Prostaglandin Research Articles

In vitro and in vivo anti-inflammatory and antinociceptive activities of a synthetic hydrangenol derivative: 5-hydroxy-2-(4-hydroxyphenyl)-4H-chromen-4-one.

In the present study, we developed and synthesized novel hydrangenol derivatives and featured their anti-inflammatory activities. Especially, a synthetic derivative 11 (compound 11), which possesses the 4H-1-benzopyran-4-one moiety, 5-hydroxyl group in A-ring, and 4'-hydroxyl group in B-ring, most dominantly downregulated nitric oxide (NO) and prostaglandin E2 (PGE2) production in lipopolysaccharide (LPS)-induced RAW264.7 macrophages. In addition, compound 11 suppressed the inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and interleukin 6 (IL-6) expression by inhibiting nuclear factor kappa-B (NF-κB), activator protein 1 (AP-1), and signal transducer and activator of transcription protein (STAT) pathways in LPS-provoked RAW264.7 macrophages. Additionally, we confirmed that compound 11 had better plasma stability than hydrangenol with a plasma-labile δ-valerolactone moiety. In carrageenan-induced rats, compound 11 potently reduced paw inflammation (as measured by paw volume, width, and thickness) by inhibiting the iNOS and COX-2 expression in paw tissue, thereby reducing inflammatory pain. All things considered, as compound 11 shows anti-inflammatory and antinociceptive properties, converting metabolically unstable hydrangenol into a stable compound 11 could be a promising strategy for developing new drugs.

Eu-Doped TiO2 Coatings via One-Step In Situ Preparation Enhance Macrophage Polarization and Osseointegration of Implants.

The controllable regulation of immune and osteogenic processes plays a critical role in the modification of biocompatible materials for tissue regeneration. In this study, titanium dioxide-europium coatings (MAO/Eu) were prepared on the surface of a titanium alloy (Ti-6Al-4V) via a one-step process combining microarc oxidation (MAO) and in situ doping. The incorporation of Eu significantly improved the hydrophilic and mechanical properties of the TiO2 coatings without altering their morphology. The presence of Eu effectively stimulated calcium influx in macrophages and activated β-catenin through the wnt/β-catenin signaling pathway. Consequently, macrophage M2 polarization was accelerated through the overexpression of prostaglandin E2 (PGE2). Additionally, Ca2+ promoted the osteogenic differentiation of MC3T3-E1 cells through the synergistic upregulation of transcription factors (e.g., AP-1, BMP-2). In vivo studies demonstrated that MAO/Eu coatings significantly enhanced osseointegration compared with the titanium alloy group. Therefore, MAO/Eu shows promising potential as an ideal coating for implants that offers effective immunomodulatory strategies and improves bone integration.

Association of Urinary Prostaglandin E2 with Plasma Potassium in Patients with Chronic Kidney Disease and the General Population.

Association of Urinary Prostaglandin E2 with Plasma Potassium in Patients with Chronic Kidney Disease and the General Population.

NLRP3: a key regulator of skin wound healing and macrophage-fibroblast interactions in mice

Wound healing is a highly coordinated process driven by intricate molecular signaling and dynamic interactions between diverse cell types. Nod-like receptor pyrin domain-containing protein 3 (NLRP3) has been implicated in the regulation of inflammation and tissue repair; however, its specific role in skin wound healing remains unclear. This study highlights the pivotal role of NLRP3 in effective skin wound healing, as demonstrated by delayed wound closure and altered cellular and molecular responses in NLRP3-deficient (NLRP3−/−) mice. Histological analysis revealed impaired healing processes, accompanied by reduced expression of key inflammatory mediators, including interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and prostaglandin E2 (PGE2). Deficiencies in apoptosis were evident through altered expression of cysteine-aspartic acid protease 3 (Caspase-3), P53, and B-cell lymphoma-2 (Bcl-2). Furthermore, critical growth factors such as vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), and matrix metalloproteinase-9 (MMP-9) were significantly decreased at the excisional skin wound sites. Furthermore, using co-culture systems, we found that NLRP3 mediated the interaction between macrophages and myofibroblasts. Wild-type fibroblast-conditioned media (MFbCM) enhanced nitric oxide (NO), IL-6, and tumor necrosis factor-α (TNF-α) production in M1 macrophages and arginase activity, chitinase 3-like protein 1 (Ym1), and IL-10 expression in M2 macrophages, effects significantly diminished with NLRP3−/− MFbCM. Similarly, conditioned media from wild-type M1 or M2 macrophages promoted the expression of FGF-2, VEGF, and MMP-2 expression in myofibroblasts, which was attenuated when using NLRP3−/− macrophage-conditioned media. PGE2 levels were reduced in both NLRP3−/− macrophages and myofibroblasts. Supplementing NLRP3−/− conditioned media with PGE2 partially restored the impaired functions, suggesting that PGE2 acts as a downstream mediator of NLRP3-regulated macrophage-myofibroblast interactions. These findings indicate that NLRP3 is a key regulator of skin wound healing, facilitating macrophage-myofibroblast communication.

Persistent changes in the dorsal root ganglion nociceptor translatome governs hyperalgesic priming in mice: roles of GPR88 and Meteorin.

Hyperalgesic priming is a model system that has been widely used to understand plasticity in painful stimulus-detecting sensory neurons, called nociceptors. A key feature of this model system is that following priming, stimuli that do not normally cause hyperalgesia now readily provoke this state. We hypothesized that hyperalgesic priming occurs because of reorganization of translation of mRNA in nociceptors. To test this hypothesis, we used paclitaxel treatment as the priming stimulus and translating ribosome affinity purification to measure persistent changes in mRNA translation in Nav1.8+ nociceptors. Translating ribosome affinity purification sequencing revealed 161 genes with persistently altered mRNA translation in the primed state. Among these genes, we identified Gpr88 as upregulated and Metrn as downregulated. To provide functional evidence for these changes in hyperalgesic priming in a related priming model, we used the interleukin-6 priming model. A GPR88 agonist injection into the paw had no effect in naive mice but caused mechanical hypersensitivity and grimacing responses in female primed mice. Systemic Meteorin treatment in primed mice completely reversed established hyperalgesic priming mechanical hypersensitivity and grimacing responses to prostaglandin E2 in female mice. Our work demonstrates that altered nociceptor translatomes are causative in producing hyperalgesic priming in multiple models in female mice.

The liver’s dilemma: sensing real danger in a sea of PAMPs: the (arterial) sinusoidal segment theory

The liver is susceptible to viruses and bacterial infections, tumors, and sterile tissue damage, but immunological danger recognition in the liver is highly unconventional. When analyzing innate and adaptive immunity in the organ, the valid concepts that guide danger recognition and immune response in the periphery should be put aside. In the liver, the vascular anatomy is a game changer, as about 80% of the blood that percolates the organ arrives from the hepatic portal vein, draining blood rich in molecules from the intestinal flora. This 24/7 exposure to high amounts of pathogen-associated molecular pattern (PAMPs) molecules results in hepatic immunological tolerance. In the liver, dendritic, Kupffer (KC), liver sinusoidal endothelial cells (LSECs), and even hepatocytes express PD-L1, a T lymphocyte downregulatory molecule. Most cells express Fas-L, IL-10, TGF-β, low levels of co-stimulatory molecules, lack of or have low levels of MHC-I and/or MHC-II expression. Moreover, other negative regulators such as CTLA-4, IDO-1, and prostaglandin E2 (PGE2) are regularly expressed. Then, how can real danger be discerned and recognized in this sea of PAMPs? This is an open question. Here, we hypothesize that conventional immunological danger recognition can occur in the liver but in specific and minor arterial sinusoidal segments,. Then, in the portal triad, where the hepatic artery ramificates into the stroma and carries arterial blood with no gut-derived PAMPs, there is no evolutive or environmental pressure for immunosuppressive pathways, and conventional immunological danger recognition could occur. Therefore, in arterial sinusoidal segments with no sea of PAMPs, the liver could recognize real danger and support innate and adaptive immunity.

Effect of nalbuphine on analgesia and pain factors after gastric cancer resection.

Gastric cancer (GC) is a prevalent tumor in the digestive system, with around one million new cases reported annually, ranking it as the third most common malignancy. Reducing pain is a key research focus. This study evaluates the effect of nalbuphine on the analgesic effect and the expression of pain factors in patients after radical resection. To provide a reference for postoperative analgesia methods. One hundred eight patients with GC, admitted between January 2022 and June 2024, underwent radical gastrectomy. They received a controlled analgesia pump and a transverse abdominis muscle plane block, divided into two groups of 54 patients in each group. The control group received sufentanil, while the observation group received nalbuphine as an analgesic. Postoperative analgesic effects, pain factor expression, and adverse effects were compared. The resting pain and activity pain scores in the observation group at 6, 12, 24 and 48 hours were significantly lower than those in the control group. Additionally, the number of presses and consumption of the observation group at 48 hours were lower than those of the control group; and the response rate of the observation group was higher than that of the control group (P < 0.05). The prostaglandin E2, substance P, and serotonin levels 24 hours after the observation group were lower than those in the control group, and the incidence of adverse reactions was 5.56% lower than 22.22% in the control group (P < 0.05). The findings suggest that nalbuphine enhances postoperative multimodal analgesia in patients with radical GC, effectively improving postoperative analgesic effect, relieving postoperative resting and active pain, and reducing postoperative pain factor expression, demonstrating its potential for clinical application.

Pharmacological modulation of Sigma-1 receptor ameliorates pathological neuroinflammation in rats with diabetic neuropathic pain via the AKT/GSK-3β/NF-κB pathway.

Diabetic neuropathic pain (DNP) is a common complication of diabetes mellitus (DM) and is characterized by spontaneous pain and neuroinflammation. The Sigma-1 receptor (Sig-1R) has been proposed as a target for analgesic development. It is an important receptor with anti-inflammatory properties and has been found to regulate DNP. However, it is not known whether Sig-1R can ameliorate pathological neuroinflammation in DNP. The present study used a rat model of DNP and a highly selective agonist of Sig-1R to assess the effects of the protein on neuropathic pain in rats with type 2 diabetes mellitus. The rats were divided into Control, Model, Sig-1R agonist PRE-084 (0.3, 0.6, 1mg/kg), and metformin (Met, 20mg/kg) groups, with seven rats per group, and their body weight, fasting blood glucose, mechanical withdrawal threshold and thermal withdrawal latency were tested weekly for two weeks. After treatment with PRE-084, the pain thresholds in the DNP rats were significantly improved, together with pathological changes in the dorsal root ganglion, reductions in the serum levels of TNF-α, IL-1β, IL-6, MOD, and prostaglandin E2 (PGE2), and the activity of superoxide dismutase was increased. The mRNA levels of TNF-α, IL-1β, and cyclooxygenase 2 (COX-2) were reduced. Pharmacological inhibition of Sig-1R with BD1047 (10μM) abolished Sig-1R-mediated activation of lipopolysaccharide-treated BV-2 microglial cells. It was also found that PRE-084 increased phosphorylation of serine/threonine protein kinase B (AKT) and glycogen synthase kinase 3β (GSK-3β) at Ser9, inhibiting nuclear factor kappa B (NF-κB)-mediated neuroinflammation in the dorsal root ganglion, thus reducing DNP. The findings suggest that the effect of Sig-1R agonist PRE-084 on DNP may reduce the level of inflammation through the up-regulation of AKT/GSK-3β and down-regulation of the NF-κB signaling, thereby contributing to the treatment of the disease.

The role of cyclooxygenase-2 (COX-2) and inflammatory markers in the progress of Alport syndrome in Egyptian children

BackgroundChronic inflammation and its control are crucial to the responses of glomerular and renal tubular cells. This contributes to the pathogenic mechanisms and advancement of the disease in Alport syndrome. The study aimed to elucidate the role of cyclooxygenase-2, Interleukin 4, Plasminogen activating inhibitor 1, and Prostaglandin E2 in the development and course of Alport syndrome.MethodsIn our study inflammatory markers were evaluated in 26 Alport syndrome patients, 15 males and 11 females and 24 controls.ResultsTheir age ranged from 4 to 16 years (mean ± SD was 8.50 ± 2.877) and 24 were normal controls matching age and sex. The serum levels of cyclooxygenase-2, Prostaglandin E2, Interleukin 4, and Plasminogen activating inhibitor 1 were evaluated in all patients. The serum level of cyclooxygenase-2, Prostaglandin E2, Interleukin 4, and Plasminogen activating inhibitor 1 were all increased significantly in the Alport syndrome patients compared to control (588.68 ± 73.08, 42.57 ± 4.18, 42.32 ± 3.49, and 846.47 ± 45.433, respectively versus controls (369.12 ± 50.28, 25.52 ± 4.98, 28.89 ± 3.19, and 312.79 ± 40.53 respectively).ConclusionThe role of inflammatory markers cyclooxygenase-2, Prostaglandin E2, Interleukin 4, and Plasminogen activating inhibitor 1 in Alport syndrome that are causally connected and have a role in the development and course of Alport disease was delineated. This may highlight and speculate an innovative strategy for targeting the creation of safe and efficient anti-inflammatory treatments to inhibit disease progression in Alport syndrome.

Effects of Salmonella Typhimurium infection on intestinal flora and intestinal tissue arachidonic acid metabolism in Wenchang chickens

Salmonella infections can lead to intestinal inflammation and metabolic disorders in birds. However, whether arachidonic acid (ARA) metabolism is involved in Salmonella-induced intestinal inflammation remains unclear. This experiment investigated the changes in cecal flora and ARA metabolism in Hainan Wenchang chickens infected with S. Typhimurium using 16s rDNA sequencing and targeted metabolomics. The results showed that the levels of ARA metabolites were increased in the cecum tissue of Wenchang chickens after infection with S. Typhimurium, including prostaglandin E2 (PGE2), prostaglandin F2α (PGF2α), lipoxin A4 (LXA4), ± 8(9)-EET, ± 11(12)-EET, and ± 8,9-DiHETrE. The content of key enzymes for ARA production and metabolism (Phospholipase A2 PLA2 and Cyclooxygenase-2 COX-2) in chicken cecum tissues was increased after S. Typhimurium infection. The relative mRNA levels of inflammatory factors were also increased after infection, including Interferon-γ (IFN-γ), Transforming growth factor-β1 (TGF-β1), Interleukin-4 (IL-4), and Interleukin-6 (IL-6). In HD11 cells, the use of a cyclooxygenase (COX) inhibitor reduced the increased levels of COX-2 and PGF2α induced by S. Typhimurium infection and effectively reduced the inflammatory response. In addition, the number of beneficial genera (e.g., Bifidobacterium, Lactobacillus, and Odorobacterium) in the cecum of Wenchang chickens was significantly reduced after infection with S. Typhimurium. The present study revealed the structure of cecal flora in S. Typhimurium-infected Wenchang chickens. In addition, this study demonstrated that S. Typhimurium activates the ARA cyclooxygenase metabolic pathway, which in turn mediates the development of intestinal inflammation in Wenchang chickens. The results can provide data support and theoretical support for the prevention and control of avian salmonellosis.

Anti-arthritic Effects of Undifferentiated and Chondrogenic Differentiated MSCs in MIA-induced Osteoarthritis in Wistar Rats: Involvement of Oxidative Stress and Immune Modulation.

Osteoarthritis (OA) is a degenerative joint disease that can affect the many tissues of the joint. There are no officially recognized disease-modifying therapies for clinical use at this time probably due to a lack of complete comprehension of the pathogenesis of the disease. In recent years, emerging regenerative therapy and treatments with stem cells both undifferentiated and differentiated cells have gained much attention as they can efficiently promote tissue repair and regeneration. To determine how bone marrow-derived mesenchymal stem cells (BM-MSCs) and chondrogenic differentiated MSCs (CD-MSCs) can treat OA in rats, OA was induced in Wistar rats by injecting three doses of 100 μL physiological saline containing 1 mg of MIA into rat ankle joint of the right hind leg for three consecutive days. Following the induction, the osteoarthritic rats were injected weekly with BM-MSCs or CD-MSCs at a dose of 1x106 cells/rat/dose for three weeks. In addition to morphological and histological investigations of the ankle, spectrophotometric, ELISA, and Western blot analyses were applied to detect various immunological and molecular parameters in serum and ankle. The results of the study showed that in osteoarthritic rats, BM-MSCs and CD-MSCs significantly reduced right hind paw circumference, total leucocyte count (TLC), differential leukocyte count (DLC) of neutrophils, monocytes, lymphocytes, and eosinophils, serum rheumatoid factor (RF), prostaglandin E2 (PGE2) and interleukin (IL-) 1β levels, while they elevated serum IL-10 level. Additionally, BM-MSCs and CD-MSCs markedly reduced lipid peroxides (LPO) levels while they elevated superoxide dismutase (SOD) and glutathione-S-transferase (GST) activities. The monocyte chemoattractant protein-1 (MCP-1) level was significantly downregulated in ankle joint articular tissues by treatment with BM-MSCs or CD-MSCs while nuclear factor erythroid 2-related factor 2 (Nrf2) was upregulated; CD-MSCs treatment was more effective. According to these findings, it can be inferred that BM-MSCs and CD-MSCs have anti-arthritic potential in MIA-induced OA; CD-MSCs therapy is more effective than MSCs. The ameliorative anti-arthritic effects may be mediated by suppressing inflammation and oxidative stress through the downregulation of MCP-1 and upregulation of Nrf2. Based on the obtained results, BM-MSCs and CD-MSCs therapies are promising new options that can be associated with other clinical treatments to improve cartilage regeneration and joint healing. However, more preclinical and clinical research is required to assess the benefits and safety of treating osteoarthritic patients with BM-MSCs and CD-MSCs.

A Self-Amplifying Photodynamic Biomedicine for Cascade Immune Activation Against Triple-Negative Breast Cancer.

The efficacy of immunotherapy in triple-negative breast cancer (TNBC) is significantly hindered by its low immunogenicity and immunosuppressive tumor microenvironment. Non-invasive photodynamic therapy (PDT) is increasingly recognized as a potential immunotherapeutic stimulant in the treatment of TNBC. However, photodynamic immunotherapy is constrained by tumor hypoxia and excessive inflammation suppression during the course of treatment. Herein, a simple and efficacious biomedicine is formulated to overcome adverse influences by amplifying photodynamic immunotherapy, thereby stimulating the systemic immune response. Specifically, the approach targeted tumor delivery by employing specific agents such as the photosensitizer (verteporfin), the hypoxic ameliorator (atovaquone), and the cyclooxygenase-2/prostaglandin E2 (COX-2/PGE2) signaling blocker (celecoxib). More importantly, the biomedicine effectively ameliorated hypoxia and inhibited COX-2/PGE2 signaling, thereby amplifying PDT-induced immunogenic cell death. This, in turn, enhanced the efficacy of photodynamic immunotherapy and triggered a robust immune response cascade. Notably, the self-amplifying photodynamic biomedicine significantly inhibited primary tumors, distal tumors, lung metastases, and post-operative recurrence while maintaining high biocompatibility. To sum up, the work provides a viable cascade stimulation approach and an efficient biomedical nanoplatform, offering a novel strategy for photodynamic immunotherapy of TNBC in the clinic.

Platelet Function Assay Using Dielectric Blood Coagulometry.

The hemostatic function of platelets is complementary to blood coagulation. However, traditional platelet function tests have primarily focused on measuring platelet aggregation, reducing their clinical effectiveness for antiplatelet drug monitoring. To address this limitation, we propose a new test principle that evaluates platelet function and the effects of antiplatelet drugs through blood coagulation reactions. This principle was validated in model experimental systems using blood samples from healthy volunteers (n = 11), where antiplatelet drugs such as aspirin, prostaglandin E1, or ticagrelor were added to the blood samples. Ticagrelor was tested at four concentration levels, covering the expected therapeutic range. We found that the complementary function of platelets can be assessed by monitoring the 1 MHz dielectric permittivity during the blood coagulation process, particularly the peak value. When reagents such as agonists (arachidonic acid, collagen, or adenosine diphosphate ADP) and calcium were mixed into the citrated blood with turbulence by pipetting, platelets became activated and aggregated before thrombin generation, resulting in a "consumed" state of platelets. Consequently, the contribution to the permittivity peak was minimal. By contrast, when blood spiked with antiplatelet drugs was tested, agonist-induced platelet aggregation was inhibited during the initial stage of the measurement. However, after thrombin generation, platelets were activated through the thrombin receptor. These activated platelets interacted with fibrin, thereby affecting the permittivity peak. The results of this validation process with Student's t-tests confirm the fundamental operating principle of the proposed platelet function assay, thereby contributing to antiplatelet therapy monitoring.

Increasing matrix metalloproteinase-2 activity by treatment of ovine cervical explants with a long-acting analogue of oxytocin (Carbetocin) at the expected time of artificial insemination.

The aim was to study the effect of long-acting analogue of oxytocin (Carbetocin) on cervical collagenolysis of MAP-eCG synchronized ewes. At the expected time of artificial insemination, five ewes were slaughtered (n = 5) and their cervical explants (100-200mg) were incubated during 12h with MEM supplemented with 0, 8, 16, 32 and 64 ng/mL of Cb. Activities of activated and latent forms of matrix metalloproteinases-2 and - 9 (MMP-2 and MMP-9, respectively) in the supernatant were determined by a SDS-PAGE zymography and prostaglandin E2 concentration by immunoassay. Data were analyzed by ANOVA test. The MMP-9 activity was detected weakly and sporadically. The activity of activated MMP-2 was higher in 32 ng/mL Carbetocin treated samples than in untreated samples (P < 0.03). The activity of latent MMP-2 tended to be higher in 32 ng/mL than in 8 ng/mL Carbetocin treated samples (P = 0.083). The activated/latent ratio of MMP-2 tended to be higher in 64 ng/mL Cb treated samples than in untreated samples (P = 0.089). Prostagladin E2 concentration was not affected by Carbetocin dose. The data show that Carbetocin treatment of cervical explants induces an increase in MMP-2 activity by prostaglandin E2-independent mechanisms, suggesting Carbetocin as a potential inducer of cervical dilation in sheep.

Observational study on the effectiveness of misoprostol for induction of labour as a low-cost method in a tertiary care hospital in Sri Lanka

Labour induction is a critical obstetric intervention to ensure safe delivery for both mother and baby. In resource-limited settings like Sri Lanka, cost-effective methods for labour induction are essential. Misoprostol, a prostaglandin E1 analogue, has emerged as a promising option due to its affordability and effectiveness. This observational study investigates the efficacy of misoprostol for labour induction in a tertiary care hospital in Sri Lanka. By analysing real-world data, this research aims to provide insights into misoprostol’s efficacy, safety, and cost-effectiveness as an induction method in this setting, ultimately aiming to improve maternal and neonatal outcomes1.

SW033291 promotes liver regeneration after acetaminophen-induced liver injury in mice.

Acetaminophen (APAP) is a commonly utilized antipyretic and analgesic drug. Overdose of APAP is a primary contributor to drug-induced liver injury and acute liver failure (ALF). SW033291 has been shown to play a role in tissue regeneration in various diseases; however, its potential to facilitate liver regeneration following APAP-induced hepatic injury remains unexamined. Thus, this study focused on exploring the therapeutic impacts and mechanisms of SW033291 on liver damage by establishing models of APAP-induced acute liver injury in mice. The results showed that treatment with SW033291 reduces serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, decreases the area of hepatic necrosis, increases glutathione (GSH) levels, and decreases tissue malondialdehyde (MDA) content, as well as the expression levels of tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in mice with liver injury. It could also promote hepatocyte proliferation and inhibit apoptosis by increasing tissue prostaglandin E2 (PGE2) levels. In conclusion, SW033291 demonstrates the capacity to ameliorate APAP-induced hepatic injury in mice by fostering liver regeneration, attenuating oxidative stress, and modulating inflammatory responses, thereby presenting itself as a promising candidate for the development of therapeutic interventions targeting acute liver failure.

Janus Kinase 2/Signal Transducer and Activator of Transcription 3/Cyclooxygenase 2 Signaling Pathway Mediates the Effect of Central Angiotensin II on the Elevation of Rostral Ventrolateral Medulla Prostaglandin E2-Induced Oxidative Stress in Hypertension.

Prostaglandin E2 (PGE2) in the rostral ventrolateral medulla (RVLM) has been recognized as a pivotal pressor substance in hypertension, yet understanding of its effects and origins in the RVLM remains largely elusive. This study aimed to elucidate the pivotal enzymes and molecular mechanisms underlying PGE2 synthesis induced by central Ang II (angiotensin II) and its implications in the heightened oxidative stress and sympathetic outflow in hypertension. RVLM microinjections of PGE2 and Tempol were administered in Wistar-Kyoto rats. Intracisternal drug delivery and adeno-associated viral vectors microinjection were used in both Wistar-Kyoto rats and spontaneous hypertensive rats to modulate the function of Ang II, PGE2 receptor 3, and expression of COX2 (cyclooxygenase 2). Microinjection of PGE2 into the RVLM significantly augmented sympathetic activity (25.380±1.566%) and oxidative stress level, whereas intracisternal infusion of a prostaglandin E receptor 3 antagonist attenuated sympathetic activity in both spontaneous hypertensive rats and Ang II-induced hypertensive rats. Furthermore, Ang II treatment upregulated COX2 expression in RVLM neurons (1.000±0.112 versus 1.506±0.370 fold change), with no significant effect on other enzymes involved in PGE2 synthesis. Additionally, inhibition of the JAK2/STAT3 (Janus kinase 2/signal transducer and activator of transcription 3) signaling pathway nullified Ang II-mediated elevation of COX2 expression, as evidenced by phosphorylated STAT3 binding to the COX2 sequence in PC12 cells. Central Ang II induces the accumulation of RVLM PGE2 through the neuronal AT1R (angiotensin type 1 receptor)/JAK2/STAT3/COX2 pathway, thereby promoting oxidative stress, augmenting sympathetic outflow, and contributing to essential hypertension.

Investigating the antioxidant and anti-inflammatory potential of Nypa fruticans: a multifaceted approach to skin protection and aging

Reactive oxygen species (ROS) produced in the mitochondria of skin cells play a significant role in the degradation of the extracellular matrix and induction of inflammatory responses, both of which are major contributors to skin aging. Antioxidants that reduce ROS production and inhibit inflammatory skin lesions are considered beneficial for the treatment of inflammatory skin diseases and prevention of skin aging. In this study, we evaluated the potential of Nypa fruticans (NF), which is known for its antioxidant properties, to mitigate tumor necrosis factor-alpha (TNF-α)- and interferon-gamma (IFN-γ)-induced damage in normal human epidermal keratinocytes. The major active constituents identified in NF include protocatechuic acid, hydroxybenzoic acid, procyanidin B, catechin, and epicatechin. NF significantly suppressed the production of ROS, nitric oxide (NO), and prostaglandin E2 (PGE2), while also reducing the levels of inflammatory cytokines interleukin-6 (IL-6) and interleukin-1 beta (IL-1β), which were elevated by TNF-α/IFN-γ stimulation. Furthermore, NF restored the expression of key skin barrier-related proteins such as serine peptidase inhibitor kazal type 5 (SPINK5), collagen type I alpha 1 chain (COLIA1), loricrin (LOR), aquaporin-3 (AQP3), and filaggrin (FLG). Additionally, NF significantly upregulated the expression of hyaluronan synthase (HAS) -1 and − 2 and human β-defensin (HBD) -2 and − 3, which are important for skin hydration and innate immune defense. These findings underscore the potential therapeutic applications of Nypa fruticans (NF) in mitigating oxidative stress, inflammation, skin barrier dysfunction, dehydration, and microbial imbalances. By targeting multiple pathways implicated in skin aging, NF represents a promising comprehensive approach for preserving skin health and addressing age-related dermatological conditions. Moreover, NF holds significant potential not only to alleviate the manifestations of skin aging but also to provide a basis for the development of innovative dermatological therapies. Future investigations should aim to further elucidate the clinical applications of NF in dermatology to maximize its therapeutic benefits.

Protein kinase A suppresses anti-proliferative effect of interferon-α in hepatocellular carcinoma by activation of protein tyrosine phosphatase SHP2.

Src homology-2-containing protein tyrosine phosphatase 2 (SHP2) plays a dual role in cancer initiation and progression. Identifying signals that modulate the function of SHP2 can improve current therapeutic approaches for IFN-α/β in HCC. We showed that cAMP-dependent protein kinase A (PKA) suppresses IFN-α/β-induced JAK/STAT signaling by increasing the phosphatase activity of SHP2, promoting the dissociation of SHP2 from the receptor for activated C-kinase 1 (RACK1) and binding to STAT1. Additionally, cAMP-degrading phosphodiesterase 4D5 (PDE4D) physically interacts with RACK1 to regulate PKA-mediated SHP2 activity and STAT1 phosphorylation. IFN-α activates PKA by inducing the expression of cyclooxygenase 2 (COX2) and the production of prostaglandin E2 (PGE2), which in turn stimulates the binding of SHP2 to IFNAR2 via RACK1. A COX inhibitor aspirin potently increases the antitumor effects of IFN-α in the suppression of HCC cell proliferation in vivo. Higher expression of COX2 and phosphorylated STAT3 is associated with poor development and prognosis in HCC patients by analyzing human HCC clinical samples. These observations suggest that a fundamental PKA/SHP2-dependent negative feedback loop acts on IFN signaling, and inhibition of this signaling by the selective COX2 inhibitors may enhance the clinical efficacy of type I IFNs in treating HCC.

Coordinated regulation of eosinophil production and migration by glucocorticoids, prostaglandins, and cysteinyl-leukotrienes.

The spectrum of eosinophil functions has expanded from fighting helminths to multiple novel roles in malignancy, infection, cancer, and metabolism. In asthma, glucocorticoids, prostaglandins (PG), and cysteinyl-leukotrienes (LT) regulate eosinophil biology through separate signaling pathways. Here we've evaluated the complex interplay between Dexa, PGE2, and CysLTs in eosinopoiesis and eosinophil biology in an allergic asthma model. We used different inbred mouse strains to probe the interactions between these agents in eosinophil differentiation and maturation in bone marrow culture. Flow cytometry and histological analyses evaluated eosinophil precursor proliferation, maturation, and VLA-4 expression. The in vivo function of eosinophils was assessed by their in vivo migration into allergen-challenged sites. Eosinophil production in IL-5-stimulated bone marrow cultures is enhanced by dexamethasone but suppressed by PGE2, which triggers eosinophil apoptosis via inducible NO synthase (iNOS). Dexamethasone-primed cultures contain mostly immature eosinophils; by contrast, dexamethasone associated with PGE2 leads to the production of mature eosinophils (without inducing eosinophil apoptosis), by a mechanism independent of iNOS. Interaction between dexamethasone and LTD4 in culture produces mostly mature eosinophils expressing VLA-4, capable of migration into the lungs in ovalbumin-sensitized and -challenged mice. The combination of dexamethasone and either PGE2 or LTD4 - both mediators of allergic inflammation - supports the maturation of eosinophils (overcoming the maturation blockade observed with dexamethasone alone), which are functional in an in vivo model of asthma.