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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 -
Journal of Cellular Physiology Dec 2023Understanding the factors that influence the biological response to inflammation is crucial, due to its involvement in physiological and pathological processes,...
Understanding the factors that influence the biological response to inflammation is crucial, due to its involvement in physiological and pathological processes, including tissue repair/healing, cancer, infections, and autoimmune diseases. We have previously demonstrated that in vivo stretching can reduce inflammation and increase local pro-resolving lipid mediators in rats, suggesting a direct mechanical effect on inflammation resolution. Here we aimed to explore further the effects of stretching at the cellular/molecular level in a mouse subcutaneous carrageenan-inflammation model. Stretching for 10 min twice a day reduced inflammation, increased the production of pro-resolving mediator pathway intermediate 17-HDHA at 48 h postcarrageenan injection, and decreased both pro-resolving and pro-inflammatory mediators (e.g., PGE and PGD ) at 96 h. Single-cell RNA sequencing analysis of inflammatory lesions at 96 h showed that stretching increased the expression of both pro-inflammatory (Nos2) and pro-resolution (Arg1) genes in M1 and M2 macrophages at 96 h. An intercellular communication analysis predicted specific ligand-receptor interactions orchestrated by neutrophils and M2a macrophages, suggesting a continuous neutrophil presence recruiting immune cells such as activated macrophages to contain the antigen while promoting resolution and preserving tissue homeostasis.
Topics: Animals; Mice; Carrageenan; Dinoprostone; Inflammation; Inflammation Mediators; Macrophages; Neutrophils; Single-Cell Analysis; Mice, Inbred C57BL; Transcriptome
PubMed: 37909412
DOI: 10.1002/jcp.31133 -
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 -
Journal of Ethnopharmacology Nov 2023Based on the notion of traditional Chinese medicine, the theory of invigorating the circulation of blood is a prominent treatment for cancer in clinic. Therefore, Salvia...
Salvia mitiorrhiza Bunge aqueous extract attenuates infiltration of tumor-associated macrophages and potentiates anti-PD-L1 immunotherapy in colorectal cancer through modulating Cox2/PGE2 cascade.
ETHNOPHARMACOLOGICAL RELEVANCE
Based on the notion of traditional Chinese medicine, the theory of invigorating the circulation of blood is a prominent treatment for cancer in clinic. Therefore, Salvia miltiorrhiza Bunge, as a representative of Chinese medicine of invigorating the circulation of blood, has been proved to be an effective medicinal herb for treating cancer.
AIM OF THE STUDY
To clarify the anti-cancer effect of Salvia miltiorrhiza Bunge aqueous extract (SMAE) on colorectal cancer (CRC) and investigate whether the therapeutic effect of SMAE was mediated by attenuating the infiltration of tumor-associated macrophages (TAMs) into the tumor microenvironment (TME).
MATERIALS AND METHODS
High-performance liquid chromatography (HPLC) was used for determined the main compounds of SMAE. MC38 cells were subcutaneously injected into the mice to establish the mouse model of CRC. Tumor growth curve was detected by tumor volume measurement. The model group received distilled water irrigation once a day. SMAE-treated group received 5 g/kg or 10 g/kg SMAE once a day. Anti-PD-L1 treated group received 5 mg/kg anti-PD-L1 once every three days. Protein expression of Cox2 and PD-L1 was determined by Western blot assay. The secretion levels of PGE2, IL-1β, IL-6, MCP-1, and GM-CSF were evaluated through ELISA. The mRNA expression of CSF1, CCL2, CXCL1, CXCL2, and CXCL3 was measured by using RT-qPCR. Staining of Ki67, TUNEL and Caspase3 was used to investigate cell proliferation and apoptosis. Immunohistochemical staining was used to determine CD8 T cell distribution. H&E staining was used to confirm histopathological changes. The expressions of F4/80 and CD68 were measured by flow cytometry to identify macrophages in tumors and lymph nodes. The number of CD8 T cells and the expression of PD-1, IFN-γ, and Granzyme B (GZMB) were determined by flow cytometry.
RESULTS
SMAE significantly retarded the growth of MC38 mouse colorectal cancer. SMAE strikingly inhibited the expression of Cox2 and impaired the secretion of PGE2 in tumors, contributing to the attenuated intra-tumoral infiltration of TAMs via Cox2/PGE2 cascade. Meanwhile, SMAE augmented anti-tumor immunity by the elevated proportion of IFN-γ CD8 T cells and GZMB CD8 T cells, which decreased the tumor load. Furthermore, the combination of SMAE and anti-PD-L1 showed a higher therapeutic efficacy than either monotherapy in controlling tumor growth in MC38 xenograft model.
CONCLUSIONS
SMAE attenuated the infiltration of TAMs into tumors and synergized with anti-PD-L1 to treat CRC via modulating Cox2/PGE2 cascade.
Topics: Mice; Humans; Animals; Tumor-Associated Macrophages; Dinoprostone; Salvia; CD8-Positive T-Lymphocytes; Salvia miltiorrhiza; Disease Models, Animal; Colorectal Neoplasms; Immunotherapy; Water; Tumor Microenvironment; Cell Line, Tumor
PubMed: 37286115
DOI: 10.1016/j.jep.2023.116735 -
International Journal of Molecular... Nov 2023Gintonin, newly extracted from ginseng, is a glycoprotein that acts as an exogenous lysophosphatidic acid (LPA) receptor ligand. This study aimed to demonstrate the in...
Gintonin, newly extracted from ginseng, is a glycoprotein that acts as an exogenous lysophosphatidic acid (LPA) receptor ligand. This study aimed to demonstrate the in vivo preventive effects of gintonin on gastric damage. ICR mice were randomly assigned to five groups: a normal group (received saline, 0.1 mL/10 g, p.o.); a control group (administered 0.3 M HCl/ethanol, 0.1 mL/10 g, p.o.) or indomethacin (30 mg/kg, p.o.); gintonin at two different doses (50 mg/kg or 100 mg/kg, p.o.) with either 0.3 M HCl/ethanol or indomethacin; and a positive control (Ranitidine, 40 mg/kg, p.o.). After gastric ulcer induction, the gastric tissue was examined to calculate the ulcer index. The expression of gastric damage markers, such as tumor necrosis factor (TNF)-α, cyclooxygenase 2 (COX-2), and LPA2 and LPA5 receptors, were measured by Western blotting. Interleukin-6 (IL-6) and prostaglandin E2 (PGE2) levels were measured by enzyme-linked immunosorbent assay. The platelet endothelial cell adhesion molecule (PECAM-1), Evans blue, and occludin levels in gastric tissues were measured using immunofluorescence analysis. Both HCl/ethanol- and indomethacin-induced gastric ulcers showed increased TNF-α, IL-6, Evans blue permeation, and PECAM-1, and decreased COX-2, PGE2, occludin, and LPA5 receptor expression levels. However, oral administration of gintonin alleviated the gastric ulcer index induced by HCl/ethanol and indomethacin in a dose-dependent manner. Gintonin suppressed TNF-α and IL-6 expression, but increased COX-2 expression and PGE2 levels in mouse gastric tissues. Gintonin intake also increased LPA5 receptor expression in mouse gastric tissues. These results indicate that gintonin can play a role in gastric protection against gastric damage induced by HCl/ethanol or indomethacin.
Topics: Mice; Animals; Indomethacin; Stomach Ulcer; Platelet Endothelial Cell Adhesion Molecule-1; Cyclooxygenase 2; Tumor Necrosis Factor-alpha; Ethanol; Interleukin-6; Dinoprostone; Evans Blue; Occludin; Mice, Inbred ICR; Gastric Mucosa
PubMed: 38069044
DOI: 10.3390/ijms242316721 -
British Journal of Pharmacology Sep 2023High salt (HS) intake has been associated with hypertension and cognitive impairment. It is well known that the angiotensin II (Ang II)-AT receptor and prostaglandin E2...
BACKGROUND AND PURPOSE
High salt (HS) intake has been associated with hypertension and cognitive impairment. It is well known that the angiotensin II (Ang II)-AT receptor and prostaglandin E2 (PGE2)-EP receptor systems are involved in hypertension and neurotoxicity. However, the involvement of these systems in HS-mediated hypertension and emotional and cognitive impairments remains unclear.
EXPERIMENTAL APPROACH
Mice were loaded with HS solution (2% NaCl drinking water) for 12 weeks, and blood pressure was monitored. Subsequently, effects of HS intake on emotional and cognitive function and tau phosphorylation in the prefrontal cortex (PFC) and hippocampus (HIP) were investigated. The involvement of Ang II-AT and PGE2-EP systems in HS-induced hypertension and neuronal and behavioural impairments was examined by treatment with losartan, an AT receptor blocker (ARB), or EP gene knockout.
KEY RESULTS
We demonstrate that hypertension and impaired social behaviour and object recognition memory following HS intake may be associated with tau hyperphosphorylation, decreased phosphorylation of Ca /calmodulin-dependent protein kinase II (CaMKII), and postsynaptic density protein 95 (PSD95) expression in the PFC and HIP of mice. These changes were blocked by pharmacological treatment with losartan or EP receptor gene knockout.
CONCLUSIONS AND IMPLICATIONS
Our findings suggest that the interaction of Ang II-AT receptor and PGE2-EP receptor systems could be novel therapeutic targets for hypertension-induced cognitive impairment.
Topics: Mice; Animals; Losartan; Sodium Chloride; Dinoprostone; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Hypertension; Sodium Chloride, Dietary; Cognitive Dysfunction; Receptor, Angiotensin, Type 1
PubMed: 37076133
DOI: 10.1111/bph.16093 -
Molecular Reproduction and Development Jul 2023Pregnancy establishment in mammals, including pigs, requires coordinated communication between developing conceptuses (embryos with associated membranes) and the... (Review)
Review
Pregnancy establishment in mammals, including pigs, requires coordinated communication between developing conceptuses (embryos with associated membranes) and the maternal organism. Porcine conceptuses signalize their presence by secreting multiple factors, of which estradiol-17β (E2) is considered the major embryonic signal initiating the maternal recognition of pregnancy. During this time, a limited supply of prostaglandin (PGF2α) to the corpora lutea and an increased secretion of luteoprotective factors (e.g., E2 and prostaglandin E2 [PGE2]) lead to the corpus luteum's maintained function of secreting progesterone, which in turn primes the uterus for implantation. Further, embryo implantation is related to establishing an appropriate proinflammatory environment coordinated by the secretion of proinflammatory mediators including cytokines, growth factors, and lipid mediators of both endometrial and conceptus origin. The novel, dual role of PGF2α has been underlined. Recent studies involving high-throughput technologies and sophisticated experimental models identified a number of novel factors and revealed complex relationships between these factors and those already established. Hence, it seems that early pregnancy should be regarded as a sequence of processes orchestrated by pleiotropic factors that are involved in redundancy and compensatory mechanisms that preserve the essential functions critical for implantation and placenta formation. Therefore, establishing the hierarchy between all molecules present at the embryo-maternal interface is now even more challenging.
Topics: Pregnancy; Female; Animals; Swine; Dinoprost; Pregnancy, Animal; Embryo Implantation; Prostaglandins; Dinoprostone; Mammals
PubMed: 35385215
DOI: 10.1002/mrd.23567 -
Mediators of Inflammation 2023Inflammation is a major cause of hepatic tissue damage and accelerates the progression of nonalcoholic fatty liver disease (NAFLD). Amphiregulin (AREG), an epidermal...
BACKGROUND
Inflammation is a major cause of hepatic tissue damage and accelerates the progression of nonalcoholic fatty liver disease (NAFLD). Amphiregulin (AREG), an epidermal growth factor receptor ligand, is associated with human liver cirrhosis and hepatocellular carcinoma. We aimed to investigate the effects of AREG on hepatic inflammation during NAFLD progression, and .
METHODS
AREG gene expression was measured in the liver of mice fed a methionine choline-deficient (MCD) diet for 2 weeks. We evaluated inflammatory mediators and signaling pathways in HepG2 cells after stimulation with AREG. Nitric oxide (NO), prostaglandin E2 (PGE2), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) were analyzed using an enzyme-linked immunosorbent assay and western blotting. Nuclear transcription factor kappa-B (NF-B) and mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase, were analyzed using western blotting.
RESULTS
Proinflammatory cytokines (interleukin (IL)-6, IL-1, and IL-8) and immune cell recruitment (as indicated by L3T4, F4/80, and ly6G mRNA expression) increased, and expression of AREG increased in the liver of mice fed the MCD diet. AREG significantly increased the expression of IL-6 and IL-1 and the production of NO, PGE2, and IL-8 in HepG2 cells. It also activated the protein expression of iNOS and COX-2. AREG-activated NF-B and MAPKs signaling, and together with NF-B and MAPKs inhibitors, AREG significantly reduced the protein expression of iNOS and COX-2.
CONCLUSION
AREG plays a role in hepatic inflammation by increasing iNOS and COX-2 expression via NF-B and MAPKs signaling.
Topics: Mice; Humans; Animals; NF-kappa B; Cyclooxygenase 2; Amphiregulin; Nitric Oxide Synthase Type II; Non-alcoholic Fatty Liver Disease; Dinoprostone; Interleukin-8; Inflammation; Extracellular Signal-Regulated MAP Kinases; Interleukin-6; Lipopolysaccharides; Nitric Oxide
PubMed: 37868614
DOI: 10.1155/2023/2364121 -
Prostaglandins, Leukotrienes, and... Oct 2023The role of the lipoxygenase (LOX) and cyclooxygenase (COX) enzymes in maintaining cellular homeostasis and regulating immune responses promoted us in this study to...
BACKGROUND
The role of the lipoxygenase (LOX) and cyclooxygenase (COX) enzymes in maintaining cellular homeostasis and regulating immune responses promoted us in this study to analyze the pattern of changes in 15-lipoxygenase and cyclooxygenase isoforms and their related cytokines in SARS-CoV-2 infection.
METHODS
15-LOX-1, 15-LOX-2, COX-1 and COX-2 gene expression levels were determined using qRT-PCR in nasopharynx specimens from patients with severe [N = 40] and non-severe [N = 40] confirmed SARS-CoV-2 infections and healthy controls. Circulating levels of lL-6, lL-10, PGE2, and IFN-γ were measured in patients and healthy controls using ELISA assay. The associations between the measured variables and the patient's clinic-pathological characteristics were assessed for all groups.
RESULTS
The expression level of 15-LOX-1 was elevated significantly in male patients with severe infection; although female patients showed a different expression profile. 15-LOX-2 expression level was considerably increased in male patients with severe infection; while changes in its expression remained inconclusive in female patients. The relationship between 15-LOX expression and the male gender was prominent. Both COX isoforms expression showed elevation in male and female patients that were correlated with disease severity. The simultaneous increase in lL-6, PGE2 and IFN-γ levels also decrease in lL-10 in patients with severe infection indicating the possible regulatory network related to the COX and 15-LOX enzymes in the output of the SARS-CoV-2 infection.
CONCLUSION
The results of this study determined the pattern of possible changes in key enzymes of prostaglandin and eicosanoids synthesis pathway and their mediators, which can be helpful in mapping the SARS-CoV-2 pathogenicity and pharmaceutical approaches.
Topics: Humans; Male; Female; Cyclooxygenase 2; Arachidonate 15-Lipoxygenase; Dinoprostone; COVID-19; SARS-CoV-2; Cyclooxygenase 1; Protein Isoforms; Scavenger Receptors, Class E; Arachidonate 5-Lipoxygenase
PubMed: 37716021
DOI: 10.1016/j.plefa.2023.102587