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Communications Biology May 2024Accumulating evidence suggests that endothelial cells can be useful therapeutic targets. One of the potential targets is an endothelial cell-specific protein,...
Accumulating evidence suggests that endothelial cells can be useful therapeutic targets. One of the potential targets is an endothelial cell-specific protein, Roundabout4 (ROBO4). ROBO4 has been shown to ameliorate multiple diseases in mice, including infectious diseases and sepsis. However, its mechanisms are not fully understood. In this study, using RNA-seq analysis, we found that ROBO4 downregulates prostaglandin-endoperoxide synthase 2 (PTGS2), which encodes cyclooxygenase-2. Mechanistic analysis reveals that ROBO4 interacts with IQ motif-containing GTPase-activating protein 1 (IQGAP1) and TNF receptor-associated factor 7 (TRAF7), a ubiquitin E3 ligase. In this complex, ROBO4 enhances IQGAP1 ubiquitination through TRAF7, inhibits prolonged RAC1 activation, and decreases PTGS2 expression in inflammatory endothelial cells. In addition, Robo4-deficiency in mice exacerbates PTGS2-associated inflammatory diseases, including arthritis, edema, and pain. Thus, we reveal the molecular mechanism by which ROBO4 suppresses the inflammatory response and vascular hyperpermeability, highlighting its potential as a promising therapeutic target for inflammatory diseases.
Topics: Cyclooxygenase 2; Animals; Mice; Inflammation; Humans; Receptors, Cell Surface; Mice, Knockout; Mice, Inbred C57BL; Male; Endothelial Cells; Roundabout Proteins
PubMed: 38762541
DOI: 10.1038/s42003-024-06317-z -
Scientific Reports May 2024Delayed cerebral ischemia (DCI) is a serious, life-threatening, complication affecting patients who have survived the initial bleeding from a ruptured intracranial...
Delayed cerebral ischemia (DCI) is a serious, life-threatening, complication affecting patients who have survived the initial bleeding from a ruptured intracranial aneurysm. Due to the challenging diagnosis, potential DCI prognostic markers should be of value in clinical practice. According to recent reports isoprostanes and red blood cell distribution (RDW) showed to be promising in this respect. We conducted a prospective study of 27 aSAH patients and control group (n = 8). All patients from the study group were treated within the first day of the initial bleeding. We collected data regarding clinical status and results of biochemical, and radiological examinations. We measured cerebrospinal fluid (CSF) concentration of 8-iso-prostaglandin F2α (F2-IsoP) and RDW on days 1, 3, and 5. Both CSF F2-IsoP level and RDW-SD measured on day 1 were significant predictors of DCI. The receiver operating characteristics curve for DCI prediction based on the multivariate model yielded an area under the curve of 0.924 (95% CI 0.824-1.000, p < 0.001). In our study, the model based on the combination of RDW and the level of isoprostanes in CSF on the first day after the initial bleeding showed a prognostic value for DCI prediction. Further studies are required to validate this observation.
Topics: Humans; Subarachnoid Hemorrhage; Female; Male; Middle Aged; Biomarkers; Dinoprost; Prognosis; Brain Ischemia; Prospective Studies; Erythrocyte Indices; Aged; Erythrocytes; Adult; ROC Curve
PubMed: 38760404
DOI: 10.1038/s41598-024-61956-w -
Animal Reproduction 2024As a positional and geometrical isomer of linoleic acid, trans 10, cis 12 conjugated linoleic acid (t10c12-CLA) reduces white fat by reducing food intake, modulating...
As a positional and geometrical isomer of linoleic acid, trans 10, cis 12 conjugated linoleic acid (t10c12-CLA) reduces white fat by reducing food intake, modulating lipid metabolism, and stimulating energy expenditure. However, the t10c12-CLA products are mostly mixtures, making it difficult to obtain accurate results. Studies are needed to investigate the effects of pure t10c12-CLA on animals and humans. In this study, we used the biallelic transgenic (tg) mice, which could produce t10c12-CLA itself, to investigate the effects of pure t10c12-CLA on female reproductive ability. The results showed that the body and relative ovary weights had no significant difference between tg and wild-type (wt) littermates at ages 3 or 10 weeks. While the fecundity test found that tg mice had a significantly longer first litter time (32.0 ± 4.70 days vs. 21.3 ± 2.31 days, <0.05), and a significantly lower number of litters (4.75 ± 2.75 vs. 6.67 ± 0.57, <0.05) when compared with wt mice during continuous mating within seven months. Hormone profiles showed that serum estradiol levels did not change in tg mice; however, significantly (<0.05) decreased progesterone and increased prostaglandin E2 levels were observed in tg mice compared with those of wt mice. Hematoxylin-eosin staining showed no pathological characteristics in tg ovaries, except for the increased atresia follicles (<0.05). Moreover, the tg mice had a significantly more extended diestrus period than the wt mice (48.4 ± 6.38% vs. 39.6 ± 3.81%, <0.05). In summary, t10c12-CLA could affect serum progesterone and prostaglandin E2 levels, lead to a disordered estrus cycle, and impact the reproductive performance of female mice. This study provided theoretical and biosafety recommendations for applying t10c12-CLA in female mammals.
PubMed: 38756621
DOI: 10.1590/1984-3143-AR2024-0010 -
Zhong Nan Da Xue Xue Bao. Yi Xue Ban =... Feb 2024One of the most common and significant symptoms for skin disorders is pruritus. Additionally, it serves as a significant catalyst for the exacerbation or reoccurrence of... (Review)
Review
One of the most common and significant symptoms for skin disorders is pruritus. Additionally, it serves as a significant catalyst for the exacerbation or reoccurrence of skin diseases. Pruritus seriously affects patients' physical and mental health, and even the quality of life. It brings a heavy burden to the patients, the families, even the whole society. The pathogenesis and regulation mechanisms for pruritus are complicated and have not yet been elucidated. Previous clinical studies have shown that itch worsens at night in scabies, chronic pruritus, atopic dermatitis, and psoriasis, suggesting that skin pruritus may change with circadian rhythm. Cortisol, melatonin, core temperature, cytokines, and prostaglandins are the main regulatory factors of the circadian rhythm of pruritus. Recent studies have shown that some CLOCK genes, such as , , , and , play an important role in the regulation of the circadian rhythm of pruritus by regulating the Janus tyrosine kinase (JAK)-signal transducer and activator of transcription (STAT) and nuclear factor kappa-B (NF-κB) signaling pathways. However, the mechanisms for circadian clock genes in regulation of circadian rhythm of pruritus have not been fully elucidated. Further studies on the mechanism of circadian clock genes in the regulation of circadian rhythm of pruritus will lay a foundation for elucidating the regulatory mechanisms for pruritus, and also provide new ideas for the control of pruritus and the alleviation of skin diseases.
Topics: Pruritus; Humans; Circadian Rhythm; CLOCK Proteins; Signal Transduction; Melatonin; ARNTL Transcription Factors; NF-kappa B; Circadian Clocks
PubMed: 38755715
DOI: 10.11817/j.issn.1672-7347.2024.230397 -
PloS One 2024Echinatin is an active ingredient in licorice, a traditional Chinese medicine used in the treatment of inflammatory disorders. However, the protective effect and...
Echinatin is an active ingredient in licorice, a traditional Chinese medicine used in the treatment of inflammatory disorders. However, the protective effect and underlying mechanism of echinatin against acute lung injury (ALI) is still unclear. Herein, we aimed to explore echinatin-mediated anti-inflammatory effects on lipopolysaccharide (LPS)-stimulated ALI and its molecular mechanisms in macrophages. In vitro, echinatin markedly decreased the levels of nitric oxide (NO) and prostaglandin E2 (PGE2) in LPS-stimulated murine MH-S alveolar macrophages and RAW264.7 macrophages by suppressing inducible nitric oxide synthase and cyclooxygenase-2 (COX-2) expression. Furthermore, echinatin reduced LPS-induced mRNA expression and release of interleukin-1β (IL-1β) and IL-6 in RAW264.7 cells. Western blotting and CETSA showed that echinatin repressed LPS-induced activation of mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) pathways through targeting transforming growth factor-beta-activated kinase 1 (TAK1). Furthermore, echinatin directly interacted with Kelch-like ECH-associated protein 1 (Keap1) and activated the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway to enhance heme oxygenase-1 (HO-1) expression. In vivo, echinatin ameliorated LPS-induced lung inflammatory injury, and reduced production of IL-1β and IL-6. These findings demonstrated that echinatin exerted anti-inflammatory effects in vitro and in vivo, via blocking the TAK1-MAPK/NF-κB pathway and activating the Keap1-Nrf2-HO-1 pathway.
Topics: Animals; Male; Mice; Acute Lung Injury; Anti-Inflammatory Agents; Heme Oxygenase-1; Inflammation; Kelch-Like ECH-Associated Protein 1; Lipopolysaccharides; Macrophages; MAP Kinase Kinase Kinases; Membrane Proteins; NF-E2-Related Factor 2; NF-kappa B; RAW 264.7 Cells; Signal Transduction
PubMed: 38753858
DOI: 10.1371/journal.pone.0303556 -
PloS One 2024Myxomatous mitral valve disease (MMVD) is the most common cardiovascular disorder in dogs with a high prevalence, accounting for approximately 75% of all canine heart...
Myxomatous mitral valve disease (MMVD) is the most common cardiovascular disorder in dogs with a high prevalence, accounting for approximately 75% of all canine heart disease cases. MMVD is a complex disease and shows variable progression from mild valve leakage to severe regurgitation, potentially leading to heart failure. However, the molecular mechanisms and age-related changes that govern disease progression, especially at the early stage (B1) before the development of discernable clinical signs, remain poorly understood. In this prospective study, we aimed to compare gene expression differences between blood samples of aged beagle dogs with stage B1 MMVD and those of healthy controls using RNA sequencing. Clinical evaluation was also conducted, which revealed minimal differences in radiographic and echocardiographic measurements despite distinct biomarker variations between the two groups. Comparative transcriptomics revealed differentially expressed genes associated with extracellular matrix remodeling, prostaglandin metabolism, immune modulation, and interferon-related pathways, which bear functional relevance for MMVD. In particular, the top 10 over- and under-expressed genes represent promising candidates for influencing pathogenic changes in MMVD stage B1. Our research findings, which include identified variations in clinical markers and gene expression, enhance our understanding of MMVD. Furthermore, they underscore the need for further research into early diagnosis and treatment strategies, as, to the best of our knowledge, no prior studies have explored the precise molecular mechanisms of stage B1 in MMVD through total RNA sequencing.
Topics: Animals; Dogs; Dog Diseases; Sequence Analysis, RNA; Male; Female; Mitral Valve; Heart Valve Diseases; Transcriptome; Prospective Studies; Gene Expression Profiling
PubMed: 38753730
DOI: 10.1371/journal.pone.0300813 -
PloS One 2024This study seeks to investigate the impact of co-administering either a Prostaglandin EP2 receptor agonist or an EP1 receptor antagonist alone with a low dose BMP7 on in...
PURPOSE
This study seeks to investigate the impact of co-administering either a Prostaglandin EP2 receptor agonist or an EP1 receptor antagonist alone with a low dose BMP7 on in vitro healing process, collagen content and maturation of human osteoblasts.
METHODOLOGY
Human osteoblast cells were used in this study. These cells were cultured and subjected to different concentrations of Prostaglandin EP2 receptor agonist, EP1 receptor antagonist, BMP7, Control (Ct) (Vehicle alone), and various combinations treatments. Cell viability at 24, 48 and 72 hours (h) was evaluated using the XTT assay. A wound healing assay was conducted to observe the migration ability of human osteoblast cells. Additionally, Sirius red staining and Fourier-Transform Infrared Spectroscopy Imaging (FT-IR) was employed to analyze various parameters, including total protein concentration, collagen production, mature collagen concentration, and mineral content.
RESULTS
The combination of low dose BMP7 and Prostaglandin EP2 receptor agonist resulted to the lowest cell viability when compared to both the Ct and individual treatments. In contrast, the Prostaglandin EP1 receptor antagonist alone showed the highest cellular viability at 72 h. In the wound healing assay, the combined treatment of low dose BMP7 with the Prostaglandin EP2 receptor agonist and EP1 receptor antagonist showed a decrease in human osteoblast healing after 24 h. Analysis of FT-IR data indicated a reduction in total protein content, collagen maturity, collagen concentration and mineral content in combination treatment compared to the single or Ct treatments.
CONCLUSION
The combination of a Prostaglandin EP2 receptor agonist or an EP1 receptor antagonist when combined with low dose BMP7 significantly hinders both human osteoblast healing and collagen maturity/concentration in comparison to low dose BMP7 treatment alone.
Topics: Humans; Osteoblasts; Collagen; Bone Morphogenetic Protein 7; Cell Survival; Receptors, Prostaglandin E, EP2 Subtype; Wound Healing; Cell Movement; Receptors, Prostaglandin E, EP1 Subtype; Spectroscopy, Fourier Transform Infrared; Cell Line
PubMed: 38753641
DOI: 10.1371/journal.pone.0303202 -
Communications Biology May 2024Lymph node metastasis, primarily caused by the migration of oral squamous cell carcinoma (OSCC) cells, stands as a crucial prognostic marker. We have previously...
Lymph node metastasis, primarily caused by the migration of oral squamous cell carcinoma (OSCC) cells, stands as a crucial prognostic marker. We have previously demonstrated that EP4, a subtype of the prostaglandin E2 (PGE2) receptor, orchestrates OSCC cell migration via Ca signaling. The exact mechanisms by which EP4 influences cell migration through Ca signaling, however, is unclear. Our study aims to clarify how EP4 controls OSCC cell migration through this pathway. We find that activating EP4 with an agonist (ONO-AE1-473) increased intracellular Ca levels and the migration of human oral cancer cells (HSC-3), but not human gingival fibroblasts (HGnF). Further RNA sequencing linked EP4 to calmodulin-like protein 6 (CALML6), whose role remains undefined in OSCC. Through protein-protein interaction network analysis, a strong connection is identified between CALML6 and calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2), with EP4 activation also boosting mitochondrial function. Overexpressing EP4 in HSC-3 cells increases experimental lung metastasis in mice, whereas inhibiting CaMKK2 with STO-609 markedly lowers these metastases. This positions CaMKK2 as a potential new target for treating OSCC metastasis. Our findings highlight CALML6 as a pivotal regulator in EP4-driven mitochondrial respiration, affecting cell migration and metastasis via the CaMKK2 pathway.
Topics: Humans; Cell Movement; Mouth Neoplasms; Mitochondria; Receptors, Prostaglandin E, EP4 Subtype; Animals; Mice; Cell Line, Tumor; Carcinoma, Squamous Cell; Calcium-Calmodulin-Dependent Protein Kinase Kinase; Calmodulin; Squamous Cell Carcinoma of Head and Neck
PubMed: 38745046
DOI: 10.1038/s42003-024-06231-4 -
Frontiers in Immunology 2024The parasitic helminth is a potent inducer of type 2 immune responses by stimulating dendritic cells (DCs) to prime T helper 2 (Th2) responses. We previously found that...
The parasitic helminth is a potent inducer of type 2 immune responses by stimulating dendritic cells (DCs) to prime T helper 2 (Th2) responses. We previously found that soluble egg antigens (SEA) promote the synthesis of Prostaglandin E (PGE2) by DCs through ERK-dependent signaling via Dectin-1 and Dectin-2 that subsequently induces OX40L expression, licensing them for Th2 priming, yet the ligands present in SEA involved in driving this response and whether specific targeting of PGE2 synthesis by DCs could affect Th2 polarization are unknown. We here show that the ability of SEA to bind Dectin-2 and drive ERK phosphorylation, PGE2 synthesis, OX40L expression, and Th2 polarization is impaired upon cleavage of high-mannose glycans by Endoglycosidase H treatment. This identifies high-mannose glycans present on glycoproteins in SEA as important drivers of this signaling axis. Moreover, we find that OX40L expression and Th2 induction are abrogated when microsomal prostaglandin E synthase-1 (mPGES) is selectively inhibited, but not when a general COX-1/2 inhibitor is used. This shows that the synthesis of PGE2 is vital for the Th2 priming function of SEA-stimulated DCs as well as points to the potential existence of other COX-dependent lipid mediators that antagonize PGE2-driven Th2 polarization. Lastly, specific PGE2 inhibition following immunization with eggs dampened the egg-specific Th cell response. In summary, our findings provide new insights in the molecular mechanisms underpinning Th2 induction by and identify druggable targets for potential control of helminth driven-Th2 responses.
Topics: Animals; Mice; Antigens, Helminth; Dendritic Cells; Dinoprostone; Lectins, C-Type; Mannose; Mice, Inbred C57BL; Ovum; OX40 Ligand; Polysaccharides; Schistosoma mansoni; Schistosomiasis mansoni; Th2 Cells
PubMed: 38742105
DOI: 10.3389/fimmu.2024.1372927 -
Frontiers in Pharmacology 2024Osteoarthritis (OA) is a common chronic disease characterized by progressive cartilage degeneration and secondary synovial inflammation. Bergamottin (Ber) is an...
Osteoarthritis (OA) is a common chronic disease characterized by progressive cartilage degeneration and secondary synovial inflammation. Bergamottin (Ber) is an important natural derivative of the furanocoumarin compound, extracted from natural foods, such as the pulp of grapefruits and pomelos. Ber exhibits several characteristicsthat are beneficial to human health, such as anti-inflammation, antioxidant, and anti-cancer effects. However, the role of Ber in the treatment of OA has not been elucidated to date. Therefore, in the present study, experiments were conducted, which demonstrated that Ber reduces the secretion of inducible nitric oxide synthase (iNOS), nitric oxide (NO), cyclooxygenase-2 (COX2), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and prostaglandin E2 (PGE2) under the stimulation of interleukin-1β (IL-1β). Ber also reversed the IL-1 β-mediated aggrecan and type II collagen degradation within the extracellular matrix (ECM). In addition, experiments were conducted, in which Ber ameliorated the progression of OA in mice. It was revealed that Ber exerted its cellular effect by activating the Sirt1/NF-kB pathways. In conclusion, the present study demonstrated the therapeutic potential of Ber in the context of OA.
PubMed: 38741587
DOI: 10.3389/fphar.2024.1389786