It is widely recognized that foods, biodiversity, and human health are strongly interconnected, and many efforts have been made to understand the nutraceutical value of diet. In particular, diet can affect the progression of intestinal diseases, including inflammatory bowel disease (IBD) and intestinal cancer. In this context, we studied the anti-inflammatory and antioxidant activities of extracts obtained from a local endangered variety of Phaseolus vulgaris L. (Fagiola di Venanzio, FV). Using in vitro intestinal cell models, we evaluated the activity of three different extracts: soaking water, cooking water, and the bioaccessible fraction obtained after mimicking the traditional cooking procedure and gastrointestinal digestion. We demonstrated that FV extracts reduce inflammation and oxidative stress prompted by interleukin 1β through the inhibition of cyclooxygenase 2 expression and prostaglandin E2 production and through the reduction in reactive oxygen species production and NOX1 levels. The reported data outline the importance of diet in the prevention of human inflammatory diseases. Moreover, they strongly support the necessity to safeguard local biodiversity as a source of bioactive compounds.

Previous studies have shown prostaglandin E2 (PGE2) produced a marked increase in calcitonin secretion in human C-cells derived from medullary thyroid carcinoma. However, it\'s unclear whether PGE2 can increase the growth of C cells. In this study, we use TT cells as a C cell model to investigate the effect of PGE2 on the growth of C cells. The results revealed that both PGE2 and arachidonic acid (AA) significantly increased the count of TT cells, whereas indomethacin and Dup697 reduced this count. Notably, an increase in the level of AA was associated with an increase in the number of proliferating TT cells, indicating a dose-response relationship. PGE2 and its receptor agonists (sulprostone and butaprost) enhanced the proliferation of TT cells. By contrast, 17-phenyl-trinor-PGE2 exerted no significant effect on TT cell proliferation, whereas L161982 suppressed it. The positive effect of AA on TT cell proliferation was inhibited by indomethacin, NS398, Dup697 (complete inhibition), and SC560. Both PGE2 and AA increased the level of p-STAT5a. The positive effect of AA on p-STAT5a was completely inhibited by Dup697 but not indomethacin, NS398, or SC560. Treatment with indomethacin or Dup697 alone reduced the level of STAT5a in TT cells. AA increased the level of STAT5a, but this effect was inhibited by indomethacin, NS398, and Dup697. Overall, this study confirms the effect of PGE2 on the proliferation of TT cells. This effect is likely mediated through EP2, EP3, and EP4 receptors and associated with an increase in p-STAT5a level within TT cells.

Tarsocrural osteochondrosis (OCD) is a developmental orthopedic disease commonly affecting young Standardbreds, with different fragment localization and size. Clinically, it is characterized by variable synovial effusion in the absence of lameness, whose determinants are ill-defined. We hypothesized that localization and physical characteristics of the osteochondral fragments like dimensions, multifragmentation, and instability influence joint effusion and correlate with synovial markers of cartilage degradation and inflammation. Clinical data, synovial fluid and intact osteochondral fragments were collected from 79 Standardbred horses, aged between 12 and 18 months, operated for tarsocrural OCD. The severity of tarsocrural joint effusion was assessed semi-quantitatively. The osteochondral fragment site was defined radiographically at the distal intermediate ridge of the tibia (DIRT), medial malleolus (MM) of the tibia, and/or lateral trochlear ridge (LTR) of the talus. Size, stability, and arthroscopic appearance (unique or multi-fragmented aspect) of the fragments were determined intra-operatively. Synovial concentrations of C-terminal cross-linked telopeptides of type II collagen (CTX-II), leukotriene B4 (LTB4), and prostaglandin E2 (PGE2) were quantified. Tarsocrural synovial effusion was significantly affected by localization and stability of the fragments, with MM-located and unstable fragments being associated with highest joint effusion. Concentrations of CTX-II, LTB4, and PGE2 positively correlated with the severity of synovial effusion. This study underlines characteristics of the osteochondral fragments determining higher synovial effusion in OCD-affected tarsocrural joints and suggests both inflammation and extra-cellular matrix degradation are active processes in OCD pathology.

Immunotherapy has captured attention for its high clinical efficacy. However, its efficacy is limited by inadequate immune activation. Therefore, a platform to activate the immune system and amplify the host\'s immune response against tumors is urgently needed. Herein, a self-delivery photodynamic nanodrug (VAC@HSA) is reported as inducing immunogenic cell death (ICD), promoting the recruitment of dendritic cells (DCs), and normalizing tumor blood vessels. Firstly, verteporfin with laser assistance releases tumor-associated antigen to induce ICD, while celecoxib downregulates prostaglandin E2 and releases CCL5 to activate DC recruitment. Moreover, vasculature is normalized through axitinib, which contributes to reducing tumor hypoxia and reversing the immunosuppressive effects of vascular endothelial growth factor. This joint action promotes the infiltration of immune effector cells into the tumor. Therefore, the amplified photodynamic nanodrug with excellent biocompatibility effectively inhibits tumor growth and lung metastasis and produces a cascade of immune responses. Our study demonstrates a practically innovative strategy for activating cancer immunotherapy, which can alter the \"cold\" properties of tumors.

Prostaglandin E2 (PGE2) is a major contributor to inflammatory pain hyperalgesia, however, the extent to which it modulates the activity of nociceptive axons is incompletely understood. We developed and characterized a microfluidic cell culture model to investigate sensitisation of the axons of dorsal root ganglia neurons. We show that application of PGE2 to fluidically isolated axons leads to sensitisation of their responses to depolarising stimuli. Interestingly the application of PGE2 to the DRG axons elicited a direct and persistent spiking activity propagated to the soma. Both the persistent activity and the membrane depolarisation in the axons are abolished by the EP4 receptor inhibitor and a blocker of cAMP synthesis. Further investigated into the mechanisms of the spiking activity showed that the PGE2 evoked depolarisation was inhibited by Nav1.8 sodium channel blockers but was refractory to the application of TTX or zatebradine. Interestingly, the depolarisation of axons was blocked by blocking ANO1 channels with T16Ainh-A01. We further show that PGE2-elicited axonal responses are altered by the changes in chloride gradient within the axons following treatment with bumetanide a Na-K-2Cl cotransporter NKCC1 inhibitor, but not by VU01240551 an inhibitor of potassium-chloride transporter KCC2. Our data demonstrate a novel role for PGE2/EP4/cAMP pathway which culminates in a sustained depolarisation of sensory axons mediated by a chloride current through ANO1 channels. Therefore, using a microfluidic culture model, we provide evidence for a potential dual function of PGE2 in inflammatory pain: it sensitises depolarisation-evoked responses in nociceptive axons and directly triggers action potentials by activating ANO1 and Nav1.8 channels.

UNASSIGNED: The dietary fat hypothesis links increases in allergic diseases to reduced consumption of n-3 polyunsaturated fatty acids from fish, for example, eicosapentaenoic acid, and increased intake of n-6 polyunsaturated fatty acids from vegetable oils, for example, arachidonic acid.
UNASSIGNED: Building upon the \"fat hypothesis,\" we sought to investigate the association between 24 types of serum fatty acid levels in infants and the risk of subsequent food-induced anaphylaxis (FIA) by age 2 years as the primary outcome.
UNASSIGNED: This study was conducted as a prespecified supplemental analysis within the ABC randomized clinical trial. We measured levels of 24 fatty acids in residual serum samples collected from 268 infants at age 5 to 6 months using gas chromatography-mass spectrometry.
UNASSIGNED: Among the 258 infants, 58 exhibited immediate-type food allergies, whereas 200 showed no food allergy. Of the 58 infants, 12 were diagnosed with FIA, whereas the remaining 46 had nonanaphylactic food allergy. Unexpectedly, among the 24 fatty acids, only adrenic acid, also known as docosatetraenoic acid, which is one of the n-6 polyunsaturated fatty acids, showed significantly lower levels in infants with FIA (median [interquartile range] (wt.%), 0.16 [0.14-0.17]), compared with those with no food allergy (0.19 [0.17-0.21]) (P = .0007). In contrast, adrenic acid levels in infants with nonanaphylactic food allergy were 0.19 [0.16-0.21] (wt.%), which did not differ significantly from those in infants with no food allergy (P = .69).
UNASSIGNED: This study generated a hypothesis suggesting that infants with low serum adrenic acid levels might be at greater risk of subsequent FIA. This unexpected result warrants further investigation.

OBJECTIVE: The objective was to evaluate the periodontal clinicoradiographic status and whole salivary prostaglandin E2 (PgE2) levels among users of water pipe and cigarettes.
METHODS: Demographic data, duration of smoking (pack years), and familial history of smoking were recorded using a questionnaire. Participants were allocated into three groups based on their smoking status: group 1: self-reported cigarette smokers (CS); group 2: self-reported water-pipe-users; and group 3: non-smokers. The assessment included measurements of full-mouth plaque and gingival indices (PI and GI), as well as probing depth (PD), clinical attachment loss (CAL), and marginal bone loss (MBL). Unstimulated whole saliva samples were collected and PgE2 levels were measured. Group comparisons were done and p<0.05 was considered statistically significant.
RESULTS: Thirty-three, 34 and 33 individuals were included in groups 1, 2 and 3, respectively. Full mouth PI (p<0.05), GI (p<0.05), PD (p<0.05) and mesial (p<0.05) and distal (p<0.05) MBL were statistically significantly higher among patients in groups 1 and 2 than group 3. The scores of CAL in groups 1 and 2 were 3.45 ± 0.97 and 3.62 ± 1.2 mm, respectively. None of the individuals in the control group displayed CAL. PgE2 levels were statistically significantly higher among patients in groups 1 (231.5 ± 66.3 pg/ml) (p<0.05) and 2 (231.5 ± 66.3 pg/ml) (p<0.05) compared with group 3 (76.6 ± 10.6 pg/ml). In groups 1 and 2, a statistically significant relationship was observed between pack-years, the duration of water-pipe smoking, and the levels of PgE2 and PD.
CONCLUSIONS: There is no difference in periodontal clinicoradiographic status and whole salivary PgE2 levels between CS and waterpipe-users; however, these parameters are worse in CS and water-pipe users than in non-smokers.

Tumor-derived prostaglandin E2 (PGE2) impairs anti-tumor immunity by priming suppressive functions on various immune cell types, including dendritic cells (DCs). In this way, tumors mediate DC dysfunction and hamper their anti-tumoral activity. PGE2 is known to modulate DC function via signaling through the E-prostanoid receptor type (EP) 2 and EP4. Preclinical studies have demonstrated the therapeutic value of targeting EP2/4 receptor signaling in DCs. Ongoing phase I clinical trials with EP antagonists have shown immunomodulation in cancer patients. However, the systemic drug administration leads to off-target events and subsequent side-effects. To limit the off-target effects of EP targeting, EP2 and EP4 antagonists were encapsulated in polymeric nanoparticles (NPs). In this study we evaluated the efficacy of EP2/4 specific antagonists encapsulated in NPs to protect cDC2s from suppressive effects of tumor-derived PGE2 in different tumor models. We show that tumor-derived PGE2 signals via EP2/4 to mediate the acquisition of a suppressive phenotype of cDC2s. EP2/4 antagonists encapsulated NPs impaired the conversion of cDC2s towards a suppressive state and inhibited the occurrence of suppressive features such as IL-10 production or the ability to expand Tregs. Importantly, the NPs abolished the transition towards this suppressive state in different tumor models: Melanoma-conditioned media, ascites fluid derived from ovarian cancer patients (2D), and upon coculture with colorectal cancer patient-derived organoids (3D). We propose that targeting the PGE2-EP2/4 axis using NPs can achieve immunomodulation in the immune system of cancer patients, alleviate tumor-derived suppression, and thus facilitate the development of potent anti-tumor immunity in cancer patients.

OBJECTIVE: To study the role of PGE2 in regulating plasminogen activator inhibitor-1 (PAI-1) and tissue plasminogen activator (tPA) in human primary endometrial endothelial cells (HEECs) from women with normal menstrual bleeding (NMB) and heavy menstrual bleeding (HMB).
METHODS: In vitro study using endometrial endothelial cells.
METHODS: Research laboratory setting.
METHODS: Women with normal menstrual bleeding (NMB) and heavy menstrual bleeding (HMB) provided endometrial biopsy samples.
METHODS: PGE2 and PGE2 receptor-selective agonists were administered to cultured HEECs.
METHODS: Levels of PAI-1 and tPA in NMB-HEECs and HMB-HEECs after treatment with PGE2 and receptor-selective agonists.
RESULTS: PGE2 increased total PAI-1 levels in NMB-HEECs, but not in HMB-HEECs, which had higher baseline PAI-1 levels. PTGER1 and PTGER2 agonists increased PAI-1 in NMB-HEECs, while PTGER3 and PTGER4 did not. PGE2 had no effect on tPA levels in either NMB-HEECs or HMB-HEECs.
CONCLUSIONS: PGE2, through PTGER1 and PTGER2, regulates the plasminogen activator system in NMB-HEECs, suggesting a role in reducing fibrinolytic activity during normal menstrual cycles. The lack of PGE2 effect and elevated baseline PAI-1 in HMB-HEECs support using this in vitro model to further understand prostaglandin pathways in normal and heavy menstrual bleeding.

Despite the success of anti-programmed cell death-1 (anti-PD-1) immunotherapy, many cancer patients remain unresponsive, and reliable predictive biomarkers are lacking. Here, we show that aberrant expression of the pyrimidinergic receptor P2RY6 is frequent in human cancers and causes immune evasion. In mouse syngeneic and human xenograft tumor models, ectopic expression of P2RY6 shapes an immunosuppressive tumor microenvironment (TME) to enhance tumor growth and resistance to immunotherapy, whereas deletion of P2RY6 from tumors with high P2RY6 expression inflames the TME to inhibit tumor growth. As a G protein-coupled receptor, P2RY6 activates Gq/phospholipase C-β signaling and stimulates the synthesis of prostaglandin E2, which is a key mediator of immunosuppression in the TME. In contrast to the essential role of P2RY6 in tumors, global deletion of P2ry6 from mice does not compromise viability. Our study thus nominates P2RY6 as a precision immunotherapy target for patients with high tumor-intrinsic P2RY6 expression.