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Ophthalmic Research 2023Dry eye disease (DED) is a multifactor-induced disease accompanied by increased osmolarity of the tear film and inflammation of the ocular surface. Traditional...
INTRODUCTION
Dry eye disease (DED) is a multifactor-induced disease accompanied by increased osmolarity of the tear film and inflammation of the ocular surface. Traditional anti-inflammation agent corticosteroids applied in DED treatment could result in high intraocular pressure, especially in long-term treatment. Therefore, we explored a nano drug that aimed to block the formation pathway of DED which had anti-inflammatory, sustained release, and good biocompatibility characteristics in this study.
METHODS
We prepared a novel nanomedicine (Tet-ATS@PLGA) by the thin film dispersion-hydration ultrasonic method and detected its nanostructure, particle size, and zeta potential. Flow cytometry was used to detect the cell survival rate of each group after 24 h of drug treatment on inflammed Statens Seruminstitut Rabbit Corneal (SIRC) cells. Observed and recorded corneal epithelial staining, tear film rupture time, and Schirmer test to detect tear secretion on the ocular surface of rabbits. The corneal epithelial thickness, morphology, and number of bulbar conjunctival goblet cells were recorded by H&E staining. Finally, we detected the expression of VEGF, IL-1β, PGE2, and TNF-α by cellular immunofluorescence staining and enzyme-linked immunosorbent assay (ELISA).
RESULTS
The encapsulation efficiency and drug loading of Tet-ATS@PLGA were 79.85% and 32.47%, respectively. At eye surface temperature, Tet can easily release from Tet-ATS@PLGA while that it was difficult to release at storage temperature and room temperature. After 2 weeks medication, Tet-ATS@PLGA can effectively improve the tear film rupture time and tear secretion time in a DED model (p <0.05). Compared with the normal group (62.34 ± 4.86 mm), the thickness of corneal epithelium in ATS (29.47 ± 3.21 mm), Tet-ATS (46.23 ± 2.87 mm), and Tet-ATS@PLGA (55.76 ± 3.95 mm) gradually increased. Furthermore, the flow cytometry indicated that Tet-ATS@PLGA can effectively promote the apoptosis of inflammatory SIRC cells, and the cellular immunofluorescence and ELISA experiments showed that the expression intensity of inflammatory factors such as VEGF, IL-1β, PGE2, and TNF-α decreased in this process. Interestingly, Tet also had the effect of reducing intraocular pressure.
CONCLUSION
Tet-ATS@PLGA can effectively promote the apoptosis of inflammatory corneal epithelial cells, thus inhibiting the expression of inflammatory factors to block the formation of DED and improve the secretion of tear on the ocular surface.
Topics: Animals; Rabbits; Polyglycolic Acid; Tumor Necrosis Factor-alpha; Dinoprostone; Vascular Endothelial Growth Factor A; Dry Eye Syndromes; Tears; Cornea; Anti-Inflammatory Agents; Nanoparticles
PubMed: 37690450
DOI: 10.1159/000533345 -
International Journal of Nanomedicine 2023Flurbiprofen axetil (FA) is a non-steroidal anti-inflammatory drug with good analgesic and anti-inflammatory effects. However, it suffers from poor solubility, short...
BACKGROUND
Flurbiprofen axetil (FA) is a non-steroidal anti-inflammatory drug with good analgesic and anti-inflammatory effects. However, it suffers from poor solubility, short circulation time, and off-target binding profile, which significantly limit its clinical application. Here, we loaded FA into stealth lipid microspheres modified with the arginine-glycine-aspartic acid (RGD) peptide (cRGD-FA-SLM), and examined the therapeutic potential of the resulting platform for the treatment of rheumatoid arthritis (RA).
METHODS
cRGD-FA-SLM was prepared by high pressure homogenization, and its toxicity and uptake by macrophages were examined using cultures of RAW264.7 cells. Hemolysis and hepatotoxicity tests were performed to assess the safety of the developed platform, while its pharmacokinetics, biodistribution, and therapeutic efficacy were investigated in a collagen-induced arthritis rat model.
RESULTS
cRGD-FA-SLM showed homogeneous spherical morphology and efficient encapsulation of FA. The developed platform was non-toxic to normal macrophages and was selectively internalized by lipopolysaccharide-activated macrophages in vitro, while it distributed mainly to arthritic joints and significantly prolonged FA in circulation in vivo. cRGD-FA-SLM also significantly reduced the expression of prostaglandin E2 and alleviated joint edema and bone erosion, showing prolonged analgesic effects in arthritic rats.
CONCLUSION
cRGD-FA-SLM shows good inflammation-targeting ability and prolongs drug circulation in vivo, suggesting promise as an anti-inflammatory and analgesic agent for targeted RA treatment.
Topics: Animals; Rats; Nanospheres; Tissue Distribution; Arthritis, Rheumatoid; Dinoprostone
PubMed: 37705869
DOI: 10.2147/IJN.S419502 -
The FEBS Journal Jan 2023Prostaglandin E2 (PGE2) is one of the most abundant prostaglandins and has been implicated in various diseases. Here, we aimed to explore the role of the PGE2 pathway in...
Prostaglandin E2 (PGE2) is one of the most abundant prostaglandins and has been implicated in various diseases. Here, we aimed to explore the role of the PGE2 pathway in mediating ferroptosis during acute kidney injury. When renal tubular epithelial cells stimulated by H O , the contents of glutathione (GSH) and glutathione peroxidase 4 (GPX4) decreased, whereas the level of lipid peroxide increased. Ferrostatin-1 can effectively attenuate these changes. In this process, the expression levels of cyclooxygenase (COX)-1 and COX-2 were up-regulated. Meanwhile, the expression of microsomal prostaglandin E synthase-2 was elevated, whereas the expression of microsomal prostaglandin E synthase-1 and cytosolic prostaglandin E synthase were down-regulated. Furthermore, the expression of 15-hydroxyprostaglandin dehydrogenase decreased. An excessive accumulation of PGE2 promoted ferroptosis, whereas the PGE2 inhibitor pranoprofen minimized the changes for COX-2, GSH, GPX4 and lipid peroxides. A decrease in the levels of the PGE2 receptor E-series of prostaglandin 1/3 partially restored the decline of GSH and GPX4 levels and inhibited the aggravation of lipid peroxide. Consistent with the in vitro results, increased PGE2 levels led to increased levels of 3,4-methylenedioxyamphetamine, Fe accumulation and decreased GSH and GPX4 levels during renal ischaemia/reperfusion injury injury in mice. Our results indicate that the PGE2 pathway mediated oxidative stress-induced ferroptosis in renal tubular epithelial cells.
Topics: Mice; Animals; Dinoprostone; Ferroptosis; Cyclooxygenase 2; Prostaglandin-E Synthases; Lipid Peroxides; Oxidative Stress; Epithelial Cells
PubMed: 36031392
DOI: 10.1111/febs.16609 -
Journal of Nanobiotechnology Mar 2023Intervertebral disc degeneration (IDD) has been identified as one of the predominant factors leading to persistent low back pain and disability in middle-aged and...
Intervertebral disc degeneration (IDD) has been identified as one of the predominant factors leading to persistent low back pain and disability in middle-aged and elderly people. Dysregulation of Prostaglandin E2 (PGE2) can cause IDD, while low-dose celecoxib can maintain PGE2 at the physiological level and activate the skeletal interoception. Here, as nano fibers have been extensively used in the treatment of IDD, novel polycaprolactone (PCL) nano fibers loaded with low-dose celecoxib were fabricated for IDD treatment. In vitro studies demonstrated that the nano fibers had the ability of releasing low-dose celecoxib slowly and sustainably and maintain PGE2. Meanwhile, in a puncture-induced rabbit IDD model, the nano fibers reversed IDD. Furthermore, low-dose celecoxib released from the nano fibers was firstly proved to promote CHSY3 expression. In a lumbar spine instability-induced mouse IDD model, low-dose celecoxib inhibited IDD in CHSY3 mice rather than CHSY3 mice. This model indicated that CHSY3 was indispensable for low-dose celecoxib to alleviate IDD. In conclusion, this study developed a novel low-dose celecoxib-loaded PCL nano fibers to reverse IDD by maintaining PGE2 at the physiological level and promoting CHSY3 expression.
Topics: Animals; Mice; Rabbits; Celecoxib; Dinoprostone; Disease Models, Animal; Intervertebral Disc Degeneration
PubMed: 36864461
DOI: 10.1186/s12951-023-01823-4 -
Proceedings of the National Academy of... Jul 2023To accomplish concerted physiological reactions, nature has diversified functions of a single hormone at at least two primary levels: 1) Different receptors recognize...
To accomplish concerted physiological reactions, nature has diversified functions of a single hormone at at least two primary levels: 1) Different receptors recognize the same hormone, and 2) different cellular effectors couple to the same hormone-receptor pair [R.P. Xiao, , re15 (2001); L. Hein, J. D. Altman, B.K. Kobilka, , 181-184 (1999); Y. Daaka, L. M. Luttrell, R. J. Lefkowitz, , 88-91 (1997)]. Not only these questions lie in the heart of hormone actions and receptor signaling but also dissecting mechanisms underlying these questions could offer therapeutic routes for refractory diseases, such as kidney injury (KI) or X-linked nephrogenic diabetes insipidus (NDI). Here, we identified that G-biased signaling, but not G activation downstream of EP4, showed beneficial effects for both KI and NDI treatments. Notably, by solving Cryo-electron microscope (cryo-EM) structures of EP3-G, EP4-G, and EP4-G in complex with endogenous prostaglandin E (PGE)or two synthetic agonists and comparing with PGE-EP2-G structures, we found that unique primary sequences of prostaglandin E2 receptor (EP) receptors and distinct conformational states of the EP4 ligand pocket govern the G/G transducer coupling selectivity through different structural propagation paths, especially via TM6 and TM7, to generate selective cytoplasmic structural features. In particular, the orientation of the PGE ω-chain and two distinct pockets encompassing agonist L902688 of EP4 were differentiated by their G/G coupling ability. Further, we identified common and distinct features of cytoplasmic side of EP receptors for G/G coupling and provide a structural basis for selective and biased agonist design of EP4 with therapeutic potential.
Topics: Dinoprostone; Signal Transduction; Receptors, Prostaglandin; GTP-Binding Protein alpha Subunits, Gs; Hormones; Receptors, Prostaglandin E, EP4 Subtype; Receptors, Prostaglandin E, EP2 Subtype; Receptors, Prostaglandin E, EP3 Subtype
PubMed: 37478163
DOI: 10.1073/pnas.2216329120 -
Archives of Gynecology and Obstetrics Feb 2024The aim of this study was to comparatively assess the efficacy and safety of double balloon catheter (DBC) and dinoprostone as labor-inducing agents just for multipara...
PURPOSE
The aim of this study was to comparatively assess the efficacy and safety of double balloon catheter (DBC) and dinoprostone as labor-inducing agents just for multipara at term.
METHODS
A retrospective cohort study was conducted among multipara at term with a Bishop score < 6 who needed planned labor induction from January 1, 2020, to December 30, 2020 in Maternal and Child Health Hospital of Hubei province, Tongji Medical College, Huazhong University of Science and Technology. They were divided into DBC group and dinoprostone group, respectively. Baseline maternal data, maternal and neonatal outcomes were recorded for statistical analysis. Total vaginal delivery rate, rate of vaginal delivery within 24 h, rate of uterine hyperstimulation combined with abnormal fetal heart rate(FHR) were regarded as the primary outcome variables. The difference between groups was considered statistically significant when p value < 0.05.
RESULTS
A total of 202 multiparas was included for analysis (95 women in DBC group vs 107 women in dinoprostone group). There were no significant differences in total vaginal delivery rate and rate of vaginal delivery within 24 h between groups. Uterine hyperstimulation combined with abnormal FHR occurred exclusively in dinoprostone group.
CONCLUSION
DBC and dinoprostone seem to be equally effective, while, DBC seems to be safer than dinoprostone.
Topics: Pregnancy; Infant, Newborn; Child; Female; Humans; Dinoprostone; Oxytocics; Retrospective Studies; Administration, Intravaginal; Labor, Induced; Urinary Catheters; Cervical Ripening
PubMed: 36801968
DOI: 10.1007/s00404-022-06891-9 -
Frontiers in Immunology 2023Immune stress in broiler chickens is characterized by the development of persistent pro-inflammatory responses that contribute to degradation of production performance....
AIMS
Immune stress in broiler chickens is characterized by the development of persistent pro-inflammatory responses that contribute to degradation of production performance. However, the underlying mechanisms that cause growth inhibition of broilers with immune stress are not well defined.
METHODS
A total of 252 1-day-old Arbor Acres(AA) broilers were randomly allocated to three groups with six replicates per group and 14 broilers per replicate. The three groups comprised a saline control group, an Lipopolysaccharide (LPS) (immune stress) group, and an LPS and celecoxib group corresponding to an immune stress group treated with a selective COX-2 inhibitor. Birds in LPS group and saline group were intraperitoneally injected with the same amount of LPS or saline from 14d of age for 3 consecutive days. And birds in the LPS and celecoxib group were given a single intraperitoneal injection of celecoxib 15 min prior to LPS injection at 14 d of age.
RESULTS
The feed intake and body weight gain of broilers were suppressed in response to immune stress induced by LPS which is an intrinsic component of the outer membrane of Gram-negative bacteria. Cyclooxygenase-2 (COX-2), a key enzyme that mediates prostaglandin synthesis, was up-regulated through MAPK-NF-κB pathways in activated microglia cells in broilers exposed to LPS. Subsequently, the binding of prostaglandin E2 (PGE2) to the EP4 receptor maintained the activation of microglia and promoted the secretion of cytokines interleukin-1β and interleukin-8, and chemokines CX3CL1 and CCL4. In addition, the expression of appetite suppressor proopiomelanocortin protein was increased and the levels of growth hormone-releasing hormone were reduced in the hypothalamus. These effects resulted in decreased expression of insulin-like growth factor in the serum of stressed broilers. In contrast, inhibition of COX-2 normalized pro-inflammatory cytokine levels and promoted the expression of Neuropeptide Y and growth hormone-releasing hormone in the hypothalamus which improved the growth performance of stressed broilers. Transcriptomic analysis of the hypothalamus of stressed broilers showed that inhibition of COX-2 activity significantly down-regulated the expression of the TLR1B, IRF7, LY96, MAP3K8, CX3CL1, and CCL4 genes in the MAPK-NF-κB signaling pathway.
CONCLUSION
This study provides new evidence that immune stress mediates growth suppression in broilers by activating the COX-2-PGE2-EP4 signaling axis. Moreover, growth inhibition is reversed by inhibiting the activity of COX-2 under stressed conditions. These observations suggest new approaches for promoting the health of broiler chickens reared in intensive conditions.
Topics: Animals; Celecoxib; Chickens; Cyclooxygenase 2; Cytokines; Dinoprostone; Lipopolysaccharides; NF-kappa B; Signal Transduction; Inflammation
PubMed: 37207231
DOI: 10.3389/fimmu.2023.1193798 -
ELife Jan 2023In organ regeneration, progenitor and stem cells reside in their native microenvironment, which provides dynamic physical and chemical cues essential to their survival,...
In organ regeneration, progenitor and stem cells reside in their native microenvironment, which provides dynamic physical and chemical cues essential to their survival, proliferation, and differentiation. However, the types of cells that form the native microenvironment for renal progenitor cells (RPCs) have not been clarified. Here, single-cell sequencing of zebrafish kidney reveals as a principal marker of renal interstitial cells (RICs), which can be specifically labeled by GFP under the control of promoter in the transgenic zebrafish. During nephron regeneration, the formation of nephrons is supported by RICs that form a network to wrap the RPC aggregates. RICs that are in close contact with RPC aggregates express cyclooxygenase 2 (Cox2) and secrete prostaglandin E2 (PGE2). Inhibiting PGE2 production prevents nephrogenesis by reducing the proliferation of RPCs. PGE2 cooperates with Wnt4a to promote nephron maturation by regulating β-catenin stability of RPC aggregates. Overall, these findings indicate that RICs provide a necessary microenvironment for rapid nephrogenesis during nephron regeneration.
Topics: Animals; Dinoprostone; Zebrafish; Nephrons; Kidney; Animals, Genetically Modified
PubMed: 36645741
DOI: 10.7554/eLife.81438 -
Rheumatology (Oxford, England) Mar 2022In pre-clinical studies, pinolenic acid (PNLA), an omega-6-polyunsaturated fatty acid from pine nuts, has shown anti-inflammatory effects. We aimed to investigate the...
OBJECTIVES
In pre-clinical studies, pinolenic acid (PNLA), an omega-6-polyunsaturated fatty acid from pine nuts, has shown anti-inflammatory effects. We aimed to investigate the effect of PNLA in human cell lines and peripheral blood mononuclear cells (PBMCs) from RA patients and healthy controls (HCs).
METHODS
A modified Boyden chamber was used to assess chemokine-induced migration of THP-1 monocytes. Macropinocytosis was assessed using Lucifer yellow and oxidized low-density lipoprotein (oxLDL) uptake using DiI-labelled oxLDL in THP-1 macrophages and human monocyte-derived macrophages (HMDMs). IL-6, TNF-α and prostaglandin E2 (PGE2) release by lipopolysaccharide (LPS)-stimulated PBMCs from RA patients and HCs was measured by ELISA. The transcriptomic profile of PNLA-treated, LPS-activated PBMCs was investigated by RNA-sequencing.
RESULTS
PNLA reduced THP-1 cell migration by 55% (P < 0.001). Macropinocytosis and DiI-oxLDL uptake were reduced by 50% (P < 0.001) and 40% (P < 0.01), respectively, in THP-1 macrophages and 40% (P < 0.01) and 25% (P < 0.05), respectively, in HMDMs. PNLA reduced IL-6 and TNF-α release from LPS-stimulated PBMCs from RA patients by 60% (P < 0.001) and from HCs by 50% and 35%, respectively (P < 0.01). PNLA also reduced PGE2 levels in such PBMCs from RA patients and HCs (P < 0.0001). Differentially expressed genes whose expression was upregulated included pyruvate dehydrogenase kinase-4, plasminogen activator inhibitor-1, fructose bisphosphatase1 and N-Myc downstream-regulated gene-2, which have potential roles in regulating immune and metabolic pathways. Pathway analysis predicted upstream activation of the nuclear receptors peroxisome proliferator-activated receptors involved in anti-inflammatory processes, and inhibition of nuclear factor-κB and signal transducer and activator of transcription 1.
CONCLUSIONS
PNLA has immune-metabolic effects on monocytes and PBMCs that are pathogenic in RA and atherosclerosis. Dietary PNLA supplementation may be beneficial in RA.
Topics: Arthritis, Rheumatoid; Case-Control Studies; Cell Movement; Dinoprostone; Gene Expression Profiling; Humans; Interleukin-6; Leukocytes, Mononuclear; Linolenic Acids; Lipoproteins, LDL; Macrophages; THP-1 Cells; Tumor Necrosis Factor-alpha
PubMed: 34080609
DOI: 10.1093/rheumatology/keab467 -
Biochemical Pharmacology Feb 2021Overactive bladder (OAB) syndrome is a prevalent condition of the lower urinary tract that causes symptoms, such as urinary frequency, urinary urgency, urge... (Review)
Review
Overactive bladder (OAB) syndrome is a prevalent condition of the lower urinary tract that causes symptoms, such as urinary frequency, urinary urgency, urge incontinence, and nocturia, and disproportionately affects women and the elderly. Current medications for OAB merely provide symptomatic relief with considerable limitations, as they are no more than moderately effective, not to mention that they may cause substantial adverse effects. Identifying novel molecular targets to facilitate the development of new medical therapies with higher efficacy and safety for OAB is in an urgent unmet need. Although the molecular mechanisms underlying the pathophysiology of OAB largely remain elusive and are likely multifactorial, mounting evidence from preclinical studies over the past decade reveals that the pro-inflammatory pathways engaging cyclooxygenases and their prostanoid products, particularly the prostaglandin E2 (PGE), may play essential roles in the progression of OAB. The goals of this review are to summarize recent progresses in our knowledge on the pathogenic roles of PGE in the OAB and to provide new mechanistic insights into the signaling pathways transduced by its four G-protein-coupled receptors (GPCRs), i.e., EP1-EP4, in the overactive detrusor smooth muscle. We also discuss the feasibility of targeting these GPCRs as an emerging strategy to treat OAB with better therapeutic specificity than the current medications.
Topics: Animals; Dinoprostone; Humans; Prostaglandin-Endoperoxide Synthases; Receptors, Prostaglandin E; Urinary Bladder; Urinary Bladder, Overactive
PubMed: 33309520
DOI: 10.1016/j.bcp.2020.114363