Prostaglandin E2 Secretion Research Articles

Possible Involvement of Dermal Fibroblasts in Modulating Nrf2 Signaling in Epidermal Keratinocytes.

Epidermal keratinocytes protect themselves by cooperating with neighboring cells against internal and external stresses, which leads not only to the maintenance of cell homeostasis but also to the prevention of skin aging. Although it is known that nuclear factor (NF)-E2-related factor 2 (Nrf2) signaling plays a pivotal role in ameliorating oxidative stress and inflammatory responses under stress situations, it is unclear whether Nrf2 signaling in keratinocytes cooperates with neighboring cells such as dermal fibroblasts. Thus, this study was conducted to examine the influence of dermal fibroblasts on Nrf2 signaling in epidermal keratinocytes using a co-culture system. The results show that expression levels of Nrf2-regulated antioxidant factors, such as glutathione and heme oxygenase-1, in HaCaT keratinocytes (HaCaT KCs) are up-regulated in the presence of normal human dermal fibroblasts (NHDFs). In addition, the secretion of pro-inflammatory molecules, including interleukin-1α (IL-1α) and prostaglandin E2 (PGE2), is suppressed in co-cultures of NHDFs and UVB-irradiated HaCaT KCs. Interestingly, the localization of Nrf2 protein in HaCaT KCs was immediately translocated from the cytoplasm to the nucleus after the co-culture with NHDFs. These results suggest the possibility that Nrf2 signaling in keratinocytes is regulated in cooperation with dermal fibroblasts.

Study on Definitive Role of Smoking Over Alcohol on Peptic Ulcer Disease.

Peptic ulcer disease is characterized by erosive lesions of the lining of the gastrointestinal tract, the mucosa being damaged by the action of Hydrochloric acid and Pepsin, spread deeply into the submucosa and lamina propria, mainly of the stomach and duodenum. Smoking, directly and indirectly, affects the lining of the stomach and duodenum, increases the duodenal gastric reflux with mucosal damage, decreases prostaglandin secretion, and slow and consistent exposure radically affects the prognosis allied with detained healing. Furthermore, the effects of smoking are related to long-term exposure, accelerating chronic ulcers with slow healing. This study focuses on a defined number of patients and tries to fulfill the lack of significance of smoking in other studies previously established. It stands out from other studies because most of the studies conducted give the general impression that alcohol consumption is more associated with peptic ulcers; this study is aimed to investigate as well as compare the role of smoking and alcohol, and the novelty of this study is intended to confirm the strong and indispensable capacity of smoking in the causation and complications of peptic ulcer disease, focusing on patients who are already known and newly diagnosed, to elaborate our investigation on how despite treatment, smoking proves to be a significant cause delaying healing and affecting prognosis. The study group of hundred patients first and foremost revealed that only 50% to 60% were aware of their peptic ulcer disease, accounting for about fiftythree patients. And 92% of the patient's presented with hematemesis, coexisting with heartburn, regurgitation, Abdominal pain, or epigastric pain. This retrospective study of 100 patients distinctly revealed that the patients suffering from peptic ulcer disease had a compelling etiological factor as smoking, while alcohol was only an aggravating cofactor.

Staphylococcus aureus increases Prostaglandin E2 secretion in cow neutrophils by activating TLR2, TLR4, and NLRP3 inflammasome signaling pathways.

In clinical settings, dairy cows are often attacked by pathogenic bacteria after delivery, especially Staphylococcus aureus (S. aureus). Neutrophils have long been regarded as essential for host defense against S. aureus. Prostaglandin E2 (PGE2) can additionally be used as an inflammatory mediator in pathological conditions to promote the repair of inflammatory injuries. However, whether S. aureus can promote the accumulation of PGE2 after the infection of neutrophils in cows and its mechanism remain unclear. Lipoprotein is an important immune bioactive ingredient of S. aureus. In this study, the changes in neutrophils were monitored in dairy cows infected with wild-type S. aureus (SA113) and an S. aureus lipoprotein-deficient strain (Δlgt); meanwhile, we established whether pattern recognition receptors mediate this process and whether S. aureus lipoproteins are necessary for causing the release of PGE2 from cow neutrophils. The results showed that Δlgt was less effective than SA113 in inducing the production of IL-1β, IL-6, IL-8, IL-10, and PGE2 within neutrophils; furthermore, TLR2, TLR4, and NLRP3 receptors were found to mediate the inducible effect of lipoprotein on the above inflammation mediators and cytokines, which depended on MAPK and Caspase-1 signaling pathways. In addition, TLR2, TLR4, and NLRP3 inhibitors significantly inhibited PGE2 and cytokine secretion, and PGE2 was involved in the interaction of S. aureus and neutrophils in dairy cows, which could be regulated by TLR2, TLR4, and NLRP3 receptors. We also found that S. aureus was more likely to be killed by neutrophils when it lacked lipoprotein and TLR2, TLR4, and NLRP3 were involved, but PGE2 seemed to have no effect. Taken together, these results suggest that lipoprotein is a crucial component of S. aureus in inducing cytokine secretion by neutrophils as well as killing within neutrophils, which could be accomplished by the accumulation of PGE2 by activating MAPK and the Caspase-1 signaling pathways through TLR2, TLR4, and NLRP3 receptors. These results will contribute to a better understanding of the interaction between S. aureus and host immune cells in dairy cows.

TNF-α/IL-1β-licensed hADSCs alleviate cholestatic liver injury and fibrosis in mice via COX-2/PGE2 pathway

BackgroundAdipose tissue-derived stem cell (ADSC) transplantation has been shown to be effective for the management of severe liver disorders. Preactivation of ADSCs enhanced their therapeutic efficacy. However, these effects have not yet been examined in relation to cholestatic liver injury.MethodsIn the present study, a cholestatic liver injury model was established by bile duct ligation (BDL) in male C57BL/6 mice. Human ADSCs (hADSCs) with or without tumor necrosis factor-alpha (TNF-α) and interleukin-1beta (IL-1β) pretreatment were administrated into the mice via tail vein injections. The efficacy of hADSCs on BDL-induced liver injury was assessed by histological staining, real-time quantitative PCR (RT-qPCR), Western blot, and enzyme-linked immune sorbent assay (ELISA). In vitro, the effects of hADSC conditioned medium on the activation of hepatic stellate cells (HSCs) were investigated. Small interfering RNA (siRNA) was used to knock down cyclooxygenase-2 (COX-2) in hADSCs.ResultsTNF-α/IL-1β preconditioning could downregulate immunogenic gene expression and enhance the engraftment efficiency of hADSCs. Compared to control hADSCs (C-hADSCs), TNF-α/IL-1β-pretreated hADSCs (P-hADSCs) significantly alleviated BDL-induced liver injury, as demonstrated by reduced hepatic cell death, attenuated infiltration of Ly6G + neutrophils, and decreased expression of pro-inflammatory cytokines TNF-α, IL-1β, C-X-C motif chemokine ligand 1 (CXCL1), and C-X-C motif chemokine ligand 2 (CXCL2). Moreover, P-hADSCs significantly delayed the development of BDL-induced liver fibrosis. In vitro, conditioned medium from P-hADSCs significantly inhibited HSC activation compared to that from C-hADSCs. Mechanistically, TNF-α/IL-1β upregulated COX-2 expression and increased prostaglandin E2 (PGE2) secretion. The blockage of COX-2 by siRNA transfection reversed the benefits of P-hADSCs for PGE2 production, HSC activation, and liver fibrosis progression.ConclusionIn conclusion, our results suggest that TNF-α/IL-1β pretreatment enhances the efficacy of hADSCs in mice with cholestatic liver injury, partially through the COX-2/PGE2 pathway.

Alteration of Mesenchymal Stem Cells Isolated from Glioblastoma Multiforme under the Influence of Photodynamic Treatment.

The central hypothesis for the development of glioblastoma multiforme (GBM) postulates that the tumor begins its development by transforming neural stem cells into cancer stem cells (CSC). Recently, it has become clear that another kind of stem cell, the mesenchymal stem cell (MSC), plays a role in the tumor stroma. Mesenchymal stem cells, along with their typical markers, can express neural markers and are capable of neural transdifferentiation. From this perspective, it is hypothesized that MSCs can give rise to CSC. In addition, MSCs suppress the immune cells through direct contact and secretory factors. Photodynamic therapy aims to selectively accumulate a photosensitizer in neoplastic cells, forming reactive oxygen species (ROS) upon irradiation, initiating death pathways. In our experiments, MSCs from 15 glioblastomas (GB-MSC) were isolated and cultured. The cells were treated with 5-ALA and irradiated. Flow cytometry and ELISA were used to detect the marker expression and soluble-factor secretion. The MSCs' neural markers, Nestin, Sox2, and glial fibrillary acid protein (GFAP), were down-regulated, but the expression levels of the mesenchymal markers CD73, CD90, and CD105 were retained. The GB-MSCs also reduced their expression of PD-L1 and increased their secretion of PGE2. Our results give us grounds to speculate that the photodynamic impact on GB-MSCs reduces their capacity for neural transdifferentiation.

Role of Noradrenaline and Adrenoreceptors in Regulating Prostaglandin E2 Synthesis Cascade in Inflamed Endometrium of Pigs.

In the inflamed uterus, the production and secretion of prostaglandins (PGs) and noradrenergic innervation pattern are changed. Receptor-based control of prostaglandin E2 (PGE2) production and secretion by noradrenaline during uterine inflammation is unknown. The aim of this study was to determine the role of α1-, α2- and β-adrenoreceptors (ARs) in noradrenaline-influenced PG-endoperoxidase synthase-2 (PTGS-2) and microsomal PTGE synthase-1 (mPTGES-1) protein levels in the inflamed pig endometrium, and in the secretion of PGE2 from this tissue. E. coli suspension (E. coli group) or saline (CON group) was injected into the uterine horns. Eight days later, severe acute endometritis developed in the E. coli group. Endometrial explants were incubated with noradrenaline and/or α1-, α2- and β-AR antagonists. In the CON group, noradrenaline did not significantly change PTGS-2 and mPTGES-1 protein expression and increased PGE2 secretion compared to the control values (untreated tissue). In the E. coli group, both enzyme expression and PGE2 release were stimulated by noradrenaline, and these values were higher versus the CON group. The antagonists of α1- and α2-AR isoforms and β-AR subtypes do not significantly alter the noradrenaline effect on PTGS-2 and mPTGES-1 protein levels in the CON group, compared to noradrenaline action alone. In this group, α1A-, α2B- and β2-AR antagonists partly eliminated noradrenaline-stimulated PGE2 release. Compared to the noradrenaline effect alone, α1A-, α1B-, α2A-, α2B-, β1-, β2- and β3-AR antagonists together with noradrenaline reduced PTGS-2 protein expression in the E. coli group. Such effects were also exerted in this group by α1A-, α1D-, α2A-, β2- and β3-AR antagonists with noradrenaline on mPTGES-1 protein levels. In the E. coli group, the antagonists of all isoforms of α1-ARs and subtypes of β-ARs as well as α2A-ARs together with noradrenaline decreased PGE2 secretion versus noradrenaline action alone. Summarizing, in the inflamed pig endometrium, α1(A, B)-, α2(A, B)- and β(1, 2, 3)-ARs mediate the noradrenaline stimulatory effect on PTGE-2 protein expression, while noradrenaline via α1(A, D)-, α2A- and β(2, 3)-ARs increases mPTGES-1 protein expression and α1(A, B, D)-, α2A- and β(1, 2, 3)-ARs are involved in PGE2 release. Data suggest that noradrenaline may indirectly affect the processes regulated by PGE2 by influencing its production. Pharmacological modulation of particular AR isoforms/subtypes can be used to change PGE2 synthesis/secretion to alleviate inflammation and improve uterine function.

Expression of NFIL3 and CEBPA regulated by IFNT induced-PGE2 in bovine endometrial stromal cells during the pre-implantation period.

Prostaglandin E2 (PGE2) is considered as a luteoprotective factor, influencing the corpus luteum during the early pregnant period in the bovine species. Cyclic AMP (cAMP) is activated in response to PGE2 and plays a role in many physiological processes. The maternal recognition signal, interferon τ (IFNT), induces PGE2 secretion from the endometrial epithelial cells, the function of which in stroma cells has not been completely understood. In this study, PGE2 was found to activate cAMP in the bovine endometrial stromal cells (STRs). STRs were then treated with forskolin to activate the cAMP signaling, from which RNA extracted was subjected to global expression analysis. Transcripts related to transcription regulatory region nucleic acid binding of molecular function, nucleus of cellular component, and mitotic spindle organization of biological processes were up-regulated in cAMP-activated bovine STRs. An increase in the transcription factors, NFIL3, CEBPA, and HIF1A via the cAMP/PKA/CREB signaling pathway in the bovine STRs was also found by qPCR. Knockdown of NFIL3, CEBPA, or HIF1A blocked forskolin-induced PTGS1/2 and IGFBP1/3 expression. Moreover, NFIL3 and CEBPA were localized in endometrial stroma on pregnant day 17 (day 0 = estrous cycle), but not on cyclic day 17. These observations indicated that uterine PGE2 induced by conceptus IFNT is involved in the early pregnancy-related gene expression in endometrial stromal cells, which could facilitate pregnancy establishment in the bovine.

Megastigmane glycosides from Streblus ilicifolius (S.Vidal) Corner and their anti-inflammatory activity

Twelve undescribed megastigmane glycosides, streilicifolosides A−L (1–12), together with 8 known analogues (13–21) were isolated from the leaves of Streblus ilicifolius (S.Vidal) Corner. Their plannar structures were elucidated using extensive NMR spectroscopic methods (1D and 2D-NMR spectroscopy), and HRESIMS spectroscopic data analyses. The absolute configurations of the undescribed compounds were determined by the glucose-induced shift-trend, calculated and experimental circular dichroism spectroscopy. All the compounds were tested for inhibitory effects on the production of NO in LPS-treated RAW264.7 cells, and streilicifoloside E and platanionoside D exhibited potent anti-inflammatory activity comparable to that of the positive control, with IC50 values of 26.33 and 21.84 μM, respectively. Furthermore, these two compounds markedly decreased the secretion of PGE2 and TNF-α and inhibited the expression of COX‒2, iNOS and NF-κB/p65 in LPS-induced RAW264.7 cells in a dose-dependent manner. In addition, the structure−activity relationships of the isolates were also discussed. The results suggest that streilicifoloside E and platanionoside D could be used as potential candidates for the development of new anti-inflammatory agents.

Neuroprotection by Skimmianine in Lipopolysaccharide-Activated BV-2 Microglia.

Skimmianine is a furoquinoline alkaloid which is found in the Zanthoxylum genus and also in other plants of the Rutaceae family. This study evaluated the effects of skimmianine on the production of pro-inflammatory mediators in LPS-activated BV-2 microglia. Cultured BV-2 cells were treated with skimmianine (10, 20 and 30 μM), followed by stimulation with LPS (100 ng/mL). Levels of TNFα and IL-6 in cell supernatants were measured using ELISA, while NO and PGE2 levels were evaluated with Griess assay and EIA, respectively. Western blotting was used to determine the protein expression of iNOS, COX-2, phospho-p65 and phospho-IκBα. Results showed that Skimmianine reduced LPS-induced elevated the secretion of TNFα, IL-6, NO, and PGE2, as well as the increased protein expression of iNOS and COX-2. Experiments to elucidate the mechanisms of the anti-neuroinflammatory activity of skimmianine revealed the significant inhibition of LPS-induced increased NF-κB-mediated luciferase activity. Pre-treatment with skimmianine also reduced LPS-induced the increased phosphorylation of NF-κB/p65 and IκBα proteins. Furthermore, skimmianine interfered with the binding capacity of NF-κB to consensus sites. Skimmianine pre-treatment protected HT-22 cells from toxicity induced by microglia-conditioned media, as well as increasing MAP-2 expression. The results of this study suggest that skimmianine inhibits neuroinflammation in LPS-activated microglia by targeting the NF-κB activation pathway. Skimmianine also produced neuroprotection against neurotoxicity induced by microglia-conditioned media.

N-3 polyunsaturated fatty acids (PUFAs) and physical exercise have the potential to reduce pain intensity in women with primary dysmenorrhea: Systematic Review

This review aims to highlight the potential of n-3 PUFAs and physical exercise in reducing pain intensity in women with primary dysmenorrhea. This type of research is a systematic review using comprehensive strategies such as searching for articles in research journal databases. The databases used are Pubmed/MEDLINE, Scopus, Web of Science, and Embase. The populations analyzed in this paper are: the potential of n-3 PUFAs and physical exercise to reduce primary dysmenorrhea. The inclusion criteria in this study were journals that discussed n-3 PUFAs, exercise, primary dysmenorrhea, and menstrual pain. The exclusion criteria in this study were disreputable international journals. For standard operationalization, This study follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). This review explains that N-3 PUFAs given at the right dose, around 1000 mg/day have the potential to reduce pain intensity by suppressing the production of pro-inflammatory cytokines and eicosanoids. In addition, N-3 PUFAs have the potential to prevent and reduce pain intensity by inhibiting prostaglandin synthesis. Progesterone is very important in women with primary dysmenorrhea in order to control prostaglandin secretion. This review explains that regular exercise with low to moderate intensity (30-75% of maximum ability) performed 3 times in 1 week can increase progesterone concentrations. Physical exercises that can be done to reduce pain intensity due to primary dysmenorrhea include stretching exercises, jogging, and yoga exercises. Keywords: N-3 PUFAs, Physical Exercise; Dismenore Primer; Menstrual Pain

Anti-Inflammatory Effect of Garcinol Extracted from Garcinia dulcis via Modulating NF-κB Signaling Pathway.

Garcinia is a significant medicinal plant with many beneficial phytoconstituents, including garcinol. This study investigated the anti-inflammatory effect of garcinol isolated from Garcinia dulcis fruit in LPS-activated THP-1 and Raw 264.7 macrophages. The results demonstrated that the low concentration of garcinol did not alter cell viability. Furthermore, co-incubation of garcinol with LPS inhibited the production of pro-inflammatory cytokines, including TNF-α, IL-8, IL-6, IL-1β, and pro-inflammatory mediators, including iNOS and COX-2 at the mRNA and protein expression levels. Garcinol also decreased the secretion of TNF-α, IL-6, IL-1β, PGE2, and NO. Moreover, the anti-inflammatory effects involved an alteration in the NF-κB signaling pathway. Downregulation of pIKKα/β, pIκBα, and pNF-κB was observed, hence reducing the translocation of pNF-κB from the cytosol into the nucleus, which subsequently decreased the production of pro-inflammatory molecules. Therefore, garcinol isolated from Garcinia dulcis is a potential candidate as an anti-inflammatory agent for inflammation-related disease treatment.

Renal interstitial cells promote nephron regeneration by secreting prostaglandin E2.

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 fabp10a as a principal marker of renal interstitial cells (RICs), which can be specifically labeled by GFP under the control of fabp10a promoter in the fabp10a:GFP 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.

Anti-neuroinflammatory effects of alkaloid-enriched extract from Huperzia serrata on lipopolysaccharide-stimulated BV-2 microglial cells

Context Alkaloid-enriched extract of Huperzia serrata (Thunb.) Trevis (Lycopodiaceae) (HsAE) can potentially be used to manage neuronal disorders. Objective This study determines the anti-neuroinflammatory effects of HsAE on lipopolysaccharide (LPS)-stimulated BV-2 microglial cells and the underlying mechanisms. Materials and methods BV-2 cells were pre- or post-treated with different concentrations of HsAE (25-150 µg/mL) for 30 min before or after LPS induction. Cell viability was assessed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and no cytotoxicity was found. Nitric oxide (NO) concentration was determined using Griess reagent. The levels of prostaglandin E2 (PGE2), tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 were determined using enzyme-linked immunosorbent assay. The levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 and the phosphorylation of mitogen-activated protein kinase (MAPK) were analyzed using western blotting. Results HsAE reduced LPS-induced NO production with half-maximal inhibitory concentration values of 99.79 and 92.40 µg/mL at pre- and post-treatment, respectively. Pre-treatment with HsAE at concentrations of 50, 100, and 150 µg/mL completely inhibited the secretion of PGE2, TNF-α, IL-6, and IL-1β compared to post-treatment with HsAE. This suggests that prophylactic treatment is better than post-inflammation treatment. HsAE decreased the expression levels of iNOS and COX-2 and attenuated the secretion of pro-inflammatory factors by downregulating the phosphorylation of p38 and extracellular signal-regulated protein kinase in the MAPK signaling pathway. Discussion and Conclusions HsAE exerts anti-neuroinflammatory effects on LPS-stimulated BV-2 cells, suggesting that it may be a potential candidate for the treatment of neuroinflammation in neurodegenerative diseases.

The antioxidant trolox inhibits aging and enhances prostaglandin E-2 secretion in mesenchymal stem cells

Mesenchymal stem cells (MSCs) have been widely used in regenerative medicine and clinical therapy due to their capabilities of proliferation, differentiation, and immune regulation. However, during in vitro expansion, MSCs are prone to aging, which largely limits their application. Prostaglandin E-2 (PGE-2) is a key effector secreted by MSCs to exert immunomodulatory effects. By screening the compound library for PGE-2 secretion, the antioxidant trolox was verified as a stimulator of MSCs to secrete PGE-2. The effect of antioxidant trolox on biological characteristics of MSCS, including aging, proliferation, and gene expression, was examined. The results demonstrated that trolox can resist aging, promote proliferation, and enhance PGE-2 secretion of MSCs without affecting their surface marker expression. Furthermore, trolox treatment up-regulates miR-17-92 clusters in MSCs and may contribute to its anti-aging effects. Thus, trolox addition might be beneficial for MSCs expansion and their application.

Physiotherapy Interventions as an Adjunct Approach in Patients with Primary Dysmenorrhea: A Narrative Review

Primary Dysmenorrhea (PD) is a major contributor in teenage and young female absenteeism following menstrual cramps and abdomen pain before and during their menstrual cycle. Prostaglandin secretion causes uterine muscles and blood arteries to contract. The discomfort is usually modest, but in some cases, it is so terrible that it prevents them from going to work for many days in a month without any social, psychological and physical activity. The purpose of this review was to assess impact of physiotherapy on psychological, social and physical wellbeing in patients with PD. Physiotherapy intervention without surgical management can improve psychological, physical and social wellbeing of PD patients. All articles incorporated in the review were reported to reduce the pain intensity and the frequency in PD. A healthier and more appropriate eating style, as well as more frequent physical activity can help school and college going females to avoid dysmenorrhea. Educational activities can help in raising awareness among young women about the importance of a healthy diet and physical activity. The present review concluded that physiotherapy treatment strategies are effective treatments for reducing pain and psychological effects on PD females. Conservative management by physiotherapy reduces intensity and frequency of pain, anxiety, depression, stress, poor sleep quality and improved quality of life in PD.

COX-2/PGE2/VEGF signaling promotes ERK-mediated BMSCs osteogenic differentiation under hypoxia by the paracrine action of ECs.

Understanding the crosstalk between endothelial cells (ECs) and bone-marrow mesenchymal stem cells (BMSCs) in response to hypoxic environments and deciphering of the underlying mechanisms are of great relevance for better application of BMSCs in tissue engineering. Here, we demonstrated that hypoxia promoted BMSCs proliferation, colony formation, osteogenic markers expression, mineralization, and extracellular signal-regulated protein kinase (ERK) phosphorylation, and that PD98059 (ERK inhibitor) blocked hypoxia-induced osteogenic differentiation. Hypoxia enhanced ECs migration, cyclooxygenase 2 (COX-2) and integrin αvβ3 expression, and prostaglandin E2 (PGE2), vascular endothelial growth factor (VEGF) secretion. NS398 (selective COX-2 inhibitor) and LM609 (integrin αvβ3 specific inhibitor) impaired the ECs response to hypoxia, and exogenous PGE2 partially reversed the effects of NS398. BMSCs: ECs co-culture under hypoxia upregulated BMSCs osteogenesis and ERK phosphorylation, as well as ECs migration, integrin αvβ3 expression, and PGE2 and VEGF secretion. NS398 (pretreated ECs) lessened PGE2, VEGF concentrations of the co-culture system. NS398-treated ECs and AH6809 (combined EP1/2 antagonist)/L-798106 (selective EP3 antagonist)/L-161982 (selective EP4 antagonist)/SU5416 [VEGF receptor (VEGFR) inhibitor]-treated BMSCs impaired the co-cultured ECs-induced enhancement of BMSCs osteogenic differentiation. In conclusion, hypoxia enhances BMSCs proliferation and ERK-mediated osteogenic differentiation, and augments the COX-2-dependent PGE2 and VEGF release, integrin αvβ3 expression, and migration of ECs. COX-2/PGE2/VEGF signaling is involved in intercellular BMSCs: ECs communication under hypoxia.

Amelioration of DSS-induced colitis in mice by TNF-α-stimulated mesenchymal stem cells derived from feline adipose tissue via COX-2/PGE2 activation.

Mesenchymal stem cells (MSCs) have been investigated as therapeutic agents for inflammatory bowel disease (IBD). Stimulation of MSCs with pro-inflammatory cytokines is an approach to enhance their immunomodulatory effects. However, further investigation is required to support their application in immune-mediated disorders and companion animals. This study aimed to assess the therapeutic effect of tumor necrosis factor (TNF)-α-stimulated feline adipose tissue-derived MSCs (fAT-MSCs) in a dextran sulfate sodium (DSS)-induced colitis mouse model. Colitis mice was made by drinking water with 3% DSS and fAT-MSCs were injected intraperitoneally. Colons were collected on day 10. The severity of the disease was evaluated and compared. Raw 264.7 cells were cultured with the conditioned medium to determine the mechanism, using quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay. TNF-α-stimulated fAT-MSCs more improved severity of DSS-induced colitis in disease activity, colon length, histologic score, and inflammatory cytokine. In sectionized colon tissues, the group comprising TNF-α-stimulated fAT-MSCs had higher proportion of CD11b+CD206+ macrophages than in the other groups. In vitro, TNF-α-stimulation increased cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) secretion from fAT-MSCs. The conditioned medium from TNF-α-stimulated fAT-MSCs enhanced the expression of interleukin-10 and arginase-1 in LPS-activated Raw 264.7 cells. These results represent that TNF-α-stimulated fat-mscs ameliorate the inflamed colon more effectively. Furthermore, we demonstrated that the effectiveness was interlinked with the COX-2/PGE2 pathway.

Selectively attacking tumor cells of Ru/Ir-arene complexes based on meclofenamic acid via cyclooxygenase-2 inhibition.

Breast cancer (BC) is one of the most common malignant tumors and often accompanied by inflammatory processes. Inflammation is an essential component of the tumor microenvironment, which might influence tumor proliferation and metastasis. Herein, three metal-arene complexes MA-bip-Ru, MA-bpy-Ir, and MA-bpy-Ru were prepared by tethering the non-steroidal anti-inflammatory drug meclofenamic acid (MA). Among them, MA-bip-Ru and MA-bpy-Ir showed lower cytotoxicity towards cancer cells, but MA-bpy-Ru showed significantly high selectivity and cytotoxicity towards MCF-7 cells through the autophagic pathway and exhibited no toxicity against normal HLF cells, showing potential for selective treatment of tumor cells. MA-bpy-Ru could also effectively destroy the 3D multicellular tumor spheroids, demonstrating its potential for clinical application. Besides, MA-bip-Ru, MA-bpy-Ir, and MA-bpy-Ru exhibited anti-inflammatory properties superior to MA, notably downregulating the expression of cyclooxygenase-2 (COX-2) and inhibiting the secretion of prostaglandin E2 in vitro. These findings demonstrated that MA-bpy-Ru was capable of intervening in inflammatory processes and showed the potential of MA-bpy-Ru to act as a selective anticancer agent, thus presenting a new mechanism of action for metal-arene complexes.

FABP4 mediates endoplasmic reticulum stress and autophagy to regulate endometrial epithelial cell function during early sheep gestation.

Dynamic changes in the endometrium are crucial for establishing early pregnancy in ruminants. Blastocyst elongation and implantation require hormones and nutrients to be secreted from the maternal endometrium. The fatty acid-binding protein FABP4 is a widely expressed fatty acid transport protein that promotes cell proliferation, migration, and invasion and is involved in conceptus implantation. However, the mechanism underlying the functional regulation of endometrial epithelial cells (EECs) by FABP4 during ovine peri-implantation remains unclear. We simulated hormonal changes in vitro in sheep EECs (SEECs) during the peri-implantation period and found that it elevated FABP4 expression. FABP4 inhibition significantly reduced cell migration, endoplasmic reticulum stress, and autophagy, suggesting that FABP4 regulates endometrial function in sheep. Moreover, the FABP4 inhibitor BMS309403 counteracted hormone-mediated functional changes in SEECs, and an endoplasmic reticulum stress activator and autophagy inhibitor reversed the abnormal secretion of prostaglandins induced by FABP4 inhibition. These results suggest that FABP4 affects ovine endometrial function during early gestation by regulating endoplasmic reticulum stress and autophagy in SEECs.

Approach to dysmenorrhoea in primary care.

Approach to dysmenorrhoea in primary care.