^−/− murine colitis models. Disease severity was assessed using multiple clinical scores (e.g., body weight loss, disease activity score, murine endoscopic index of colitis severity (MEICS) and histological analyses). Real-time quantitative polymerase chain reaction (qPCR), Western blot, and flow cytometry were used to investigate changes in pro-inflammatory cytokines expression and immune cells infiltration. We found that a combined loss of GPR4 and OGR1 significantly reduces colon inflammation in IBD relative to single deficiencies as evidenced by reduced body weight loss, disease score, CD4/CD8 ratio, and Il1β, Il6, and Tnf in the colon. Similarly, in the II10 deficiency model, the inflammation was significantly ameliorated upon the simultaneous deletion of GPR4 and OGR1, evidenced by a reduction in the MEICS score, colon length, Tnf and Il1β measurements, and a decrease in the number of macrophages in the colon, as compared to single deletions. Importantly, hydroxyproline levels were decreased close to baseline in Il10^−/− × Gpr4^−/− × Ogr1^−/− mice. Our findings demonstrate that the simultaneous loss of GRP4 and OGR1 functions exerts an additive effect on multiple parameters associated with colonic inflammation. These results further reinforce the hypothesis that chronic inflammatory acidosis is a driver of fibrosis and is dependent on GPR4 and OGR1 signaling. The inhibition of both GPR4 and OGR1 by pH-sensing receptor modulators may constitute as a potential therapeutic option for IBD, as both pH-sensing receptors appear to sustain inflammation by acting on complementary pro-inflammatory pathways. Full article

The increasing use of digital platforms by adolescents has brought to light critical vulnerabilities related to online grooming. This study explores the risk factors associated with grooming among adolescents aged 12 to 17 years enrolled in a Reparative Program for Abuse in Chile. Using a non-experimental, quantitative, exploratory cross-sectional design, a sample of 50 adolescents was evaluated. Data collection employed validated instruments, including the Okasha Scale for Suicidality (EOS), the Depression Anxiety Stress Scale-21 (DASS-21), the Subjective Well-being Scale (EBS-8), and the Online Grooming Risk Scale (OGR-S). Findings revealed significant associations between grooming and variables such as excessive cellphone use, number of virtual social networks, lack of social connections, economic hardships, and depressive symptoms. Regression analysis highlighted that adolescents with unrestricted internet access, poor social interaction skills in face-to-face contexts, and exposure to environmental risk factors exhibit a heightened likelihood of experiencing grooming. These results underscore the necessity for targeted preventive interventions and policy enhancements to safeguard adolescents in vulnerable circumstances. Full article

Many university students report anxiety and low confidence when undertaking research courses. In the field, healthcare professionals have further identified that new graduates lack basic research skills. The research aims were to (1) ascertain what research concepts were deemed challenging to inform the development of a gamified resource (named OGRE) and (2) to determine if the resource influenced students’ research attitudes, confidence, and knowledge. Adopting a mixed-method approach, four student group interviews were conducted and pre- and post-course surveys were embedded in two large research courses as measures. Additionally, the qualitative component of student evaluations from six courses served as secondary data. Descriptive statistical analysis and thematic analysis techniques were applied. Whilst students understood the relevance of research to practice, only a minority expressed enthusiasm for the topic. The game did not significantly impact on confidence to undertake research, nor could the increase in student knowledge be attributed to the game alone. Gamified resources can be helpful for visual learners and can assist students with ‘real-life’ applications to practice problems, but are not essential to achieve a course’s learning outcomes. Further multidisciplinary team scenarios could be incorporated in OGRE to enhance practice preparedness. Full article

With the increasing demand for outdoor recreation and fitness, this study aims to assess the connectivity of the outdoor green recreation (OGR) network from the perspective of green travel and propose optimization framework. The Point of Interest (POI) and Area of Interest (AOI) datasets of OGR spots in Zhengzhou were utilized as the primary research materials. A combination of GIS spatial analysis and Graph index calculation is employed to quantify and diagnose the connectivity of the OGR network based on multi-source data (land cover, topography, and road network). The index system for cost surface establishment was improved and proposed, shifting its focus from previous biological migration and ecological network to human green travel and improving the connectivity of the OGR network. The technical optimization process of the OGR network is explored and presented. The results show that: (1) The scale, number, and distribution of OGR spots and the connectivity of the OGR network are significantly different in urban and rural areas. Numerous small-scale OGR spots and short-distance recreational paths are distributed in urban areas, while a limited number of large-scale OGR spots and long-distance recreational paths are situated in rural areas with better natural resources. (2) Compared with driving travel, the connectivity of the OGR network is poor when walking and cycling. Graph indexes of Dg, BC, and dPC can be used to reflect the connection capability, bridging role, and contribution of each spot to overall network connectivity. (3) The current OGR network is optimized through 30 new spots based on the perspective of green travel and land suitability analysis. The network connectivity will improve by 4%, and the number of recreational paths suitable for green travel increased by 41. (4) The methodologies for quantifying and optimizing OGR network connectivity from the perspective of green travel will offer valuable references for future research in this field. Full article

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. Full article

Colorectal cancer (CRC) is one of the most frequently occurring tumors. Ferula assa-foetida oleo-gum–resin (OGR) extract is a traditional cooking spice known for its broad spectrum of biological activities such as antifungal, antiparasitic, and anti-inflammatory activities. This study evaluated the antitumor effect of OGR extract against HT-29 colorectal cancer cells. The OGR chemical composition was analyzed using LC–ESI–MS/MS; MTT, clonogenic assays, and a xenograft model were used to measure cytotoxicity, while apoptotic proteins were detected using Western blotting. Phytochemical analysis revealed that the extract was a rich source of isoflavones, xanthones, and other derivatives. In a dose-dependent manner, the OGR extract significantly inhibited colony formation ability and HT-29 cell growth (IC₅₀ was 3.60 ± 0.02 and 10.5 ± 0.1 mg/mL, respectively). On the other hand, the OGR extract significantly induced apoptosis and increased the expression of some pro-death proteins involved in cellular apoptosis including PUMA, BIM, BIK, and BAK. Moreover, in a subcutaneous HT-29 xenograft model, the tumor volume and burden decreased after treatment with the OGR extract (550 ± 32 mm³ and 16.3 ± 3.6, respectively) This study demonstrated that Ferula assa-foetida OGR ethanolic extract has potential antitumor effects against HT-29 CRC cell lines by reducing cell viability and the function of apoptosis. More studies are needed to reveal the underlying mechanisms related to cytotoxicity and apoptosis induction. Full article

Sea-level rise (SLR) is a critical consequence of climate change, posing significant threats to coastal regions worldwide. Accurate and efficient assessment of potential inundation areas is crucial for effective coastal planning and adaptation strategies. This study aimed to explore the utility of free and open-source software for geospatial (FOSS4G) tools for mapping SLR inundation, providing cost-effective solutions that are accessible to researchers and policymakers. We employed a combination of geospatial data, including high-resolution elevation models, tidal data, and projected SLR scenarios. Utilizing widely available FOSS4G tools, like QGIS, GDAL/OGR, and GRASS GIS, we developed an integrated workflow to map inundation extents, using a passive bathtub approach for various SLR scenarios. We demonstrate the approach through a case study in Virginia Key, Florida, however, the methodology can be replicated in any area where the input datasets are available. This paper demonstrates that FOSS4G tools offer a reliable and accessible means to map SLR inundation, empowering stakeholders to assess coastal vulnerabilities and to devise sustainable adaptation measures. The open-source approach facilitates collaboration and reproducibility, fostering a comprehensive understanding of the potential impacts of SLR on coastal ecosystems and communities. Full article

G-protein-coupled receptors (GPRs), including pro-inflammatory ovarian cancer GPR1 (OGR1/GPR68) and anti-inflammatory T cell death-associated gene 8 (TDAG8/GPR65), are involved in pH sensing and linked to inflammatory bowel disease (IBD). OGR1 and TDAG8 show opposite effects. To determine which effect is predominant or physiologically more relevant, we deleted both receptors in models of intestinal inflammation. Combined Ogr1 and Tdag8 deficiency was assessed in spontaneous and acute murine colitis models. Disease severity was assessed using clinical scores. Colon samples were analyzed using quantitative polymerase chain reaction (qPCR) and flow cytometry (FACS). In acute colitis, Ogr1-deficient mice showed significantly decreased clinical scores compared with wildtype (WT) mice, while Tdag8-deficient mice and double knockout (KO) mice presented similar scores to WT. In Il-10-spontaneous colitis, Ogr1-deficient mice presented significantly decreased, and Tdag8-deficient mice had increased inflammation. In the Il10^−/− × Ogr1^−/− × Tdag8^−/− triple KO mice, inflammation was significantly decreased compared with Tdag8^−/−. Absence of Ogr1 reduced pro-inflammatory cytokines in Tdag8-deficient mice. Tdag8^−/− had significantly more IFNγ⁺ T-lymphocytes and IL-23 T-helper cells in the colon compared with WT. The absence of OGR1 significantly alleviates the intestinal damage mediated by the lack of functional TDAG8. Both OGR1 and TDAG8 represent potential new targets for therapeutic intervention. Full article

A specific phenotypic variant of obesity is metabolically healthy (MHO), which is characterized by normal blood pressure and lipid and glucose profiles, in contrast to the metabolically unhealthy variant (MUO). The genetic causes underlying the differences between these phenotypes are not yet clear. This study aims to explore the differences between MHO and MUO and the contribution of genetic factors (single nucleotide polymorphisms—SNPs) in 398 Hungarian adults (81 MHO and 317 MUO). For this investigation, an optimized genetic risk score (oGRS) was calculated using 67 SNPs (related to obesity and to lipid and glucose metabolism). Nineteen SNPs were identified whose combined effect was strongly associated with an increased risk of MUO (OR = 1.77, p < 0.001). Four of them (rs10838687 in MADD, rs693 in APOB, rs1111875 in HHEX, and rs2000813 in LIPG) significantly increased the risk of MUO (OR = 1.76, p < 0.001). Genetic risk groups based on oGRS were significantly associated with the risk of developing MUO at a younger age. We have identified a cluster of SNPs that contribute to the development of the metabolically unhealthy phenotype among Hungarian adults suffering from obesity. Our findings emphasize the significance of considering the combined effect(s) of multiple genes and SNPs in ascertaining cardiometabolic risk in obesity in future genetic screening programs. Full article

Camouflage objects hide information physically based on the feature matching of the texture or boundary line within the background. Texture matching and similarities between the camouflage objects and surrounding maps make differentiation difficult with generic and salient objects, thus making camouflage object detection (COD) more challenging. The existing techniques perform well. However, the challenging nature of camouflage objects demands more accuracy in detection and segmentation. To overcome this challenge, an optimized modular framework for COD tasks, named Optimize Global Refinement (OGR), is presented. This framework comprises a parallelism approach in feature extraction for the enhancement of learned parameters and globally refined feature maps for the abstraction of all intuitive feature sets at each extraction block’s outcome. Additionally, an optimized local best feature node-based rule is proposed to reduce the complexity of the proposed model. In light of the baseline experiments, OGR was applied and evaluated on a benchmark. The publicly available datasets were outperformed by achieving state-of-the-art structural similarity of 94%, 93%, and 96% for the Kvasir-SEG, COD10K, and Camouflaged Object (CAMO) datasets, respectively. The OGR is generalized and can be integrated into real-time applications for future development. Full article

Idiopathic pulmonary fibrosis (IPF) is a disease characterized by irreversible lung scarring. The pathophysiology is not fully understood, but the working hypothesis postulates that a combination of epithelial injury and myofibroblast differentiation drives progressive pulmonary fibrosis. We previously demonstrated that a reduction in extracellular pH activates latent TGF-β1, and that TGF-β1 then drives its own activation, creating a feed-forward mechanism that propagates myofibroblast differentiation. Given the important roles of extracellular pH in the progression of pulmonary fibrosis, we sought to identify whether pH mediates other cellular phenotypes independent of TGF-β1. Proton-sensing G-protein coupled receptors are activated by acidic environments, but their role in fibrosis has not been studied. Here, we report that the Ovarian Cancer G-Protein Coupled Receptor1 (OGR1 or GPR68) has dual roles in both promoting and mitigating pulmonary fibrosis. We demonstrate that OGR1 protein expression is significantly reduced in lung tissue from patients with IPF and that TGF-β1 decreases OGR1 expression. In fibroblasts, OGR1 inhibits myofibroblast differentiation and does not contribute to inflammation. However, in epithelial cells, OGR1 promotes epithelial to mesenchymal transition (EMT) and inflammation. We then demonstrate that sub-cellular localization and alternative signaling pathways may be responsible for the differential effect of OGR1 in each cell type. Our results suggest that strategies to selectively target OGR1 expression may represent a novel therapeutic strategy for pulmonary fibrosis. Full article

Diabetes mellitus is a major public health problem with a wide range of prevalence among different ethnic groups. Early recognition of pre-diabetes is important to prevent the development of the disease, its complications, co-morbidities, and consequently early death. Insulin resistance (IR) is considered a condition that precedes type 2 diabetes; thus, understanding its underlying causes (genetic and non-genetic factors) will bring us closer to preventing it. The present study aimed to investigate the genetic susceptibility to IR and its impact on estimated longevity in populations with different ethnic origins using randomly selected samples of 372 Hungarian general (HG, as a reference with Caucasian origin) and 334 Roma participants (largest ethnic minority in Europe, with a northern India origin). In the present study, we used the Homeostasis Model Assessment—Insulin Resistance (HOMA—IR) to identify people with IR (>3.63) at the population level. To investigate the genetic predisposition to IR, 29 single nucleotide polymorphisms (SNPs) identified in a systematic literature search were selected and genotyped in sample populations. In the analyses, the adjusted p < 0.0033 was considered significant. Of these 29 SNPs, the commutative effects of 15 SNPs showing the strongest association with HOMA—IR were used to calculate an optimized genetic risk score (oGRS). The oGRS was found nominally significantly (p = 0.019) higher in the Roma population compared to HG one, and it was more strongly correlated with HOMA—IR. Therefore, it can be considered as a stronger predictor of the presence of IR among the Roma (AUCRoma = 0.673 vs. AUCHG = 0.528). Furthermore, oGRS also showed a significant correlation with reduced estimated longevity in the Roma population (β = −0.724, 95% CI: −1.230–−0.218; p = 0.005), but not in the HG one (β = 0.065, 95% CI: −0.388–0.518; p = 0.779). Overall, IR shows a strong correlation with a genetic predisposition among Roma, but not in the HG population. Furthermore, the increased genetic risk of Roma is associated with shorter estimated longevity, whereas this association is not observed in the HG one. Increased genetic susceptibility of Roma to IR should be considered in preventive programs targeting the development of type 2 diabetes, which may also reduce the risk of preventable premature death among them. Full article

Age-related injuries are often connected to alterations in redox homeostasis. The imbalance between free radical oxygen species and endogenous antioxidants defenses could be associated with a growing risk of transient ischemic attack and stroke. In this context, a daily supply of dietary antioxidants could counteract oxidative stress occurring during ischemia/reperfusion injury (I/R), preventing brain damage. Here we investigated the potential antioxidant properties of coffee-derived circulating metabolites and a coffee pulp phytoextract, testing their efficacy as ROS scavengers in an in vitro model of ischemia. Indeed, the coffee fruit is an important source of phenolic compounds, such as chlorogenic acids, present both in the brewed seed and in the discarded pulp. Therefore, rat brain endothelial cells, subjected to oxygen and glucose deprivation (OGD) and recovery (ogR) to mimic reperfusion, were pretreated or not with coffee by-products. The results indicate that, under OGD/ogR, the ROS accumulation was reduced by coffee by-product. Additionally, the coffee extract activated the Nrf2 antioxidant pathway via Erk and Akt kinases phosphorylation, as shown by increased Nrf2 and HO-1 protein levels. The data indicate that the daily intake of coffee by-products as a dietary food supplement represents a potential nutritional strategy to counteract aging. Full article

Local extracellular acidification occurs at sites of inflammation. Proton-sensing ovarian cancer G-protein-coupled receptor 1 (OGR1, also known as GPR68) responds to decreases in extracellular pH. Our previous studies show a role for OGR1 in the pathogenesis of mucosal inflammation, suggesting a link between tissue pH and immune responses. Additionally, pH-dependent signalling is associated with the progression of intestinal fibrosis. In this study, we aimed to investigate OGR1 expression and OGR1-mediated signalling in patients with inflammatory bowel disease (IBD). Our results show that OGR1 expression significantly increased in patients with IBD compared to non-IBD patients, as demonstrated by qPCR and immunohistochemistry (IHC). Paired samples from non-inflamed and inflamed intestinal areas of IBD patients showed stronger OGR1 IHC staining in inflamed mucosal segments compared to non-inflamed mucosa. IHC of human surgical samples revealed OGR1 expression in macrophages, granulocytes, endothelial cells, and fibroblasts. OGR1-dependent inositol phosphate (IP) production was significantly increased in CD14+ monocytes from IBD patients compared to healthy subjects. Primary human and murine fibroblasts exhibited OGR1-dependent IP formation, RhoA activation, F-actin, and stress fibre formation upon an acidic pH shift. OGR1 expression and signalling increases with IBD disease activity, suggesting an active role of OGR1 in the pathogenesis of IBD. Full article

The group of proton-sensing G-protein coupled receptors (GPCRs) consists of the four receptors GPR4, TDAG8 (GPR65), OGR1 (GPR68), and G2A (GPR132). These receptors are cellular sensors of acidification, a property that has been attributed to the presence of crucial histidine residues. However, the pH detection varies considerably among the group of proton-sensing GPCRs and ranges from pH of 5.5 to 7.8. While the proton-sensing GPCRs were initially considered to detect acidic cellular environments in the context of inflammation, recent observations have expanded our knowledge about their physiological and pathophysiological functions and many additional individual and unique features have been discovered that suggest a more differentiated role of these receptors in health and disease. It is known that all four receptors contribute to different aspects of tumor biology, cardiovascular physiology, and asthma. However, apart from their overlapping functions, they seem to have individual properties, and recent publications identify potential roles of individual GPCRs in mechanosensation, intestinal inflammation, oncoimmunological interactions, hematopoiesis, as well as inflammatory and neuropathic pain. Here, we put together the knowledge about the biological functions and structural features of the four proton-sensing GPCRs and discuss the biological role of each of the four receptors individually. We explore all currently known pharmacological modulators of the four receptors and highlight potential use. Finally, we point out knowledge gaps in the biological and pharmacological context of proton-sensing GPCRs that should be addressed by future studies. Full article