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Biochemical Pharmacology Oct 2022In this review it is attempted to summarize current studies about formation of eicosanoids and other oxylipins in different human macrophages. There are several reports... (Review)
Review
In this review it is attempted to summarize current studies about formation of eicosanoids and other oxylipins in different human macrophages. There are several reports on M1 and M2 cells, also other phenotypes have been described. The eicosanoids formed in the largest amounts are the COX products TxB and PGE. Thus shortlived bioactive TxA is a dominating product both in M1- and in M2-lineages, one exception seems to be M cells. 5-LOX products are produced in both M1 and M2 macrophages, as well as in not fully polarized cells of both lineages. M as well as M2 macrophages produced LTC more readily compared to M1 lineage cells. In M cells LTB is a major eicosanoid, in line with high expression of LTA hydrolase. Recent reports described increased formation of leukotrienes in macrophages subjected to trained immunity with inflammatory transcriptional reprogramming. Also in macrophages derived from monocytes collected from post-COVID-19 patients. 15-LOX-1 is strongly upregulated in CD206 M2 cells (M2a), differentiated in presence of IL-4. These macrophages also express 15-LOX-2. In incubations with pathogenic E. coli as well as other stimuli 15(S)-HETE and 17(S)-HDHA were major oxylipins formed. Also, the SPM precursor 5,15-diHETE and the SPM RvD5 were produced in considerable amounts, while other SPMs were less abundant. In M2 macrophages incubated with E. coli or S. aureus the cytosolic 15-LOX-1 enzyme accumulated to punctuate structures in a Ca dependent manner with a relatively slow time course, leading to formation of mediators from endogenous substrate. Chalcones, flavone-like anti-inflammatory natural products, induced translocation of 15-LOX-1 in M2 cells, with high formation of 15-LOX derived oxylipins.
Topics: Arachidonate 5-Lipoxygenase; Biological Products; COVID-19; Chalcones; Cyclooxygenase 2; Eicosanoids; Escherichia coli; Flavones; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Hydrolases; Hydroxyeicosatetraenoic Acids; Interleukin-4; Leukotrienes; Macrophage Colony-Stimulating Factor; Macrophages; Oxylipins; Prostaglandins E; Scavenger Receptors, Class E; Staphylococcus aureus; Transforming Growth Factor beta
PubMed: 35973581
DOI: 10.1016/j.bcp.2022.115210 -
Nature Communications Mar 2022Chemoimmunotherapy has recently failed to demonstrate significant clinical benefit in advanced bladder cancer patients; and the mechanism(s) underlying such suboptimal...
Chemoimmunotherapy has recently failed to demonstrate significant clinical benefit in advanced bladder cancer patients; and the mechanism(s) underlying such suboptimal response remain elusive. To date, most studies have focused on tumor-intrinsic properties that render them "immune-excluded". Here, we explore an alternative, drug-induced mechanism that impedes therapeutic response via disrupting the onset of immunogenic cell death. Using two immune-excluded syngeneic mouse models of muscle-invasive bladder cancer (MIBC), we show that platinum-based chemotherapy diminishes CD8+ T cell tumor infiltration and constraines their antitumoral activity, despite expression of activation markers IFNγ and granzyme B. Mechanistically, chemotherapy induces the release of prostaglandin E (PGE) from dying cancer cells, which is an inhibitory damage-associated molecular pattern (iDAMP) that hinderes dendritic cell maturation. Upon pharmaceutical blockade of PGE release, CD8+ T cells become tumoricidal and display an intraepithelial-infiltrating (or inflamed) pattern. This "iDAMP blockade" approach synergizes with chemotherapy and sensitizes bladder tumors towards anti-PD1 immune checkpoint inhibitor therapy. These findings provide a compelling rationale to evaluate this drug combination in future clinical trials.
Topics: Animals; CD8-Positive T-Lymphocytes; Cell Death; Humans; Immunotherapy; Mice; Prostaglandins E; Urinary Bladder Neoplasms
PubMed: 35347124
DOI: 10.1038/s41467-022-29026-9 -
Current Opinion in Allergy and Clinical... Dec 2014In the past few years there have been many advances in our understanding of the mechanisms by which intravenous immune globulin (IVIG) modulates immune function in... (Review)
Review
PURPOSE OF REVIEW
In the past few years there have been many advances in our understanding of the mechanisms by which intravenous immune globulin (IVIG) modulates immune function in autoimmune disorders.
RECENT FINDINGS
Previous investigations have focused on the Fc domain of the IgG molecule, and the role of the FcγRIIB receptor and the sialylated Fc domain that have been show to mediate the anti-inflammatory effects in certain murine models of autoantibody-mediated diseases. More recent findings have implicated the F(ab')₂ domain in IVIG-induced immune modulation in T-cell-mediated autoimmune disease models in which upregulation of T-regulatory cells and downregulation of the Th17 pathways are important components of this mechanism. The prostaglandin E pathway may be playing a role in the IVIG-induced changes in the T-regulatory pathway.
SUMMARY
Many of the mechanisms proposed for the immune-modulating effects of IVIG demonstrate the complexity of immune effector functions in disease processes. Although controversy exists on the role of the FcγRIIB receptor and the importance of the sialylated Fc domain in human autoimmune disorders, probably no one single mechanism is responsible for the effects of IVIG in autoimmune and inflammatory diseases. The potential role of the prostaglandin E pathway may offer alternative treatments.
Topics: Animals; Autoimmune Diseases; Disease Models, Animal; Humans; Immunoglobulin Fc Fragments; Immunoglobulins, Intravenous; Immunologic Factors; Immunomodulation; Prostaglandins E; T-Lymphocytes, Regulatory; Th17 Cells
PubMed: 25337683
DOI: 10.1097/ACI.0000000000000116 -
International Journal of Molecular... May 2023Arachidonic acid (AA) is a polyunsaturated fatty acid that is involved in male fertility. Human seminal fluid contains different prostaglandins: PGE (PGE and PGE), PGF,... (Review)
Review
Arachidonic acid (AA) is a polyunsaturated fatty acid that is involved in male fertility. Human seminal fluid contains different prostaglandins: PGE (PGE and PGE), PGF, and their specific 19-hydroxy derivatives, 18,19-dehydro derivatives of PGE and PGE. The objective of this study is to synthesize the available literature of in vivo animal studies and human clinical trials on the association between the AA pathway and male fertility. PGE is significantly decreased in the semen of infertile men, suggesting the potential for exploitation of PGE agonists to improve male fertility. Indeed, ibuprofen can affect male fertility by promoting alterations in sperm function and standard semen parameters. The results showed that targeting the AA pathways could be an attractive strategy for the treatment of male fertility.
Topics: Animals; Male; Humans; Semen; Arachidonic Acid; Prostaglandins E; Prostaglandins; Fertility
PubMed: 37175913
DOI: 10.3390/ijms24098207 -
European Journal of Cardio-thoracic... Sep 2022The aim of this study was to assess outcomes of the deferred Norwood strategy, i.e. planned Norwood following routine bilateral pulmonary artery banding and ductal...
OBJECTIVE
The aim of this study was to assess outcomes of the deferred Norwood strategy, i.e. planned Norwood following routine bilateral pulmonary artery banding and ductal stenting or continuous prostaglandin E1 administration.
METHODS
Forty-five patients with hypoplastic left heart syndrome and its variants treated with the deferred Norwood strategy between 2012 and 2021 were enrolled. Mid-term outcomes were retrospectively reviewed. The median follow-up period after Norwood in hospital survivors was 4.6 years (interquartile range: 1.9, 6.8).
RESULTS
Fourteen patients (31.1%) had no risk factors. The median age and weight at Norwood were 1.8 months (0.9, 3.5) and 3.1 kg (2.7, 3.6). Transplant-free survival at 6 years was 84.5%. Birth weight ≤2.5 kg and systemic atrioventricular valve (SAVV) regurgitation ≥ moderate after birth were not risk factors for mortality; body weight at Norwood ≤2.5 kg, however, was a risk factor [hazard ratio (HR), 11.3; 95% confidence interval (CI), 1.2-11; P = 0.036]. Twenty-two (48.9%) underwent Fontan with no mortalities, and 7 (15.5%) are awaiting Fontan. Freedom from SAVV surgery at 5 years was 53.1%. SAVV regurgitation ≥ moderate after birth was a risk factor for SAVV surgery (HR, 16; 95% CI, 3.6-71; P < 0.001); however, ductal stenting had a protective effect against SAVV surgery (HR, 0.09; 95% CI, 0.01-0.68; P = 0.019). Freedom from both surgical and catheter-based pulmonary artery intervention at 3 years was 27.1.
CONCLUSIONS
Although deferred Norwood provided acceptable intermediate-term survival, the Fontan completion rate was unsatisfactory. SAVV surgery and pulmonary artery intervention were frequently required.
Topics: Alprostadil; Humans; Hypoplastic Left Heart Syndrome; Norwood Procedures; Palliative Care; Pulmonary Artery; Retrospective Studies; Treatment Outcome
PubMed: 35178578
DOI: 10.1093/ejcts/ezac099 -
Cancer Prevention Research... Jun 2022Chronic inflammation is a well-established risk factor for several diseases, including cancer. It influences tumor cell biology and the type and density of immune cells... (Review)
Review
Chronic inflammation is a well-established risk factor for several diseases, including cancer. It influences tumor cell biology and the type and density of immune cells in the tumor microenvironment (TME), promoting cancer development. While proinflammatory cytokines and chemokines modulate cancer development, emerging evidence has shown that prostaglandin E2 (PGE2) is a known mediator connecting chronic inflammation to cancerization. This review highlights recent advances in our understanding of how the elevation of PGE2 production promotes gastrointestinal cancer initiation, progression, invasion, metastasis, and recurrence, including modulation of immune checkpoint signaling and the type and density of immune cells in the tumor/tissue microenvironment.
Topics: Dinoprostone; Gastrointestinal Neoplasms; Humans; Inflammation; Signal Transduction; Tumor Microenvironment
PubMed: 35288737
DOI: 10.1158/1940-6207.CAPR-22-0038 -
Archives of Gynecology and Obstetrics Jan 2019To assess the efficacy and safety of a double-balloon catheter versus dinoprostone insert for labour induction. (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
To assess the efficacy and safety of a double-balloon catheter versus dinoprostone insert for labour induction.
STUDY DESIGN
PubMed, MEDLINE, Embase, ClinicalTrials.gov, and the Cochrane Central Register of Clinical Trials databases were searched from 1985 to April 2018. Randomized controlled trials that compared a double-balloon catheter and dinoprostone insert for cervical ripening were identified. Eligible study populations consisted of women with singleton pregnancies that had any indication for labour induction and were randomly assigned to undergo induction with a double-balloon catheter or dinoprostone insert. The main outcomes were incidence of vaginal delivery within 24 h and caesarean section, and neonatal outcomes.
RESULTS
Five randomized trials (603 women; 305 with a double-balloon catheter and 298 with a dinoprostone insert) were eligible for inclusion. No differences were observed between the two groups in terms of vaginal delivery within 24 h [relative risk (RR) 1.21, 95% confidence interval (CI) 0.93-1.59] and incidence of caesarean section (RR 0.99, 95% CI 0.77-1.27). Compared with the double-balloon catheter, the dinoprostone insert was associated with a reduced need for oxytocin administration in the process of labour induction (RR 1.95, 95% CI 1.45-2.62). However, there was a higher incidence of excessive uterine activity (RR 0.17, 95% CI 0.06-0.54) and neonatal umbilical cord arterial blood pH < 7.1 (RR 0.36, 95% CI 0.15-0.84) in the dinoprostone insert group.
CONCLUSION
This review showed that the efficacy of labour induction using both the double-balloon catheter and dinoprostone insert was similar. However, the double-balloon catheter seemed to be a safer method.
Topics: Adult; Catheters; Cervical Ripening; Cesarean Section; Delivery, Obstetric; Dinoprostone; Female; Humans; Labor, Induced; Oxytocics; Pregnancy; Randomized Controlled Trials as Topic; Treatment Outcome; Uterus
PubMed: 30315411
DOI: 10.1007/s00404-018-4929-8 -
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 -
The Cochrane Database of Systematic... Feb 2018Prostaglandin E1 (PGE1) is used to keep the ductus arteriosus patent and can be life-saving in neonates with ductal-dependent cardiac lesions. PGE1 is used to promote... (Review)
Review
BACKGROUND
Prostaglandin E1 (PGE1) is used to keep the ductus arteriosus patent and can be life-saving in neonates with ductal-dependent cardiac lesions. PGE1 is used to promote mixing of pulmonary and systemic blood flow or improve pulmonary or systemic circulations, prior to balloon atrial septostomy or surgery. PGE1 therapy may cause several short-term and long-term adverse effects. The efficacy and safety of PGE1 in neonates with ductal-dependent cardiac lesions has not been systematically reviewed.
OBJECTIVES
To determine the efficacy and safety of both short-term (< 120 hours) and long-term (≥120 hours) PGE1 therapy in maintaining patency of the ductus arteriosus and decreasing mortality in ductal-dependent cardiac lesions.
SEARCH METHODS
We searched the literature in October 2017, using the search strategy recommended by Cochrane Neonatal. We searched electronic databases (CENTRAL (in the Cochrane Library), MEDLINE, CINAHL, Embase); abstracts of the Pediatric Academic Societies; websites for registered trials at www.clinicaltrials.gov and www.controlled-trials.com; and in the reference list of identified articles.
SELECTION CRITERIA
Randomized or quasi-randomized trials using PGE1 at any dose or duration to maintain ductal patency in term or late preterm (≥ 34 weeks' gestation) infants with ductal-dependent cardiac lesions and which reported effectiveness and safety in the short term or long term.
DATA COLLECTION AND ANALYSIS
We followed the standard Cochrane methods for conducting a systematic review. Two review authors (SA and MP) independently assessed the titles and abstracts of studies identified by the search strategy to determine eligibility for inclusion. We obtained the full-text version if eligibility could not be done reliably by title and abstract. We resolved any differences by discussion. We designed electronic forms for trial inclusion/exclusion, data extraction, and for requesting additional published information from authors of the original reports.
MAIN RESULTS
Our search did not identify any completed or ongoing trials that met our inclusion criteria.
AUTHORS' CONCLUSIONS
There is insufficient evidence from randomized controlled trials to determine the safety and efficacy of PGE1 in neonates with ductal-dependent cardiac lesions. Evidence from observational trials have informed clinical practice on the use of PGE, which is now considered the standard of care for ductal-dependent cardiac lesions. It is unlikely that randomized controlled studies will be performed for this indication but comparative efficacy of newer formulations of PGE1, different doses of PGE1 and studies comparing PGE with PDA stents or other measures to keep the ductus open may be ethical and necessary.
Topics: Alprostadil; Ductus Arteriosus, Patent; Humans; Infant, Newborn; Vasodilator Agents
PubMed: 29486048
DOI: 10.1002/14651858.CD011417.pub2 -
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