Inducible Prostaglandin Research Articles

NRP1 antagonism as a novel therapeutic target in nasal polyps of patients with chronic rhinosinusitis.

Neuropilin-1 (NRP1) is expressed on the surface epithelium of respiratory tract and immune cells, demonstrating its possible function in regulating the immune response in airway disease. However, its role in patient with chronic rhinosinusitis (CRS) remains unknown. This study aimed to elucidate the role of NRP1 in CRS with nasal polyps (CRSwNP). Sinonasal biopsy specimens were immunohistochemically stained to investigate NRP1 expression. Double immunofluorescence, immunoblotting, and real-time polymerase chain reaction were performed to evaluate NRP1 in primary human nasal epithelial cells (hNECs). An NRP1 inhibitor was administered to a murine nasal polyp (NP) model. NRP1 was highly expressed in the epithelium in patients with CRSwNP compared to nasal tissue from controls and CRS without NP patients. NRP1 and vascular endothelial growth factor were upregulated in hNECs under hypoxia. Treatment with NRP1 inhibitor (EG00229) reduced the secretion of interleukin (IL)-1β, IL-6, IL-8, and IL-33 cytokines, as well as inducible nitric oxide synthase, cyclooxygenase-2, and prostaglandin E2 in hNECs. We found that NRP1 was highly expressed in the airway epithelium in the murine NP model. The group treated with the NRP1 inhibitor had significantly fewer nasal polypoid lesions and reduced accumulations of immune cells. These findings reveal that NRP1 is upregulated in CRS and NP epithelium, and the inhibition of NRP1 may lead to a reduction in NP growth and immune cell infiltration. Our results suggest that NRP1 inhibition could be a novel possibility for treating nasal polyposis.

Unwinding the Threads of Mesoporous Silica Nanoparticles as Cutting-Edge for the Management of Inflammation: An Updated Review.

Inflammation serves as a protective response to combat cellular and tissue damage. There is currently a wide array of synthetic and traditional therapies available for the treatment of inflammatory diseases. However, it is necessary to create a drug delivery system based on nanotechnology that can improve the solubility, permeability, and bioavailability of current treatments. Mesoporous silica nanoparticles (MSNPs) are inorganic materials known for their organised porous interiors, high pore volumes, substantial surface area, exceptional selectivity, permeability, low refractive index, and customisable pore sizes. This review offers concise insights into the progression of the pathophysiology of inflammation, as well as the inducers, mediators, and effectors that are involved in the inflammatory pathway. This study focuses on the growing significance of MSNPs in the treatment of neuroinflammation, inflammatory bowel disease, arthritic inflammation, lung inflammation, and wound healing applications. This review also presents the latest information on the crucial role of MSNPs in delivering herbal medicines for the treatment of inflammation. A comprehensive literature search was conducted for this aim, utilising the Google Scholar, PubMed, and ScienceDirect databases. A systematic review was undertaken utilising scholarly articles published in peer-reviewed journals from 2000 to 2024. The inflammatory mediators involved in the pathophysiology of inflammation include platelet-activating factor, lipoxygenase, cyclooxygenase, Interferon-α, interleukin-6, interleukin- 1β, matrix metalloproteinases, inducible nitric oxide synthase, nuclear factor-κB, prostaglandins, nitric oxide, and phospholipase A2. MSNPs have the potential to be used in the treatment of neuroinflammation, inflammatory bowel disease, arthritic inflammation, lung inflammation, and wound healing. The investigation of the MSNPs of plant-based compounds such as berberine, tetrahydrocannabinol, curcumin, and resveratrol has shown successful results in recent years for the purpose of managing inflammation. This review demonstrates that MSNPs have a strong potential to play a positive role in delivering synthetic and plant-based therapies for the treatment of inflammatory illnesses.

Anticancer and anti-inflammatory effects of novel ethyl pyrazole derivatives having sulfonamide terminal moiety

In the present work, a new series of ethyl pyrazole-containing compounds with side sulphonamide moiety was designed and synthesized. The new derivatives were divided into four groups based on the linker between the sulphonamide and pyridine ring attached to position 4 of the pyrazole ring and the substitution on the phenyl ring at position 3 of the same ring. The linker could be ethyl or propyl linkers. The phenyl ring is substituted with a methoxy group or hydroxyl group at position 3. The aim compounds were tested for their JNK1, JNK2, JNK3, and BRAF(V600E) activities. Compounds 23b, 23c, and 23d showed the highest activity with nanomolar IC50s. The most potent compound over JNK1 was 23d with an IC502 nM. While compound 23c was the most potent over JNK2 with an IC5057 nM. Finally, compound 23b was the most potent over JNK2 and BRAF(V600E) with IC50s of125 nM and 98 nM, respectively. After obtaining kinase inhibitory activity, the compounds were submitted to NCI to test their activity over different cell lines. Compound 23b showed the highest activity over most tested cell lines. In the second part of the present study, the final target compounds were tested for their anti-inflammatory effect. The anti-inflammatory effect of the new final compounds was performed by measuring their ability to inhibit inducible nitric oxide release and prostaglandin E2 production inhibition. Compound 23c showed the highest activity regarding nitric oxide release with IC50 0.63 μM, while compound 21d had the highest activity regarding prostaglandin E2 production with IC50 0.52 μM. The effect of the most potent compounds was tested by western blot against iNOS, COX-1, and COX-2.

Akt, IL-4, and STAT Proteins Play Distinct Roles in Prostaglandin Production in Human Follicular Dendritic Cell-like Cells.

This study aimed to explore the role of Akt protein in the induction and inhibition of prostaglandin (PG) in human follicular dendritic cell (FDC)-like cells. FDC-like cells and B cells were isolated from human tonsils. PG production was assessed using enzyme immunoassay, while the upstream cyclooxygenase-2 (COX-2) protein levels were measured using immunoblotting with FDC-like cells transfected with Akt siRNA to analyze the impact of Akt knockdown. The COX-2 expression and PG production induced with IL-1β were significantly increased by Akt knockdown. However, IL-1β did not significantly alter either total or phosphorylated Akt protein levels. Akt knockdown resulted in the augmentation of COX-2 expression induced by B cells, although the addition of B cells did not significantly modulate both total and phosphorylated Akt proteins. In contrast, IL-4 specifically exhibited a potent inhibitory effect on COX-2 protein induction and PG production via STAT6. The inhibitory activity of IL-4 was not hampered by Akt knockdown. Interestingly, COX-2 expression levels induced with IL-1β were markedly modulated with STAT1 and STAT3 knockdown. STAT1 silencing resulted in further augmentation of COX-2, whereas STAT3 silencing prohibited IL-1β from stimulating COX-2 expression. The current results suggest that Akt, IL-4, and STAT1 play inhibitory roles in PG production in FDC-like cells and expand our knowledge of the immune inflammatory milieu.

Arctium lappa root extract based emulgels attenuate inducible cytokines and prostaglandins formation: Potential in the management of chronic inflammatory disorders

BackgroundChronic inflammation contributes significantly to the burden suffered in many disease conditions in Africa with modern treatments often inaccessible to many. Phytotherapy presents a useful way to accelerate access to Universal health coverage with minimal incurred costs. The study was aimed at exploring the in vitro anti-inflammatory action and formulation of Arctium lappa root, a plant grown and available in different regions in Africa, as an herbal emulgel for the management of chronic inflammation MethodsMethanol root extract of Arctium lappa (0.25, 0.50 and 1.00 % w/w) was used for pre-formulation analysis. Phytochemical screening of the extract was done using the Harborne's standardized method for phytochemical analyses. In vitro anti-inflammatory activity was studied by evaluating inhibitory actions of the extracts on Prostaglandin-E (PGE), tumour necrotic factor-α (TNF-α) and cyclooxygenase II (COX-2) using Enzyme-Linked Immunosorbent Assay. Post formulation, the percentage inhibition of the pro-inflammatory cytokines by the herbal emulgels were compared with commercial diclofenac emulgel. The physicochemical properties of the herbal emulgels were also determined. ResultsThe preliminary qualitative phytochemical analysis of Arctium lappa root extract gave tannins, saponins, phenolics, steroids, glycosides, flavonoids, anthocyanin, terpenoids, and alkaloids as its contents. The extract's inhibitory activities on PGE-2, COX-2 and TNF-α were dose dependent. The formulated herbal emulgel showed that the activities of PGE-2, COX-2 and TNF-α were significantly inhibited in comparison with vehicle-treated control. The physical appearance (which reflected the concentration gradient of the Arctium lappa root extract in the emulgels), consistency and homogeneity of the emulgels were acceptable and spreadable. The pH and viscosity of the emulgels were from 4.97 ± 0.04 to 5.42 ± 0.05 and 3.36 ± 0.40 and 3.95 ± 0.50 Pas, respectively. ConclusionHere, the emulgel of Arctium lappa root extract showed promising anti-inflammatory property evidenced in its ability to attenuate PGE-2, COX-2 and TNF-α activities in-vitro, which was similar to the effect of diclofenac (a currently used anti-inflammatory agent of synthetic origin). This study is novel, important and of great impact because it provides a useful indication of Arctium lappa as a topical agent in the management of chronic inflammatory disorders. As compared to previous studies, key advances in this research include the first successful attempt to formulate the root extract of Arctium lappa into an emulgel, advancing the application of pharmaceutics in phytotherapy for prospects of improved treatment of inflammation, especially in Africa; and this can be adapted globally beyond the region.

Attenuation of CFA-induced chronic inflammation by a bicyclic monoterpene fenchone targeting inducible nitric oxide, prostaglandins, C-reactive protein and urea.

Fenchone (a bicyclic monoterpene) is present in the essential oils of plant species like Foeniculum vulgare and Peumus boldus and is used to treat GIT disorders. Research reports have indicated its strong anti-inflammatory, antioxidant, and anti-nociceptive properties. The present study was designed to investigate fenchone's anti-arthritic effects in a rat model of chronic joint inflammation (Complete Freud's Adjuvant-mediated inflammation [CFA]). Molecular docking analysis revealed a high binding interaction of fenchone with inducible nitric oxide synthase (iNOS), Interleukin-17, Prostaglandin E Receptor EP4, and Cycloxygenase-2 (COX-2), indicating its anti-inflammatory efficacy using computational tests. Fenchone treatment at 100mg/kg, 200mg/kg, and 400mg/kg significantly enhanced the tail-flick latency when compared with the solvent-treated group. Correspondingly, the raised mRNA values of iNOS, IL-17, IL-1β, IL-6, TNF-α, and COX-2 in solvent-treated group were significantly reduced following treatment with fenchone. Moreover, fenchone significantly lowered spleen and thymus indices, Nitric oxide (NO) and PGE2 values as compared to solvent-treated group. Hence, the results of the present study indicated that fenchone has a potent anti-inflammatory effect by inhibiting pro-inflammatory markers and thus may have therapeutic potential for chronic joint inflammation as well as chronic inflammatory disorders.

Influence of hormonal induction of estrus and/or ovulation on embryo transfer success

The recipient mare is one of the most important elements in an equine embryo transfer program. Mare selection at the time of transfer is based on a number of established criteria such as uterine and cervical tone, absence of endometrial oedema after ovulation and the presence and morphology of the corpus luteum. However, recent studies suggest that other factors, such as estrus duration, have a favorable influence on pregnancy rates. The aim of the study was to determine if the pregnancy rate in recipient mares was influenced by estrous length, induction of estrus with prostaglandin F2alpha and/or induction of ovulation with hCG. Retrospective data from a commercial embryo transfer program in Northern Germany, was analyzed. A total of 1051 embryos were transferred into 880 recipient mares (2-24 years of age) during 2021. Recipient mares were evaluated ultrasonographically daily, from first signs of estrus until ovulation was detected. For the analysis of estrus length, mares were classified according to the number of days that edema was detected ultrasonographically into the following groups: short (1-3 days), medium (4-6 days) and long (7-9 days) estrus. Estrus was induced in 852 (81.06%) and ovulation was induced in 676 (64.31%) cycles. Overall pregnancy rate at day15 post-ovulation was 76.21% (801/1051). Spontaneous estrus had a lower pregnancy rate (70.85%) compared to estrus induced by prostaglandins (77.46%) (p=0.052). Nonetheless, there were no significant differences in embryo transfer success between spontaneous (79.2%) and hCG-induced (74.55%) ovulation (p=0.096). The duration of estrus had no influence on pregnancy rates when evaluating the 1051 embryo transfers. However, when evaluating each estrus length group individually, in the medium and long estrus groups there was a significant effect of ovulation induction on pregnancy rates (p=0.007, p=0.042 medium and long estrus, respectively), suggesting that hCG-induction reduced the success rate vs spontaneous ovulations (71.99% vs 84.05%) in medium length estrus, while increasing pregnancy rate in the long length group (80.85% vs 60.71%). These data suggest that the importance of estrus length on successful embryo transfer rate may be associated with factors such as estrogen exposure and ovulation. In long estrus cycles, ovulation induction may be beneficial in preventing lack of ovulation or estrogen overstimulation. However, a minimum duration of estrogen exposure is necessary to optimize gestation rates. Further studies are needed to evaluate the possible causes of these effects.

The inducible prostaglandin E synthase (mPGES-1) in neuroinflammatory disorders.

The cyclooxygenase (COX)/prostaglandin E2 (PGE2) signaling pathway has emerged as a critical target for anti-inflammatory therapeutic development in neurological diseases. However, medical use of COX inhibitors in the treatment of various neurological disorders has been limited due to well-documented cardiovascular and cerebrovascular complications. It has been widely proposed that modulation of downstream microsomal prostaglandin E synthase-1 (mPGES-1) enzyme may provide more specificity for inhibiting PGE2-elicited neuroinflammation. Heightened levels of mPGES-1 have been detected in a variety of brain diseases such as epilepsy, stroke, glioma, and neurodegenerative diseases. Subsequently, elevated levels of PGE2, the enzymatic product of mPGES-1, have been demonstrated to modulate a multitude of deleterious effects. In epilepsy, PGE2 participates in retrograde signaling to augment glutamate release at the synapse leading to neuronal death. The excitotoxic demise of neurons incites the activation of microglia, which can become overactive upon further stimulation by PGE2. A selective mPGES-1 inhibitor was able to reduce gliosis and the expression of proinflammatory cytokines in the hippocampus following status epilepticus. A similar mechanism has also been observed in stroke, where the overactivation of microglia by PGE2 upregulated the expression and secretion of proinflammatory cytokines. This intense activation of neuroinflammatory processes triggered the secondary injury commonly observed in stroke, and blockade of mPGES-1 reduced infarction size and edema, suppressed induction of proinflammatory cytokines, and improved post-stroke well-being and cognition. Furthermore, elevated levels of PGE2 have been shown to intensify the proliferation of glioma cells, mediate P-glycoprotein expression at the blood-brain barrier (BBB) and facilitate breakdown of the BBB. For these reasons, targeting mPGES-1, the central and inducible enzyme of the COX cascade, may provide a more specific therapeutic strategy for treating neuroinflammatory diseases.

Outpatient balloon catheter vs inpatient prostaglandin for induction of labor: a randomized trial

Approximately 1 in 4 pregnant women undergo induction of labor. Meta-analyses have shown that mechanical methods of induction of labor are safe and effective, as is starting induction in an outpatient setting. However, few studies have evaluated outpatient balloon catheter induction in comparison with pharmacologic methods. This study aimed to determine whether women who underwent outpatient induction of labor with a balloon catheter would have a lower cesarean delivery rate than women who underwent inpatient induction of labor with vaginal prostaglandin E2 without an increase in adverse maternal or neonatal events. This was a superiority randomized controlled trial. The eligibility criteria were pregnant women (nullipara and multipara) with a live singleton fetus in vertex presentation with any medical comorbidity who underwent planned induction of labor at term and who had an initial modified Bishop Score of 0 to 6 at 1 of 11 public maternity hospitals in New Zealand. The intervention groups were outpatient single balloon catheter induction in comparison with inpatient vaginal prostaglandin E2 induction. The primary hypothesis was that participants who started their induction at home with a balloon catheter would have a lower risk for cesarean delivery than participants who started their induction with prostaglandins and remained in hospital throughout. The primary outcome was cesarean delivery rate. Participants were randomized using a centralized secure online randomization website in a 1:1 ratio, stratified by parity and hospital. The participants and outcome assessors were not blinded to group allocation. An intention-to-treat analysis with adjustment for stratification variables was used. A total of 539 participants were randomized to outpatient balloon catheter induction, and 548 participants were randomized to inpatient prostaglandin induction; the mode of birth was reported for all participants. The cesarean delivery rate was 41.0% among participants allocated to outpatient balloon induction and 35.2% among those allocated to inpatient prostaglandin induction (adjusted odds ratio, 1.27; 95% confidence interval, 0.98-1.65). Women in the outpatient balloon catheter group were more likely to have artificial rupture of membranes and to received oxytocin and an epidural. No differences were found in the rates of adverse maternal or neonatal events. Outpatient balloon catheter induction was not found to reduce the cesarean delivery rate when compared with inpatient vaginal prostaglandin E2 induction. However, the use of balloon catheters in an outpatient setting does not seem to increase the rate of adverse events for mothers or babies and can be offered routinely.

7α,25-Dihydroxycholesterol-Induced Oxiapoptophagic Chondrocyte Death via the Modulation of p53-Akt-mTOR Axis in Osteoarthritis Pathogenesis.

This study aimed to exploring the pathophysiological mechanism of 7α,25-dihydroxycholesterol (7α,25-DHC) in osteoarthritis (OA) pathogenesis. 7α,25-DHC accelerated the proteoglycan loss in ex vivo organ-cultured articular cartilage explant. It was mediated by the decreasing extracellular matrix major components, including aggrecan and type II collagen, and the increasing expression and activation of degenerative enzymes, including matrix metalloproteinase (MMP)-3 and -13, in chondrocytes cultured with 7α,25-DHC. Furthermore, 7α,25-DHC promoted caspase dependent chondrocytes death via extrinsic and intrinsic pathways of apoptosis. Moreover, 7α,25-DHC upregulated the expression of inflammatory factors, including inducible nitric oxide synthase, cyclooxygenase-2, nitric oxide, and prostaglandin E2, via the production of reactive oxygen species via increase of oxidative stress in chondrocytes. In addition, 7α,25-DHC upregulated the expression of autophagy biomarker, including beclin-1 and microtubule-associated protein 1A/1B-light chain 3 via the modulation of p53-Akt-mTOR axis in chondrocytes. The expression of CYP7B1, caspase-3, and beclin-1 was elevated in the degenerative articular cartilage of mouse knee joint with OA. Taken together, our findings suggest that 7α,25-DHC is a pathophysiological risk factor of OA pathogenesis that is mediated a chondrocytes death via oxiapoptophagy, which is a mixed mode of apoptosis, oxidative stress, and autophagy.

Comparison of Labour Induction between Intracervical PGE2 Gel and Intravaginal PGE1 Analogue Tablet among Patients with Intra Uterine Foetal Death- A Cross-Sectional Study

Introduction: In spite of modern medical advancement, there is some significant pregnancy loss during antepartum period. In majority of cases labour soon follows death of the foetus, but sometimes labour does not start for several weeks. So induction of labour is needed but the unfavourable cervix remains a well-recognized impediment to success of induction of labour in intrauterine foetal death. Prostaglandins in different Seems in different routes have been widely investigated to be used for induction of labour particularly when the cervix is unripe. Both Prostaglandin E1, and Prostaglandin E2 have been proved effective equally. Dinoprostone (PGE2), has been widely used for cervical ripening and labour induction. Misoprostol, a methyl ester of prostaglandin analogue, has been shown to be effective for cervical ripening and labour induction. Aim of the study: The aim of this study was to compare the effectiveness of vaginal misoprostol (PGE1 tablet) and prostaglandin (PGE2 gel) in order to induce labour among patients with intrauterine foetal death. Methods: This was a cross-sectional study and was conducted in the Department of Obstetrics and Gynaecology of Dhaka Medical College Hospital, Dhaka, Bangladesh during the period from July, 2004 to June, 2005. In our study we included 70 patients who were given and during labour induction. Our patients were equally divided into two groups – i) Group A (Patients were given Per- vaginal prostaglandin tablet) & ii) Group B (Patients were given Intra-cervical prostaglandin gel). Result: In total 70 patients from both the groups completed the study. In our study we found the mean age was 23.94±4.19 and 24.46±2.44 years in group A and group B respectively and the mean induction to onset of labour time was less in prostaglandin E2 group (5.97±3.75) hours, than in prostaglandin E1 group (8.24±3.19) hour but induction to delivery interval time was not significantly different in most of the patients in both groups. With a .......

Virtual screening, molecular simulations and bioassays: Discovering novel microsomal prostaglandin E Synthase-1 (mPGES-1) inhibitors

Microsomal prostaglandin E synthase-1 (mPGES-1) is an inducible prostaglandin E synthase expressed following exposure to pro-inflammatory stimuli. The mPGES-1 enzyme represents a new target for the therapeutic treatment of acute and chronic inflammatory disorders and cancer. In the present study, compounds from the ZINC15 database with an indole scaffold were docked at the mPGES-1 binding site using Glide (high-throughput virtual screening [HTVS], standard precision [SP] and extra precision [XP]), and the stabilities of the complexes were determined by molecular simulation studies. Following HTVS, the top 10% compounds were retained and further screened by SP. Again, the top 10% of these compounds were retained. Finally, the Glide XP scores of the compounds were determined, 20% were analyzed, and the Prime MM-GBSA total free binding energies of the compounds were calculated. The molecular simulations (100 ns) of the reference ligand, LVJ, and the two best-scoring compounds were performed with the Desmond program to analyze the dynamics of the target protein-ligand complexes. In human lung cells treated with the hit compounds, cell viability by colorimetric method and PGE2 levels by immunoassay method were determined. These in vitro experiments demonstrated that the two indole-containing hit compounds are potential novel inhibitors of mPGES-1 and are, therefore, potential therapeutic agents for cancer/inflammation therapies. Moreover, the compounds are promising lead mPGES-1 inhibitors for novel molecule design.

Prostaglandin production in brain endothelial cells during the initiation of fever

ABSTRACT The initiation of fever has been a matter of controversy. Based on observations of little or no induction of prostaglandin synthesizing enzymes in the brain during the first phase of fever it was suggested that fever is initiated by prostaglandin released into the circulation from cells in the liver and lungs. Here we show in the mouse that prostaglandin synthesis is rapidly induced in the brain after immune challenge. These data are consistent with our recent findings in functional experiments that prostaglandin production in brain endothelial cells is both necessary and sufficient for the generation of all phases of fever.

Maternal and perinatal outcomes of failed prostaglandin induction of labour: A retrospective cohort study

BackgroundInduction of labor is performed in up to 25% of pregnant women. When the cervix is unfavorable, cervical ripening may be safely and effectively performed using slow-release vaginal inserts of prostaglandin E2. However, the risk factors, management, and outcome of patients who fail to respond remain unclear. ObjectiveTo evaluate the outcomes of women who fail to respond to cervical ripening with prostaglandins. MethodsA retrospective cohort analysis (2013–2019) was conducted. Women with a singleton gestation who underwent induction of labor due to post-date pregnancy using a slow-release prostaglandin E2 vaginal insert for cervical ripening were included. Data on clinical and outcome factors were derived from the medical files, and findings were compared between patients who achieved ripening within 24 h of treatment onset and those who did not. The primary outcome measure was the vaginal delivery rate following the ripening process. Secondary outcome measures were adverse composite maternal and neonatal outcomes. A model combining maternal characteristics and response rates to ripening was constructed. ResultsThe final cohort included 1285 women: 1202 responded to cervical ripening (93.54%) and 83 (6.46%) did not. Compared to non-responders, responders had higher rates of vaginal delivery (96.51% vs. 66.27%, P < 0.001); lower rates of adverse maternal composite outcome (12.81% vs. 24.10%, P = 0.031) and adverse neonatal composite respiratory outcome (1.33% vs. 6.02%, P = 0.009). Responders were younger than non-responders (mean 30.03 years vs 31.73 years, P = 0.005) and had a lower nulliparity rate (50.99% vs 76.92%, P < 0.001). On multivariate analysis, failure to achieve cervical ripening was an independent risk factor for intrapartum cesarean delivery due to prolonged labor (aOR 11.90, 95% CI 6.13–23.25). ConclusionWomen who achieve cervical ripening with prostaglandin E2 vaginal inserts are younger and more often multiparous than women who fail to respond. Good response to the cervical ripening process is associated with lower rates of intrapartum cesarean delivery and of adverse outcomes.

The PTGS2/COX2-PGE2 signaling cascade in inflammation: Pro or anti? A case study with type 1 diabetes mellitus.

Prostaglandins are lipid mediators involved in physiological processes, such as constriction or dilation of blood vessels, but also pathophysiological processes, which include inflammation, pain and fever. They are produced by almost all cell types in the organism by activation of Prostaglandin endoperoxide synthases/Cyclooxygenases. The inducible Prostaglandin Endoperoxide Synthase 2/Cyclooxygenase 2 (PTGS2/COX2) plays an important role in pathologies associated with inflammatory signaling. The main product derived from PTGS2/COX2 expression and activation is Prostaglandin E2 (PGE2), which promotes a wide variety of tissue-specific effects, pending environmental inputs. One of the major sources of PGE2 are infiltrating inflammatory cells - the production of this molecule increases drastically in damaged tissues. Immune infiltration is a hallmark of type 1 diabetes mellitus, a multifactorial disease that leads to autoimmune-mediated pancreatic beta cell destruction. Controversial effects for the PTGS2/COX2-PGE2 signaling cascade in pancreatic islet cells subjected to diabetogenic conditions have been reported, allocating PGE2 as both, cause and consequence of inflammation. Herein, we review the main effects of this molecular pathway in a tissue-specific manner, with a special emphasis on beta cell mass protection/destruction and its potential role in the prevention or development of T1DM. We also discuss strategies to target this pathway for future therapies.

Zhuanggu Guanjie herbal formula mitigates osteoarthritis via the NF-κB transduction mechanism.

The Zhuanggu Guanjie herbal formula has been a famous Chinese prescription for treating bone diseases since time immemorial. The anti-osteoarthritis (OA) properties of this botanical prescription are well documented in the Chinese Pharmacopoeia. However, the detailed mechanisms behind the phenomenon have not been elucidated. Hence, we aimed to investigate the anti-OA efficacy of the Zhuanggu Guanjie herbal formula and its underlying mechanism. The anti-OA properties of Zhuanggu Guanjie capsule (ZGC) were determined by the cytokine contents and inflammatory-related proteins, which were measured by RT-PCR, flow cytometry, Western blot, and laser confocal assay in ATDC5 cells. The levels of interleukin-6, tumor necrosis factor-α, inducible nitric oxide synthase, cyclooxygenase-2, and prostaglandin synthesis E2 have been markedly reduced after being treated with ZGC for 48h in a dose-dependent manner. Furthermore, ZGC prevented the translocation of NF-κB from the cytosol to the nucleus. On the other hand, we used the mono-iodoacetate (MIA)-induced OA model to confirm the in vivo efficacies of this herbal formula. Oral administration of ZGC attenuated MIA-induced OA damage through changes in histopathological and knee joint volumes. The serum matrix metalloproteinase-13 contents in the ZGC treatment group declined as compared to those in the MIA model group. Through our in vitro and in vivo studies, we confirmed the anti-OA efficacy of ZGC and uncovered its detailed mechanism, and this treatment shed light on OA pathophysiology.

Tumor-Induced T Cell Polarization by Schwann Cells.

Nerve-cancer crosstalk resulting in either tumor neurogenesis or intratumoral neurodegeneration is critically controlled by Schwann cells, the principal glial cells of the peripheral nervous system. Though the direct stimulating effect of Schwann cells on malignant cell proliferation, motility, epithelial-mesenchymal transition, and the formation of metastases have been intensively investigated, the ability of Schwann cells to affect the effector and regulatory immune cells in the tumor environment is significantly less studied. Here, we demonstrated that tumor cells could stimulate Schwann cells to produce high levels of prostaglandin E, which could be blocked by COX-2 inhibitors. This effect was mediated by tumor-derived TGF-β as neutralization of this cytokine in the tumor-conditioned medium completely blocked the inducible prostaglandin E production by Schwann cells. Similar protective effects were also induced by the Schwann cell pretreatment with TGF-βR1/ALK4/5/7 and MAPK/ERK kinase inhibitors of the canonical and non-canonical TGF-β signaling pathways, respectively. Furthermore, prostaglandin E derived from tumor-activated Schwann cells blocked the proliferation of CD3/CD28-activated T cells and upregulated the expression of CD73 and PD-1 on both CD4+ and CD8+ T cells, suggesting T cell polarization to the exhausted phenotype. This new pathway of tumor-induced T cell inhibition via the activation of neuroglial cells represents new evidence of the importance of nerve-cancer crosstalk in controlling tumor development and progression. A better understanding of the tumor-neuro-immune axis supports the development of efficient targets for harnessing this axis and improving the efficacy of cancer therapy.

Balloon catheters versus vaginal prostaglandins for labour induction (CPI Collaborative): an individual participant data meta-analysis of randomised controlled trials

Induction of labour is one of the most common obstetric interventions globally. Balloon catheters and vaginal prostaglandins are widely used to ripen the cervix in labour induction. We aimed to compare the effectiveness and safety profiles of these two induction methods. We did an individual participant data meta-analysis comparing balloon catheters and vaginal prostaglandins for cervical ripening before labour induction. We systematically identified published and unpublished randomised controlled trials that completed data collection between March 19, 2019, and May 1, 2021, by searching the Cochrane Library, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, and PubMed. Further trials done before March 19, 2019, were identified through a recent Cochrane review. Data relating to the combined use of the two methods were not included, only data from women with a viable, singleton pregnancy were analysed, and no exclusion was made based on parity or membrane status. We contacted authors of individuals trials and participant-level data were harmonised and recoded according to predefined definitions of variables. Risk of bias was assessed with the ROB2 tool. The primary outcomes were caesarean delivery, indication for caesarean delivery, a composite adverse perinatal outcome, and a composite adverse maternal outcome. We followed the intention-to-treat principle for the main analysis. The primary meta-analysis used two-stage random-effects models and the sensitivity analysis used one-stage mixed models. All models were adjusted for maternal age and parity. This meta-analysis is registered with PROSPERO (CRD42020179924). Individual participant data were available from 12 studies with a total of 5460 participants. Balloon catheters, compared with vaginal prostaglandins, did not lead to a significantly different rate of caesarean delivery (12 trials, 5414 women; crude incidence 27·0%; adjusted OR [aOR] 1·09, 95% CI 0·95-1·24; I2=0%), caesarean delivery for failure to progress (11 trials, 4601 women; aOR 1·20, 95% CI 0·91-1·58; I2=39%), or caesarean delivery for fetal distress (10 trials, 4441 women; aOR 0·86, 95% CI 0·71-1·04; I2=0%). The composite adverse perinatal outcome was lower in women who were allocated to balloon catheters than in those allocated to vaginal prostaglandins (ten trials, 4452 neonates, crude incidence 13·6%; aOR 0·80, 95% CI 0·70-0·92; I2=0%). There was no significant difference in the composite adverse maternal outcome (ten trials, 4326 women, crude incidence 22·7%; aOR 1·02, 95% CI 0·89-1·18; I2=0%). In induction of labour, balloon catheters and vaginal prostaglandins have comparable caesarean delivery rates and maternal safety profiles, but balloon catheters lead to fewer adverse perinatal events. Australian National Health and Medical Research Council and Monash Health Emerging Researcher Fellowship.

Time Matters: A Swedish Cohort Study of Labor Duration and Risk of Uterine Rupture

(Acta Obstet Gynecol Scand. 2021;100:1902–1909) In medium- to high-resource settings, a previous cesarean delivery (CD) is the main risk factor for uterine rupture, which is associated with maternal and neonatal morbidity and mortality. Induction of labor and augmentation of labor with oxytocin are both modifiable risk factors but are also common in patients who do not experience uterine rupture. One risk factor that could potentially help identify patients at risk of uterine rupture is slower progression in labor. This study aimed to examine the relationship between duration of labor and uterine rupture in the first trial of labor after one CD. The study also aimed to evaluate risk factors such as induction and use of prostaglandins, oxytocin, and epidural analgesia.

The neuroprotective effect of a novel 1,4‐Dihydroquinazolin‐3(2H)‐yl benzamide derivative against chronic constriction injury‐induced neuropathic pain in rats

BackgroundNeuropathic pain (NP) is a severe, chronic inflammatory condition affecting both the central and peripheral nervous systems and is resistant to standard treatment. Nonsteroidal anti‐inflammatory drugs (NSAIDs) are commonly used to treat NP, but they are not the best option due to their limited penetration of the blood‐brain barrier and the gastrointestinal side effects associated with long‐term use. We recently reported a new series of benzamide derivatives that inhibit cyclooxygenase 2 (COX2) with comparable selectivity to celecoxib and tolerable side effects. Among these derivatives, 4‐chloro‐N‐(2‐(4‐chlorophenyl)‐1‐methyl‐4‐oxo‐1,4‐dihydroquinazolin‐3(2H)‐yl)benzamide (4b) demonstrated potent anti‐inflammatory and analgesic properties, as well as 32‐fold greater CNS accessibility than celecoxib. We aim to investigate the anti‐inflammatory and anti‐nociceptive effects of 4b against NP utilizing chronic constriction injury (CCI) model of neuropathy, elucidating the molecular mechanisms involved in its effect on both the peripheral (sciatic nerve) and central (brainstem) levels.MethodsThe CCI was performed unilaterally in male Wistar rats (275–300 g, n=5/group) given 4b (5 and 10 mg/kg, p.o), the standard drug for NP pregabalin (30 mg/kg, p.o), or vehicle for 14 days. Pain‐related behaviors, including mechanical and thermal hyperalgesia, were performed prior to and on days 7 and 14 post‐surgery. Sciatic nerve and brainstem oxidative stress [NADPH oxidase2 (NOX2) and catalase] and inflammatory [inducible nitric oxide synthase (iNOS), prostaglandin E2 (PGE2), COX2, and 5‐lipoxygenase] markers were detected by ELISA. Myelin sheath integrity was assessed in paraformaldehyde‐fixed sciatic nerve sections (4μm) stained with osmic acid, and the ratios of myelinated to total nerve area were calculated using ImageJ software.Immunohistochemistry was used to detect the expression of the microglial marker CD68 and the astrocyte marker GFAP as indicators of glial cell activation in the brainstem.ResultsCCI rats had increased mechanical and thermal hypersensitivity, which peaked 14 days post‐surgery. Compared to sham‐operated controls, CCI‐rats had significantly higher levels of sciatic nerve and brainstem inflammatory (3‐8‐fold, p&lt;0.05) and oxidative stress (7‐10‐fold higher NOX2) markers, but lower catalase levels (sciatic nerve: 26.60 ± 4.15 vs. 203.08 ± 16.4 mU/mg protein, and brainstem: 25.90 ± 2.56 vs. 216.40 ± 7.50 mU/mg protein). 4b mitigated pain behaviors, indicating a strong central analgesic effect. Furthermore, all biochemical measurements were dose‐dependently attenuated in the 4b‐treated groups. CCI‐induced increases in microglial cell infiltration (CD68 expression) and astrocyte activation (GFAP expression) were attenuated in 4b‐treated CCI‐rats. Osmic acid stain of the sciatic nerve revealed that 4b administration restored the normal nerve architecture and integrity that had been lost due to CCI. Excitingly, 4b (10 mg/kg) was superior to pregabalin in terms of behavioral, biochemical, and structural effects.Conclusion and significanceOur data show that the novel compound tested has potent peripheral and central analgesic and anti‐inflammatory properties, highlighting the potential of its use as a promising therapeutic approach for treating NP.