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Advanced Science (Weinheim,... Dec 2023Microgravity is the primary factor that affects human physiology in spaceflight, particularly bone loss and disturbances of the central nervous system. However, little...
Microgravity is the primary factor that affects human physiology in spaceflight, particularly bone loss and disturbances of the central nervous system. However, little is known about the cellular and molecular mechanisms of these effects. Here, it is reported that in mice hindlimb unloading stimulates expression of neuropeptide Y (NPY) and tyrosine hydroxylase (TH) in the hypothalamus, resulting in bone loss and altered fat metabolism. Enhanced expression of TH and NPY in the hypothalamus occurs downstream of a reduced prostaglandin E2 (PGE2)-mediated ascending interoceptive signaling of the skeletal interoception. Sympathetic antagonist propranolol or deletion of Adrb2 in osteocytes rescue bone loss in the unloading model. Moreover, depletion of TH sympathetic nerves or inhibition of norepinephrine release ameliorated bone resorption. Stereotactic inhibition of NPY expression in the hypothalamic neurons reduces the food intake with altered energy expenditure with a limited effect on bone, indicating hypothalamic neuroendocrine factor NPY in the facilitation of bone formation by sympathetic TH activity. These findings suggest that reduced PGE2-mediated interoceptive signaling in response to microgravity or unloading has impacts on the skeletal and central nervous systems that are reciprocally regulated.
Topics: Humans; Mice; Animals; Dinoprostone; Interoception; Neuropeptide Y; Hypothalamus; Neurons
PubMed: 37880864
DOI: 10.1002/advs.202305042 -
The Journal of Veterinary Medical... Dec 2023This study investigated the preventive effect of 5-aminolevulinic acid combined with sodium ferrous citrate (5-ALA/SFC) on blood-aqueous barrier (BAB) breakdown induced...
This study investigated the preventive effect of 5-aminolevulinic acid combined with sodium ferrous citrate (5-ALA/SFC) on blood-aqueous barrier (BAB) breakdown induced after anterior chamber paracentesis (ACP) in beagles. 5-ALA/SFC (1/0.64 mg/kg or 3/1.92 mg/kg) or carprofen (4.0 mg/kg) was orally administered daily for 7 days prior to ACP. Then, a sample of the aqueous humor (AH) was collected from one eye via ACP (first sample) and again 60 min later (second sample). The protein and prostaglandin E2 (PGE2) concentrations in both samples were measured. Compared with the control group, high-dose 5-ALA/SFC and carprofen significantly reduced the AH protein and PGE2 concentrations in the second sample. Our findings suggest that 5-ALA/SFC suppresses BAB breakdown in dogs.
Topics: Animals; Dogs; Paracentesis; Blood-Aqueous Barrier; Aminolevulinic Acid; Dinoprostone; Anterior Chamber; Aqueous Humor
PubMed: 37880141
DOI: 10.1292/jvms.23-0347 -
Scientific Reports Oct 2023Ageing is associated with deteriorating urinary bladder function and an increasing prevalence of disorders such as underactive bladder. There are suggestions that G...
Ageing is associated with deteriorating urinary bladder function and an increasing prevalence of disorders such as underactive bladder. There are suggestions that G protein-coupled receptor (GPCR) second messenger pathways are altered during ageing, rather than the receptor proteins themselves. The aim of this study was to identify age-related variations in GPCR activation systems in urinary bladder smooth muscle (detrusor). Isolated porcine detrusor strips were mounted in organ baths and contractile responses induced by receptor agonists were assessed and compared between juvenile (6 months) and adult (2 years) animals. The effects of drugs disrupting intracellular calcium signalling were also studied. Adult tissue was far more sensitive to stimulation by 5-hydroxytryptamine (42% greater increase than juvenile), prostaglandin-E2 (26% greater increase), and angiotensin-II (39% greater increase), however less sensitive to histamine. Although nifedipine and Y-27632 impacted the contraction to all agonists, there were no significant differences between juvenile and adult detrusor. Impairment of IP3-mediated calcium release by 2-aminoethyl diphenylborinate had no effect on any contractile activity, except for neurokinin-A which inhibited both juvenile and adult detrusor, and prostaglandin-E2 which inhibited juvenile. Carbachol, histamine, 5-hydroxytryptamine, and angiotensin-II were not affected by the application of 2-aminoethyl diphenylborinate. In conclusion, the contractile responses to all the GPCR agonists involved extracellular calcium influx and calcium sensitisation, but for prostaglandin-E2 the dependence on calcium from intracellular sources was greater in the younger animals.
Topics: Animals; Swine; Histamine; Serotonin; Calcium; Angiotensins; Prostaglandins; Dinoprostone; rho-Associated Kinases; Carbachol; Calcium, Dietary; Aging; Muscle Contraction
PubMed: 37872186
DOI: 10.1038/s41598-023-44916-8 -
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 -
Brain and Behavior Dec 2023To provide a new insight into the diagnosis and treatment of hemiplegic shoulder pain (HSP) by investigating changes in serum pain mediators.
OBJECTIVE
To provide a new insight into the diagnosis and treatment of hemiplegic shoulder pain (HSP) by investigating changes in serum pain mediators.
DESIGN
Cross-sectional study.
SUBJECTS/PATIENTS
Shoulder pain group (n = 34) and control group (n = 21).
METHODS
Pain-free shoulder mobility, anxiety status, depression status, and shoulder pain were measured by passive range of motion (PROM), self-rating anxiety scale, self-rating depression scale (SDS), and visual analog scale, respectively. The enzyme-linked immunosorbent assay was used to test the serum pain mediators, including interleukin (IL)-1β, IL-2, IL-6, IL-10, nerve growth factor (NGF), tumor necrosis factor-α (TNF-α), substance P (SP), calcitonin gene-related peptide (CGRP), bradykinin (BK), 5-hydroxytryptamine (5-HT), prostaglandin E2 (PGE2), and lysophosphatidic acid (LPA).
RESULTS
Shoulder pain group pain-free PROM significantly lower than control (p < .01), and SDS index score of shoulder pain group was significantly higher than control (p < .05). The rate of spasticity in the flexor elbow muscles is higher in shoulder pain group (p < .01). CGRP, IL-10, and IL-2 were significantly upregulated in shoulder pain group compared with control (p < .01), whereas NGF, TNF-α, IL-6, 5-HT, PGE2, SP, LPA, BK, and IL-1β were significantly decreased (p < .01).
CONCLUSION
Patients with HSP have a higher risk of joint mobility disorders and depression; spasticity may be an important factor in the development of shoulder pain; CGRP is thought to be the major pain mediator in HSP, and HSP may not be inflammatory.
Topics: Humans; Shoulder Pain; Interleukin-10; Calcitonin Gene-Related Peptide; Tumor Necrosis Factor-alpha; Nerve Growth Factor; Dinoprostone; Hemiplegia; Cross-Sectional Studies; Interleukin-2; Interleukin-6; Serotonin; Stroke
PubMed: 37864374
DOI: 10.1002/brb3.3289 -
Cureus Oct 2023The effects of the controlled-release dinoprostone vaginal delivery system (Propess) and mechanical methods for cervical ripening in nulliparous women in late-term...
A Retrospective Comparative Study of the Effect of Controlled-Release Dinoprostone Vaginal Delivery System (Propess®) and Mechanical Methods for Cervical Ripening in Nulliparous Women in Late-Term Pregnancy.
OBJECTIVE
The effects of the controlled-release dinoprostone vaginal delivery system (Propess) and mechanical methods for cervical ripening in nulliparous women in late-term pregnancy were compared retrospectively.
METHODS
This retrospective comparative study included 46 nulliparous pregnant women (24 in the Propess group and 22 in the mechanical methods groups) with a low Bishop score (≤1) who needed labor induction at 41 weeks of gestation. The primary outcome was the success rate of cervical ripening (= Bishop score >6 or vaginal delivery) by the next day following the insertion of Propessonly or mechanical cervical dilation only. In the cases in which cervical ripening was unsuccessful, other methods were performed, and the success rate of cervical ripening the day after was compared as the secondary outcome.
RESULTS
As the primary outcome, there was not a significant difference in the success rate of cervical ripening between the Propessand mechanical methods groups (21 vs. 22%, p = 0.88). As for the secondary outcomes, there was not a significant difference in the total success rate of cervical ripening between the two groups (75 (5+13/24) vs. 73 (5+11/22)%, p = 0.86)). Of the unsuccessful cervical ripening cases as secondary outcomes, the Bishop score of all was ≤2 on the second day of hospitalization.
CONCLUSION
The combined use of Propessand mechanical methods was effective for cervical ripening in nulliparous women with a low Bishop score in late-term pregnancy, regardless of order.
PubMed: 37859678
DOI: 10.7759/cureus.47255 -
Cell Reports Oct 2023Metastasis is the leading cause of high ovarian-cancer-related mortality worldwide. Three major processes constitute the whole metastatic cascade: invasion,...
Metastasis is the leading cause of high ovarian-cancer-related mortality worldwide. Three major processes constitute the whole metastatic cascade: invasion, intravasation, and extravasation. Tumor cells often reprogram their metabolism to gain advantages in proliferation and survival. However, whether and how those metabolic alterations contribute to the invasiveness of tumor cells has yet to be fully understood. Here we performed a genome-wide CRISPR-Cas9 screening to identify genes participating in tumor cell dissemination and revealed that PTGES3 acts as an invasion suppressor in ovarian cancer. Mechanistically, PTGES3 binds to phosphofructokinase, liver type (PFKL) and generates a local source of prostaglandin E2 (PGE2) to allosterically inhibit the enzymatic activity of PFKL. Repressed PFKL leads to downgraded glycolysis and the subsequent TCA cycle for glucose metabolism. However, ovarian cancer suppresses the expression of PTGES3 and disrupts the PTGES3-PGE2-PFKL inhibitory axis, leading to hyperactivation of glucose oxidation, eventually facilitating ovarian cancer cell motility and invasiveness.
Topics: Humans; Female; Dinoprostone; Phosphofructokinases; Phosphofructokinase-1; Liver; Glucose; Ovarian Neoplasms; Cell Proliferation; Cell Line, Tumor; Neoplasm Invasiveness
PubMed: 37831605
DOI: 10.1016/j.celrep.2023.113246 -
Cell Structure and Function Dec 2023Calcium transients drive cells to discharge prostaglandin E (PGE). We visualized PGE-induced protein kinase A (PKA) activation and quantitated PGE secreted from a single...
Calcium transients drive cells to discharge prostaglandin E (PGE). We visualized PGE-induced protein kinase A (PKA) activation and quantitated PGE secreted from a single cell by combining fluorescence microscopy and a simulation model. For this purpose, we first prepared PGE-producer cells that express either an optogenetic or a chemogenetic calcium channel stimulator: OptoSTIM1 or Gq-DREADD, respectively. Second, we prepared reporter cells expressing the Gs-coupled PGE reporter EP2 and the PKA biosensor Booster-PKA, which is based on the principle of Förster resonance energy transfer (FRET). Upon the stimulation-induced triggering of calcium transients, a single producer cell discharges PGE to stimulate PKA in the surrounding reporter cells. Due to the flow of the medium, the PKA-activated area exhibited a comet-like smear when HeLa cells were used. In contrast, radial PKA activation was observed when confluent MDCK cells were used, indicating that PGE diffusion was restricted to the basolateral space. By fitting the radius of the PKA-activated area to a simulation model based on simple diffusion, we estimated that a single HeLa cell secretes 0.25 fmol PGE upon a single calcium transient to activate PKA in more than 1000 neighboring cells. This model also predicts that the PGE discharge rate is comparable to the diffusion rate. Thus, our method quantitatively envisions that a single calcium transient affects more than 1000 neighboring cells via PGE.Key words: prostaglandin E, imaging, intercellular communication, biosensor, quantification.
Topics: Animals; Dogs; Humans; HeLa Cells; Dinoprostone; Madin Darby Canine Kidney Cells; Fluorescence Resonance Energy Transfer
PubMed: 37813623
DOI: 10.1247/csf.23047 -
Molecular Therapy : the Journal of the... Dec 2023In vivo apoptosis of human mesenchymal stromal cells (MSCs) plays a critical role in delivering immunomodulation. Yet, caspase activity not only mediates the dying...
In vivo apoptosis of human mesenchymal stromal cells (MSCs) plays a critical role in delivering immunomodulation. Yet, caspase activity not only mediates the dying process but also death-independent functions that may shape the immunogenicity of apoptotic cells. Therefore, a better characterization of the immunological profile of apoptotic MSCs (ApoMSCs) could shed light on their mechanistic action and therapeutic applications. We analyzed the transcriptomes of MSCs undergoing apoptosis and identified several immunomodulatory factors and chemokines dependent on caspase activation following Fas stimulation. The ApoMSC secretome inhibited human T cell proliferation and activation, and chemoattracted monocytes in vitro. Both immunomodulatory activities were dependent on the cyclooxygenase2 (COX2)/prostaglandin E2 (PGE2) axis. To assess the clinical relevance of ApoMSC signature, we used the peripheral blood mononuclear cells (PBMCs) from a cohort of fistulizing Crohn's disease (CD) patients who had undergone MSC treatment (ADMIRE-CD). Compared with healthy donors, MSCs exposed to patients' PBMCs underwent apoptosis and released PGE2 in a caspase-dependent manner. Both PGE2 and apoptosis were significantly associated with clinical responses to MSCs. Our findings identify a new mechanism whereby caspase activation delivers ApoMSC immunosuppression. Remarkably, such molecular signatures could implicate translational tools for predicting patients' clinical responses to MSC therapy in CD.
Topics: Humans; Crohn Disease; Dinoprostone; Leukocytes, Mononuclear; Secretome; Mesenchymal Stem Cells; Immunomodulation; Apoptosis; Caspases
PubMed: 37805713
DOI: 10.1016/j.ymthe.2023.10.004 -
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