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Cells Mar 2024NAD boosting via nicotinamide riboside (NR) confers anti-inflammatory effects. However, its underlying mechanisms and therapeutic potential remain incompletely defined....
NAD boosting via nicotinamide riboside (NR) confers anti-inflammatory effects. However, its underlying mechanisms and therapeutic potential remain incompletely defined. Here, we showed that NR increased the expression of CC-chemokine receptor 7 (CCR7) in human M1 macrophages by flow cytometric analysis of cell surface receptors. Consequently, chemokine ligand 19 (CCL19, ligand for CCR7)-induced macrophage migration was enhanced following NR administration. Metabolomics analysis revealed that prostaglandin E2 (PGE2) was increased by NR in human monocytes and in human serum following in vivo NR supplementation. Furthermore, NR-mediated upregulation of macrophage migration through CCL19/CCR7 was dependent on PGE2 synthesis. We also demonstrated that NR upregulated PGE2 synthesis through SIRT3-dependent post-transcriptional regulation of cyclooxygenase 2 (COX-2). The NR/SIRT3/migration axis was further validated using the scratch-test model where NR and SIRT3 promoted more robust migration across a uniformly disrupted macrophage monolayer. Thus, NR-mediated metabolic regulation of macrophage migration and wound healing may have therapeutic potential for the topical management of chronic wound healing.
Topics: Humans; Dinoprostone; Sirtuin 3; Ligands; Receptors, CCR7; Macrophages; Niacinamide; Pyridinium Compounds
PubMed: 38474420
DOI: 10.3390/cells13050455 -
Free Radical Biology & Medicine Nov 2023Several studies have indicated that reactive oxygen species (ROS) can lead to detrusor overactivity (DO), but the underlying mechanisms are not known. Hydrogen dioxide...
HO enhances the spontaneous phasic contractions of isolated human-bladder strips via activation of TRPA1 channels on sensory nerves and the release of substance P and PGE2.
Several studies have indicated that reactive oxygen species (ROS) can lead to detrusor overactivity (DO), but the underlying mechanisms are not known. Hydrogen dioxide (HO) is used commonly to investigate the effects of ROS. In present study, we investigated the effects of HO on phasic spontaneous bladder contractions (SBCs) of isolated human-bladder strips (iHBSs) and the underlying mechanisms. Samples of bladder tissue were obtained from 26 patients undergoing cystectomy owing to bladder cancer. SBCs of iHBSs were recorded in organ-bath experiments. HO (1μM-10mM) concentration-dependently increased the SBCs of iHBSs. These enhancing effects could be mimicked by an agonist of transient receptor potential (TRP)A1 channels (allyl isothiocyanate) and blocked with an antagonist of TRPA1 channels (HC030031; 10 μM). HO induced enhancing effects also could be attenuated by desensitizing sensory afferents with capsaicin (10 μM), blocking nerve firing with TTX (1 μM), blocking neurokinin effects with NK2 receptor antagonist (SR48968, 10 μM), and blocking PGE2 synthesis with indomethacin (10 μM), respectively. Our study: (i) suggests activation of TRPA1 channels on bladder sensory afferents, and then release of substance P or PGE2 from sensory nerve terminals, contribute to the HO-induced enhancing effects on SBCs of iHBSs; (ii) provides insights for the mechanisms underlying ROS leading to DO; (iii) indicates that targeting TRPA1 channels might be the promising strategy against overactive bladder in conditions associated with excessive production of ROS.
Topics: Humans; Urinary Bladder; Substance P; Hydrogen Peroxide; Dinoprostone; Reactive Oxygen Species; Transient Receptor Potential Channels; TRPA1 Cation Channel
PubMed: 37802373
DOI: 10.1016/j.freeradbiomed.2023.10.001 -
Nature Structural & Molecular Biology Apr 2024Multidrug resistance protein 4 (MRP4) is a broadly expressed ATP-binding cassette transporter that is unique among the MRP subfamily for transporting prostanoids, a...
Multidrug resistance protein 4 (MRP4) is a broadly expressed ATP-binding cassette transporter that is unique among the MRP subfamily for transporting prostanoids, a group of signaling molecules derived from unsaturated fatty acids. To better understand the basis of the substrate selectivity of MRP4, we used cryogenic-electron microscopy to determine six structures of nanodisc-reconstituted MRP4 at various stages throughout its transport cycle. Substrate-bound structures of MRP4 in complex with PGE, PGE and the sulfonated-sterol DHEA-S reveal a common binding site that accommodates a diverse set of organic anions and suggest an allosteric mechanism for substrate-induced enhancement of MRP4 ATPase activity. Our structure of a catalytically compromised MRP4 mutant bound to ATP-Mg is outward-occluded, a conformation previously unobserved in the MRP subfamily and consistent with an alternating-access transport mechanism. Our study provides insights into the endogenous function of this versatile efflux transporter and establishes a basis for MRP4-targeted drug design.
Topics: Prostaglandins; Multidrug Resistance-Associated Proteins; Biological Transport; Dinoprostone; Membrane Transport Proteins
PubMed: 38216659
DOI: 10.1038/s41594-023-01176-4 -
Immunity, Inflammation and Disease Jan 2024For the unclear pathogenesis of Sjogren's syndrome (SS), further exploration is necessary. Mesenchymal stem cells (MSCs) and derived exosomes (MSCs-exo) have exhibited...
Human umbilical cord mesenchymal stem cells improve disease characterization of Sjogren's syndrome in NOD mice through regulation of gut microbiota and Treg/Th17 cellular immunity.
BACKGROUND
For the unclear pathogenesis of Sjogren's syndrome (SS), further exploration is necessary. Mesenchymal stem cells (MSCs) and derived exosomes (MSCs-exo) have exhibited promising results in treating SS.
OBJECT
This study aimed to investigate the effect and mechanism of human umbilical cord MSCs (UC-MSCs) on SS.
METHODS
Nonobese Diabetic (NOD) mouse splenic T cells were co-cultured with UC-MSCs and UC-MSCs-exo, and interferon-gamma (IFN-γ), interleukin (IL)-6, IL-10, prostaglandin E2 (PGE2), and transforming growth factor-β1 (TGF-β1) levels in the supernatant were assessed by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Co-cultured T cells were injected into NOD mice via the tail vein. The inflammatory cell infiltration in the intestine and the submandibular gland was characterized by hematoxylin-eosin staining. Treg/Th17 homeostasis within the spleen was determined by flow cytometry. Gut microbiota was detected by 16S rRNA sequencing, and the relationship between differential microbiota and Treg/Th17 cytokines was analyzed by the Pearson correlation coefficient.
RESULTS
UC-MSCs, UC-MSCs-exo, and NOD mouse splenic T cells were successfully cultured and identified. After T cells were co-cultured with UC-MSCs and UC-MSCs-exo, both IFN-γ and IL-6 were decreased while IL-10, PGE2, and TGF-β1 were increased in transcriptional and translational levels. UC-MSCs and UC-MSCs-exo partially restored salivary secretion function, reduced Ro/SSA antibody and α-Fodrin immunoglobulin A levels, reduced inflammatory cell infiltration in the intestine and submandibular gland, raised proportion of Treg cells, decreased IFN-γ, IL-6, IL-2, IL-17, lipopolysaccharide, and tumor necrosis factor-alpha levels, and raised IL-10, Foxp3, and TGF-β1 levels by affecting co-cultured T cells. The intervention of UC-MSCs and UC-MSCs-exo improved intestinal homeostasis in NOD mice by increasing microbiota diversity and richness. Additionally, differential microbiota was significantly associated with Treg/Th17 cytokine levels.
CONCLUSION
Human UC-MSCs and UC-MSCs-exo improved disease characterization of SS in NOD mice through regulation of gut microbiota and Treg/Th17 cellular immunity.
Topics: Animals; Mice; Humans; Gastrointestinal Microbiome; T-Lymphocytes, Regulatory; Mice, Inbred NOD; Interleukin-10; Interleukin-6; Dinoprostone; RNA, Ribosomal, 16S; Sjogren's Syndrome; Transforming Growth Factor beta1; Cytokines; Mesenchymal Stem Cells; Immunity, Cellular; Umbilical Cord
PubMed: 38270310
DOI: 10.1002/iid3.1139 -
Journal of the American Heart... Feb 2024Inhibition of prostaglandin synthesis by nonsteroidal anti-inflammatory drugs is associated with cardiovascular mortality and kidney disease. This study hypothesizes...
BACKGROUND
Inhibition of prostaglandin synthesis by nonsteroidal anti-inflammatory drugs is associated with cardiovascular mortality and kidney disease. This study hypothesizes that urinary prostaglandin E2 (PGE2) and PGE2 metabolite (PGEM) excretions are markers of cardiovascular and kidney health, because they reflect both systemic and kidney-derived PGE2 production.
METHODS AND RESULTS
PGE2 and PGEM were measured in spot urine samples from 2291 participants (≥55 years old) of the population-based Rotterdam Study. Urinary PGE2 and PGEM excretions were analyzed using linear regression analyses to identify cross-sectional associations with cardiovascular risk factors and baseline estimated glomerular filtration rate (eGFR). Longitudinal associations with cardiovascular mortality and kidney outcomes (eGFR <60 or <45 mL/min per 1.73 m and the composite outcome 40% eGFR loss or kidney failure) were assessed with Cox regression. Urinary PGE2 and PGEM excretions were higher with increasing age, lower eGFR, smoking, diabetes, and albuminuria. A 2-fold higher urinary PGE2 and PGEM excretion was associated with a higher risk of cardiovascular mortality (28 825 patient-years; 160 events; PGE2 hazard ratio [HR], 1.27, [95% CI, 1.06-1.54]; PGEM HR, 1.36 [95% CI, 1.10-1.67]). Higher PGE2 excretions were also associated with a higher risk of incident eGFR <60 mL/min per 1.73 m (31 530 person-years; 691 events; HR, 1.13 [95% CI, 1.02-1.25]) with similar HRs for the other kidney outcomes.
CONCLUSIONS
Urinary PGE2 and PGEM excretions are novel markers for the presence and progression of cardiovascular and kidney disease. Future studies should address whether these associations are causal and can be targeted to improve cardiovascular and kidney outcomes.
Topics: Humans; Middle Aged; Dinoprostone; Cardiovascular Diseases; Cross-Sectional Studies; Kidney Diseases; Kidney; Glomerular Filtration Rate; Albuminuria; Risk Factors
PubMed: 38362883
DOI: 10.1161/JAHA.123.032835 -
Acta Obstetricia Et Gynecologica... Mar 2024Obesity is an increasing public health concern worldwide and can lead to more complications in pregnancy and childbirth. Women with obesity more often require induction...
INTRODUCTION
Obesity is an increasing public health concern worldwide and can lead to more complications in pregnancy and childbirth. Women with obesity more often require induction of labor for various indications. The aim of this study is to assess which method of induction of labor is safest and most effective in women with obesity.
MATERIAL AND METHODS
This is a secondary analysis of two randomized controlled trials about induction of labor. Women with a term singleton pregnancy in cephalic presentation, an unfavorable cervix, intact membranes and without a previous cesarean section were randomly allocated to cervical priming with a Foley catheter or vaginal prostaglandin-E2-gel (PROBAAT-I) or a Foley catheter or oral misoprostol (PROBAAT-II). The inclusion and exclusion criteria for the studies were identical. Induction methods were compared in women with obesity (body mass index ≥30.0). Main outcomes were cesarean section and postpartum hemorrhage (blood loss >1000 mL).
RESULTS
A total of 2664 women, were included in the trials, 517 of whom were obese: 254 women with obesity received a Foley catheter, 176 oral misoprostol and 87 prostaglandin E2 (PGE2). A cesarean section was performed in 29.1% of women allocated to Foley vs 22.2% in the misoprostol and 23.0% in the PGE2 groups. Comparisons between groups revealed no statistically significant differences: the relative risk [RR] was 1.31 (95% confidence interval [CI] 0.94-1.84) in the Foley vs misoprostol group and 1.27 (95% CI 0.83-1.95) in the Foley vs PGE2 group. The rates of postpartum hemorrhage were comparable (10.6%, 11.4% and 6.9%, respectively; P = 0.512). In women with obesity, more often a switch to another method occurred in the Foley group, (20.1% vs 6.3% in misoprostol vs 1.1% in the PGE2 group; P < 0.001). The risk of a failed Foley placement was higher in women with obesity than in women without obesity (8.3% vs 3.2%; adjusted odds ratio 3.12, 95% CI 1.65-5.90).
CONCLUSIONS
In women with obesity we found a nonsignificant trend towards an increased rate of cesarean sections in the group induced with a Foley catheter compared to oral misoprostol; however, the study lacked power for this subgroup analysis. The finding of a higher risk of failed placement of a Foley catheter in women with obesity can be used in shared decision making.
Topics: Pregnancy; Female; Humans; Misoprostol; Dinoprostone; Oxytocics; Cesarean Section; Postpartum Hemorrhage; Labor, Induced; Randomized Controlled Trials as Topic; Cervical Ripening
PubMed: 38183287
DOI: 10.1111/aogs.14737 -
Nature Communications May 2024Resolving inflammation is thought to return the affected tissue back to homoeostasis but recent evidence supports a non-linear model of resolution involving a phase of...
Resolving inflammation is thought to return the affected tissue back to homoeostasis but recent evidence supports a non-linear model of resolution involving a phase of prolonged immune activity. Here we show that within days following resolution of Streptococcus pneumoniae-triggered lung inflammation, there is an influx of antigen specific lymphocytes with a memory and tissue-resident phenotype as well as macrophages bearing alveolar or interstitial phenotype. The transcriptome of these macrophages shows enrichment of genes associated with prostaglandin biosynthesis and genes that drive T cell chemotaxis and differentiation. Therapeutic depletion of post-resolution macrophages, inhibition of prostaglandin E2 (PGE) synthesis or treatment with an EP4 antagonist, MF498, reduce numbers of lung CD4/CD44/CD62L and CD4/CD44/CD62L/CD27 T cells as well as their expression of the α-integrin, CD103. The T cells fail to reappear and reactivate upon secondary challenge for up to six weeks following primary infection. Concomitantly, EP4 antagonism through MF498 causes accumulation of lung macrophages and marked tissue fibrosis. Our study thus shows that PGE signalling, predominantly via EP4, plays an important role during the second wave of immune activity following resolution of inflammation. This secondary immune activation drives local tissue-resident T cell development while limiting tissue injury.
Topics: Animals; Pneumonia, Pneumococcal; Disease Models, Animal; Mice; Dinoprostone; Mice, Inbred C57BL; Streptococcus pneumoniae; Receptors, Prostaglandin E, EP4 Subtype; Macrophages; Lung; Macrophages, Alveolar; Integrin alpha Chains; Female; Antigens, CD; T-Lymphocytes
PubMed: 38773113
DOI: 10.1038/s41467-024-48138-y -
Cureus Jul 2023Aims and Objectives To compare the safety and efficacy of dinoprostone pessary with Foley plus vaginal misoprostol for cervical ripening. Materials and Methods We...
Aims and Objectives To compare the safety and efficacy of dinoprostone pessary with Foley plus vaginal misoprostol for cervical ripening. Materials and Methods We randomized 115 women to the pessary or Foley plus misoprostol group. Pessary was inserted for 24 hours, and in the Foley plus misoprostol group, intravaginal misoprostol 25 mcg was administered along with trans-cervical Foley insertion and repeated every six hours to a maximum dose of 100 mcg. Singleton pregnancies requiring labor induction at more than 34 weeks with a Bishop score of <6 were included. Study outcomes included induction-delivery interval (IDI), mode of delivery, change in the Bishop score, need for oxytocin augmentation, and patient discomfort as assessed by visual analog score. Results The IDI was similar between the groups (pessary vs Foley plus misoprostol; 21.27 vs 21.10 hours, p = 0.9). The mean change in the Bishop score and need for augmentation with oxytocin was significantly more in the Foley plus misoprostol group compared to pessary (2.72 vs 1.94, p = 0.001; 89.7% vs 57.9%, p = 0.0001). Pessary was better tolerated compared to Foley plus misoprostol (VAS 7.8 vs 6.68, p = 0.0001). Mode of delivery and maternal and neonatal outcomes showed no difference. Conclusion There was no significant difference between pessary and Foley plus misoprostol in the IDI and mode of delivery. Pessary was better tolerated, and augmentation with oxytocin was required less often. Foley plus misoprostol caused a faster change in the Bishop score, but oxytocin augmentation was used more often. Maternal and neonatal outcomes were similar.
PubMed: 37605669
DOI: 10.7759/cureus.42261 -
PloS One 2024[This corrects the article DOI: 10.1371/journal.pone.0227245.].
[This corrects the article DOI: 10.1371/journal.pone.0227245.].
PubMed: 38768081
DOI: 10.1371/journal.pone.0304233 -
Theriogenology Nov 2023Recent studies have demonstrated that visfatin participates in the regulation of female reproduction. Due to the lack of data concerning the level of visfatin in the...
Expression of visfatin in the ovarian follicles of prepubertal and mature gilts and in vitro effect of gonadotropins, insulin, steroids, and prostaglandins on visfatin levels.
Recent studies have demonstrated that visfatin participates in the regulation of female reproduction. Due to the lack of data concerning the level of visfatin in the ovarian follicles of pigs, one of the most economically important livestock species, the aim of this study was to investigate the expression and localisation of visfatin and the follicular fluid concentration in the ovarian follicles of prepubertal and mature gilts. We also aimed to examine the in vitro effects of gonadotropins (LH, FSH), insulin, progesterone (P), oestradiol (E), prostaglandin E (PGE) and F (PGF) on visfatin levels. In the present study, we have demonstrated that visfatin expression is dependent on the maturity of the animals and the stage of ovarian follicle development. Visfatin signal was detected in individual follicular compartments from primordial to antral follicles and even in atretic follicles. We have shown that the expression of visfatin in granulosa cells was higher than in theca cells. The level of visfatin is upregulated by LH, FSH, E and P and downregulated by insulin, while prostaglandins have modulatory effects, dependent on the dose and type of ovarian follicular cells. To summarise, our research has shown that visfatin is widely expressed in the ovarian follicles of prepubertal and mature pigs, and its expression is regulated by gonadotropins, insulin, steroids, and prostaglandins, suggesting that visfatin appears to be an important intra-ovarian factor that could regulate porcine ovarian follicular function.
Topics: Female; Swine; Animals; Prostaglandins; Insulin; Nicotinamide Phosphoribosyltransferase; Ovarian Follicle; Granulosa Cells; Steroids; Gonadotropins; Progesterone; Estradiol; Dinoprostone; Follicle Stimulating Hormone; Sus scrofa
PubMed: 37562189
DOI: 10.1016/j.theriogenology.2023.07.040