Prostaglandin Inhibition Research Articles

Protective role of M3 muscarinic acetylcholine receptor in indomethacin-induced small intestinal injury.

EP4 prostanoid receptor (EP4R) contributes to the intestinal epithelial Cl- secretion, and inhibition of prostaglandin E (PGE) production by non-steroidal anti-inflammatory drugs (NSAIDs) plays a central role in NSAID-induced enteropathy. Although M3 muscarinic acetylcholine receptor (M3R) also contributes to the intestinal epithelial Cl- secretion, it remains unclear whether M3R is involved in NSAID-induced enteropathy due to a lack of selective agents. The present study explored how M3R is involved in the regulation of the intestinal epithelial Cl- secretion and its pathophysiological role in NSAID-induced enteropathy. Using the novel highly-selective M3 positive allosteric modulator PAM-369 that we recently developed, we evaluated the role of M3R in the intestinal epithelial secretion ex vivo by measuring the short circuit current (Isc) of intestinal epithelium with a Ussing chamber system and examined whether or not M3R protects against small intestinal injury in indomethacin-treated mice. Both the PGE1 derivative misoprostol and carbachol similarly increased the Isc in a concentration-dependent manner. The Isc increases were abolished either by receptor antagonists (an EP4R antagonist and a M3R antagonist, respectively) or by removal of extracellular Cl-. PAM-369 enhanced the carbachol-induced Isc by potentiating M3R, which could contribute to enhanced intestinal epithelial secretion. Treatment with PAM-369 ameliorated small intestinal injury in indomethacin-treated mice. Importantly, the M3R expression was significantly up-regulated, and PAM-369 potentiation of M3R was augmented in indomethacin-treated mice compared to untreated mice. These findings show that M3R plays a role in maintaining the intestinal epithelial secretion, which could contribute to protection against indomethacin-induced small intestinal injury. M3R is a promising target for treating or preventing NSAID-induced enteropathy. KEY MESSAGES: PAM-369, the M3 positive allosteric modulator, was used to potentiate M3R. PAM-369 enhanced carbachol-induced Isc in mouse ileum. PAM-369 ameliorated small intestinal injury in indomethacin-treated mice. M3R is a promising target for treating or preventing NSAID-induced enteropathy.

Label-free detection of prostaglandin transporter (SLCO2A1) function and inhibition: insights by wound healing and TRACT assays.

The prostaglandin transporter (PGT, SLCO2A1) mediates transport of prostanoids (a.o. prostaglandin E2 (PGE2)) into cells and thereby promotes their degradation. Overexpression of PGT leads to low extracellular PGE2 levels and has been linked to impaired wound healing of diabetic foot ulcers. Inhibition of PGT could thus be beneficial, however, no PGT inhibitors are currently on the market and drug discovery efforts are hampered by lack of high-through screening assays for this transporter. Here we report on a label-free impedance-based assay for PGT that measures transport activity through receptor activation (TRACT) utilizing prostaglandin E2 receptor subtype EP3 and EP4 that are activated by PGE2. We found that induction of PGT expression on HEK293-JumpIn-SLCO2A1 cells that also express EP3 and EP4 leads to an over 10-fold reduction in agonistic potency of PGE2. PGE2 potency could be recovered upon inhibition of PGT-mediated PGE2 uptake with PGT inhibitors olmesartan and T26A, the potency of which could be established as well. Moreover, the TRACT assay enabled the assessment of transport function of PGT natural variants. Lastly, HUVEC cells endogenously expressing prostanoid receptors and PGT were exploited to study wound healing properties of PGE2 and T26A in real-time using a novel impedance-based scratch-induced wound healing assay. These novel impedance-based assays will advance PGT drug discovery efforts and pave the way for the development of PGT-based therapies.

Abstract 3133: Selective Vulnerability Of Coronary Arteries To Hypercholesterolemia And Angiotensin II-induced Hypertension

Hypercholesterolemia and hypertension are major risk factors for cardiovascular disease. We aimed to determine their concomitant effects on coronary atherogenesis. An SR-BI (an HDL receptor) suppression and doxycycline-inducible angiotensin II (AngII) cassette was inserted downstream of the ApoE promoter to ablate ApoE expression and overproduce AngII. The resulting mutants (ApoE SA/SA ) exhibited mild coronary atherosclerosis after Western diet feeding. Doxycycline induced AngII-induced hypertension and drastically accelerated coronary atherosclerosis, with lesions exhibiting endothelial erosion, myeloid cell infiltration, and plaque rupture, resulting in myocardial infarction, heart failure, and male-propensity of sudden death. AngII, but not norepinephrine-induced hypertension, led to severe coronary atherogenesis under hypercholesterolemia, which was abolished by losartan. Notably, norepinephrine constricted femoral arteries, but it dilated coronary arteries. In contrast to coronary arteries, femoral arteries did not develop atherosclerosis. Proteomic analyses revealed distinctive differences between the two vascular beds. Coronary vasodilation to acetylcholine was highly susceptible to the risk factors, compared to femoral artery, and was markedly attenuated by AngII exposure and prostaglandin inhibition. Interestingly, coronary prostaglandin synthesis was suppressed in atherogenesis, and elevated coronary capacity to produce prostaglandins following methotrexate administration was associated with ameliorated early coronary endothelial dysfunction and improved cardiovascular survival, featuring markedly reduced lesional myeloid cells. Coronary arteries from patients with hypertension and hypercholesterolemia showed substantially impaired endothelium-dependent vasodilation, compared to internal mammary arteries of similar risk exposure, whereas their endothelium-independent vasodilation was intact. Thus, the combination of hypercholesterolemia and AngII-induced hypertension drastically promoted coronary atherosclerosis with spontaneous lesion rupture, which confers a selective vulnerability of coronary vasodilation to prostaglandin inhibition and AngII exposure.

Exploring Phytotherapy's Preventive and Therapeutic Impact on Global COVID-19 Management: A Narrative Review

Introduction:: The WHO Emergency Committee advocates preventive strategies for COVID-19 management, emphasising vaccines as highly effective but acknowledging their limitations. Chloroquine and hydroxychloroquine, initially effective against COVID-19, were discontinued due to severe side effects. Further clinical trials are imperative to establish the safety and efficacy of new antiviral agents, some of which may have harmful effects on human development. Objectives:: The shortcomings of various conventional treatments have prompted urgent efforts to discover safe, natural compounds that may be useful in combating COVID-19. This study aims to review research that has investigated the potential of traditional phytotherapies used by different populations for the prevention and symptomatic treatment of COVID-19 infection. Methods:: This paper reviewed scientific studies published through searching on search engines such as PubMed, Scopus, Google Scholar, ScienceDirect and Elsevier from May until October 2023. Results:: The preventive and anti-COVID-19 attributes of Traditional Chinese Medicine, Ayurvedic formulations and African medicinal plants have been substantiated in research. In Nepal, recommendations endorse the utilisation of medicinal plants for herbal teas and homemade sanitizers. Zingiber officinale, Curcuma longa L. and Curcuma xanthorriza Roxb., along with Camellia sinensis are crucial Indonesian medicinal plants with potential for treating COVID-19. Z. officinale was predominantly chosen for relieving coughs and sore throats associated with COVID-19 in Saudi Arabia. Discussion:: The immunomodulatory properties of medicinal plants, which may prove useful in combating COVID-19, have been verified via elevation of the level of peripheral WBCs, IgM, IgG; inhibition of leukotrienes and prostaglandins, maintenance of the integrity of intestinal mucosal barrier and regulation of HMGB1. The antiviral effects of herbs, including the inhibition of viral DNA and RNA replication, down-regulation of oxidative stress, and the impediment of SARS-CoV-2 access to vascular endothelial cells, suggest their potential to facilitate earlier recovery from COVID-19 infection. Conclusion:: Advancing scientific research in phytotherapy promises the possibility of novel approaches for effectively managing future infectious diseases and pandemics.

Polmacoxib: A Review of the Newer Non-steroidal Anti-inflammatory Drug in Osteoarthritis.

Osteoarthritis represents a huge socioeconomic burden and has a significant impact on daily life and productivity. Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in the management of osteoarthritis to curbinflammation, pain, and stiffness and improve physical function. However, due to the various side effects, most healthcare professionals avoid using NSAIDs for a long period. Nonselective cyclooxygenase (COX) inhibitors and cyclooxygenase-1 (COX-1) inhibitors are associated with increased gastrointestinal adverse effects due to the inhibition of prostaglandins, which are responsible for protecting the gastric mucosa. Cyclooxygenase-2 (COX-2) inhibitors are associated with an increased incidence of adverse cardiovascular effects due to their COX-2 inhibitory activity in the circulatory system. Therefore, there is a need for a newer NSAID that has a better safety profile to be used in osteoarthritis. Polmacoxib is a new, orally active, first-in-class NSAID that is a dual inhibitor of COX-2 and carbonic anhydrase (CA). The dual mode of action exhibited by polmacoxib is expected to minimize adverse cardiovascular effects while achieving maximum effectiveness in inflamed osteoarthritic joints. This article aims toreview the pharmacological properties, clinical efficacy, and safety data of polmacoxib in osteoarthritis.

Excessive hypercholesterolemia in pregnancy impairs rat uterine artery function via activation of Toll-like receptor 4.

Hypercholesterolemia in pregnancy is a physiological process required for normal fetal development. In contrast, excessive pregnancy-specific hypercholesterolemia increases the risk of complications, such as preeclampsia. However, the underlying mechanisms are unclear. Toll-like receptor 4 (TLR4) is a membrane receptor modulated by high cholesterol levels, leading to endothelial dysfunction; but whether excessive hypercholesterolemia in pregnancy activates TLR4 is not known. We hypothesized that a high cholesterol diet (HCD) during pregnancy increases TLR4 activity in uterine arteries, leading to uterine artery dysfunction. Sprague Dawley rats were fed a control diet (n=12) or HCD (n=12) during pregnancy (gestational day 6-20). Vascular function was assessed in main uterine arteries using wire myography (vasodilation to methacholine and vasoconstriction to phenylephrine; with and without inhibitors for mechanistic pathways) and pressure myography (biomechanical properties). Exposure to a HCD during pregnancy increased maternal blood pressure, induced proteinuria, and reduced the fetal-to-placental weight ratio for both sexes. Excessive hypercholesterolemia in pregnancy also impaired vasodilation to methacholine in uterine arteries, whereby at higher doses, methacholine caused vasoconstriction instead of vasodilation in only the HCD group, which was prevented by inhibition of TLR4 or prostaglandin H synthase 1. Endothelial nitric oxide synthase expression and nitric oxide levels were reduced in HCD compared with control dams. Vasoconstriction to phenylephrine and biomechanical properties were similar between groups. In summary, excessive hypercholesterolemia in pregnancy impairs uterine artery function, with TLR4 activation as a key mechanism. Thus, TLR4 may be a target for therapy development to prevent adverse perinatal outcomes in complicated pregnancies.

Hispidulin targets PTGS2 to improve cyclophosphamide-induced cystitis by suppressing NLRP3 inflammasome.

Interstitial cystitis (IC) is a chronic bladder inflammation. Inhibition of prostaglandin G/H synthase 2 (PTGS2) is the most common method for controlling inflammation-related diseases. This study aimed to analyze the effects of hispidulin on the PTGS2 and NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammation in experimental IC models. A binding activity between hispidulin and PTGS2 was measured using molecular docking. Human urothelial cells (SV-HUC-1) were stimulated by 2ng/mL of interleukin (IL)-1β for 24h and cultured in a medium with different concentrations of hispidulin (2.5, 5, 10, 20µM) for 24h to observe the expressions of PTGS2 and NLRP3 protein. Cells overexpressing PTGS2 were established by PTGS2 cDNA transfection. In the IL-1β-treated cells, the NLRP3 inflammasome was measured after 20µM hispidulin treatment. In rats, animals were performed with three injections of 40mg/kg cyclophosphamide (CYP) and orally treated with 50mg/kg/day hispidulin or ibuprofen for 3days. The bladder pain was measured using Von Frey filaments, and the bladder pathology was observed using hematoxylin and eosin (H&E) staining. The expressions of PTGS2 and NLRP3 inflammasome were also observed in the bladder tissues. A good binding activity was found between hispidulin and PTGS2 (score = - 8.9kcal/mol). The levels of PTGS2 and NLRP3 inflammasome were decreased with the hispidulin dose increase in the IL-1β-treated cells (p < 0.05). Cells overexpressing PTGS2 weakened the protective effects of hispidulin in the IL-1β-treated cells (p < 0.01). In the CYP-treated rats, hispidulin treatment improved the bladder pain through decreasing the nociceptive score (p < 0.01) and suppressed the bladder inflammation through suppressing the expressions of PTGS2 and NLRP3 inflammasome in bladder tissues (p < 0.01). Additionally, the results of ibuprofen treatment were similar to the effects of hispidulin in the CYP-treated rats. This study demonstrates that hispidulin may be a new alternative drug for the IC treatment that binds PTGS2 to perform its functions.

A phase 2 trial investigating the efficacy and safety of the mPGES-1 inhibitor vipoglanstat in systemic sclerosis-related Raynaud's.

Our objective was to test the hypothesis, in a double-blind, placebo-controlled study that vipoglanstat, an inhibitor of microsomal prostaglandin E synthase-1 (mPGES-1) which decreases prostaglandin E2 (PGE2) and increases prostacyclin biosynthesis, improves RP. Patients with systemic sclerosis (SSc) and ≥7 RP attacks during the last screening week prior to a baseline visit were randomised to four weeks treatment with vipoglanstat 120 mg or placebo. A daily electronic diary captured RP attacks (duration and pain) and Raynaud's Condition Score, with change in RP attacks/week as primary end point. Cold challenge assessments were performed at baseline and end of treatment. Exploratory endpoints included patients' and physicians' global impression of change, Assessment of Scleroderma-associated Raynaud's Phenomenon questionnaire, mPGES-1 activity, and urinary excretion of arachidonic acid metabolites. Sixty-nine subjects received vipoglanstat (n = 33) or placebo (n = 36). Mean weekly number of RP attacks (baseline; vipoglanstat 14.4[SD 6.7], placebo 18.2[12.6]) decreased by 3.4[95% CI -5.8;-1.0] and 4.2[-6.5;-2.0] attacks per week (p= 0.628) respectively. All patient reported outcomes improved, with no difference between the groups. Mean change in recovery of peripheral blood flow after cold challenge did not differ between the study groups. Vipoglanstat fully inhibited mPGES-1, resulting in 57% reduction of PGE2 and 50% increase of prostacyclin metabolites in urine. Vipoglanstat was safe and well tolerated. Although vipoglanstat was safe, and well tolerated in a dose achieving full inhibition of mPGES-1, it was ineffective in SSc-related RP. Further development and evaluation of vipoglanstat will therefore be in other diseases where mPGES-1 plays a pathogenetic role.

Prodrug Approach: NSAID Conjugates of Platinum Compounds as Anti-Cancer Agents

Prodrug based synthetic approach is a very promising area of research to enhance the pharmaco–kinetic and pharmaco-dynamic properties of the drugs with the remarkable reduction of the side effects. Prodrug can be used for drugs which are having poor solubility, poor transport properties, production of chronic side effects thus this approach provides a powerful tool for novel drug conjugate with improved therapeutic value. Platinum based anti-neoplastic agents are widely used in chemotherapeutic regimen but the side effects like hepatotoxicity, ototoxicity, cardiotoxicity, nausea and vomiting, diarrhea, mucositis, stomatitis, pain, alopecia, anorexia, cachexia, cytopenias and asthenia were reported. So the development of prodrugs by using platinum compounds and Non-steroidal anti-inflammatory drugs showed better therapeutic value with the reduction of side effects. Non-steroidal anti-inflammatory drugs are broad class of drugs showed Analgesic, Anti–inflammatory and Anti-pyretic activities based on the mechanism of cyclooxygenase (cox-1 and cox-2) enzyme inhibition and formation of prostaglandins. Also Non-steroidal anti-inflammatory drugs have different targets to elicit various pharmacological actions and are beneficial for many other diseases. The different targets are nuclear factor kappa B(NF-Κb), Peroxisome proliferator-activated receptors(PPAR), Mammalian target of rapamycin(mTOR), Autophagy, Cytochrome c, NSAID activated gene (NAG-1), Angiogenesis, Resolvins, Protectins, Maresins. This review focused on the development of platinum prodrugs by conjugating with different NSAIDs and the therapeutic applications of the developed novel molecules including dual action and triple action prodrugs. This review discussed the different aspects of prodrug based approach, Detail mechanism and other molecular targets of NSAIDs and the development of the platinum compounds –NSAID prodrugs.

CS585 Demonstrates Favorable Selectivity and Sustained In Vivo Action in Preventing Platelet Activation and Thrombosis Compared to Existing IP Receptor Agonists

Anti-platelet therapeutics are common tools in the treatment of thrombotic diseases, decreasing morbidity and mortality resulting from cardiovascular complications. However, many patients remain at risk for a cardiovascular event while others experience bleeding due to hemostatic dysregulation. The need for target specificity and lasting stability presents a major challenge in the development of novel antithrombotic therapeutics. While increasing platelet cAMP levels through activation of the prostacyclin (IP) receptor is a viable therapeutic approach, the IP receptor is currently considered a challenging target due to the non-selectivity and instability of existing IP agonists. Our lab has developed a novel IV and orally available IP receptor agonist, CS585, with selectivity towards the IP receptor and sustained in vivo protection from injury-induced thrombosis without observed bleeding. CS585 demonstrates IP receptor-dependent activity, leading to activation of protein kinase A (PKA), a key player in inhibitory signaling. While indications of current IP receptor agonists are limited to pulmonary arterial hypertension and temporary relief of peripheral artery disease, CS585 presents a new approach to selectively regulate platelet activation and thrombosis. CS585 and other IP receptor agonists, iloprost and selexipag, were assessed by direct comparison to elucidate potential differences in selectivity and sustained action. Selectivity was determined using aggregation and VASP phosphorylation. The effects of CS585 are inhibited by pharmacological inhibition of the IP receptor, but not by inhibition of the DP1, EP2, or EP4 prostaglandin receptors. Meanwhile, the activities of iloprost and selexipag were affected by other prostaglandin inhibitors, supporting the improved selectivity toward activation of the IP receptor with CS585. Arterial thrombosis was measured and quantified in a laser-induced cremaster thrombosis assay in IP agonist-treated WT mice to assess platelet activation and thrombus formation in vivo in mouse models of thrombosis. In WT mice treated with CS585, we observed sustained effects of CS585 following both IV and oral administration. Platelets and fibrin were labeled and accumulation at the site of injury was measured using intravital microscopy. In contrast to the FDA-approved IP receptor agonists (iloprost and selexipag) which showed short-term protection from thrombosis, treatment with CS585 resulted in sustained inhibition of clot and fibrin formation at the site of injury in the same model between 24 and 48 hours post-administration. To determine if the anti-thrombotic effects of CS585 impact coagulation, coagulation parameters were assessed in whole blood using thromboelastography (TEG). Treatment with CS585 did not impact coagulation parameters in whole blood, while a significant increase in lysis was observed with iloprost. Here, we show for the first time a head-to-head comparison of CS585, a novel IP receptor agonist, with selexipag and iloprost. Our preclinical results with CS585 indicate a favorable profile for inhibiting platelet activation and clot formation and demonstrate a sustained duration of action in mice in the ability of CS585 to inhibit platelet activation through multiple routes of administration. Importantly, CS585 does not affect coagulation parameters and previous studies demonstrated no potential for increased bleeding in mouse models. Overall, CS585 provides a new option of activating the IP receptor to decrease platelet reactivity and could represent the first viable option for targeting the IP receptor on platelets for primary inhibition of thrombosis with a reduced risk of bleeding.

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.

The crucial role that hippocampus Cyclooxygenase-2 plays in memory.

It is generally accepted that Cyclooxygenase-2 (COX-2) is activated to cause inflammation. However, COX-2 is also constitutively expressed at the postsynaptic dendrites and excitatory terminals of the cortical and spinal cord neurons. Although some evidence suggests that COX-2 release during neuronal signalling may be pivotal for regulating the function of memory, the significance of constitutively expressed COX-2 in neuron is still unclear. This research aims to discover the role of COX-2 in memory beyond neuroinflammation and to determine whether the inhibition of COX-2 can cause cognitive dysfunction by influencing dendritic plasticity and its underlying mechanism. We found COX-2 gene knockout (KO) could significantly impact the learning and memory ability, cause neuronal structure disorder and influence gamma oscillations. These might be mediated by the inhibition of prostaglandin (PG) E2/cAMP pathway and phosphorylated protein kinase A (p-PKA)-phosphorylated cAMP response element binding protein (p-CREB)-brain derived neurotrophic factor (BDNF) axis. It suggested COX-2 might play a critical role in learning, regulating neuronal structure and gamma oscillations in the hippocampus CA1 by regulating COX-2/BDNF signalling pathway.

Chromatin remodeling of prostaglandin signaling in smooth muscle enables mouse embryo passage through the female reproductive tract.

Early mammalian development occurs during embryo transit of the female reproductive tract. Transport is orchestrated by secreted oviduct fluid, unidirectional beating of epithelial cilia, and smooth muscle contractions. Using gene-edited mice, we document that conditional disruption of a component of the SWI/SNF chromatin remodeling complex in smooth muscle cells prevents transport through the oviduct without perturbing embryogenesis. Analysis with RNA sequencing (RNA-seq), transposase-accessible chromatin with sequencing (ATAC-seq), chromatin immunocleavage sequencing (ChIC-seq), and pharmacologic rescue experiments implicated prostaglandin signaling pathways. In comparison with controls, gene-edited mice had compromised chromatin accessibility at enhancer/promoters of Ptgs2, Pla2g16, Pla2r1, and Ptger3 (EP3) as well as decreased enhancer-promoter interactive looping critical for Ptgs2 (aka Cox-2) expression in a SWI/SNF complex-dependent manner. Treatment of wild-type mice with prostaglandin inhibitors phenocopied the genetically induced defect.

Comparing Current Therapeutic Modalities of Androgenic Alopecia: A Literature Review of Clinical Trials.

Androgenic alopecia (AGA), commonly known as male pattern baldness (MPB), is a hereditary condition characterized by hair follicles that are sensitive to androgens. This article focuses on examining the recent advancements in the comprehension and management of AGA. The genetic factors and pathophysiology of AGA, including the role of dihydrotestosterone (DHT) and the androgen receptor gene, are discussed. The consequences of hair loss on self-esteem and identity, as well as on mental health, are examined. Diagnostic methods, such as the hair-pull test and trichoscopy, are discussed. The article also presents the Hamilton-Norwood classification, which is the most commonly employed system for classifying MPB. The article then delves into the various treatment options available, including topical minoxidil, oral finasteride, platelet-rich plasma therapy, low-level light therapy, hair transplant, and other alternative treatments. The efficacy and combination therapies for these treatments are examined. Additionally, emerging treatments such as caffeine-based solutions and prostaglandin inhibitors are discussed. By examining the recent advancements in AGA treatment, this article provides a comprehensive overview for healthcare professionals to make informed decisions when selecting the best treatment options for their patients.

What are the effects of prostaglandin inhibitor drugs for the treatment of symptomatic patent ductus arteriosus (PDA)?

What are the effects of prostaglandin inhibitor drugs for the treatment of symptomatic patent ductus arteriosus (PDA)?

2,5-dimethylcelecoxib alleviated NK and T-cell exhaustion in hepatocellular carcinoma via the gastrointestinal microbiota-AMPK-mTOR axis

Background2,5-dimethylcelecoxib (DMC), a derivative of celecoxib, is an inhibitor of microsomal prostaglandin E synthase-1 (mPGES-1). Our previous studies have demonstrated that DMC inhibits the expression of programmed death-ligand 1 on...

Spasmolytic and Uroprotective Effects of Apigenin by Downregulation of TGF-β and iNOS Pathways and Upregulation of Antioxidant Mechanisms: In Vitro and In Silico Analysis.

Apigenin is a phytochemical obtained from Chamomilla recutita. Its role in interstitial cystitis is not yet known. The present study is aimed at understanding the uroprotective and spasmolytic effects of apigenin in cyclophosphamide-induced interstitial cystitis. The uroprotective role of apigenin was analyzed by qRT-PCR, macroscopic analysis, Evans blue dye leakage, histological evaluation, and molecular docking. The spasmolytic response was measured by adding cumulative concentrations of apigenin to isolated bladder tissue pre-contracted with KCl (80 mM) and carbachol (10-9-10-4) on non-incubated and pre-incubated tissues with atropine, 4DAMP, methoctramine, glibenclamide, barium chloride, nifedipine, indomethacin, and propranolol. Apigenin inhibited pro-inflammatory cytokines (IL-6, TNF-α and TGF 1-β) and oxidant enzymes (iNOS) while increasing antioxidant enzymes (SOD, CAT, and GSH) in CYP-treated groups compared to the control. Apigenin restored normal tissue of the bladder by decreasing pain, edema, and hemorrhage. Molecular docking further confirmed the antioxidant and anti-inflammatory properties of apigenin. Apigenin produced relaxation against carbachol-mediated contractions, probably via blockade of M3 receptors, KATP channels, L-type calcium channels, and prostaglandin inhibition. While the blockade of M2 receptors, KIR channels, and β-adrenergic receptors did not contribute to an apigenin-induced spasmolytic effect, apigenin presented as a possible spasmolytic and uroprotective agent with anti-inflammatory, antioxidant effects by attenuating TGF-β/iNOS-related tissue damage and bladder muscle overactivity. Thus, it is a potential agent likely to be used in treatment of interstitial cystitis.

Metformin attenuates high-fat diet induced metabolic syndrome related osteoarthritis through inhibition of prostaglandins.

High-fat diet induces bone marrow inflammation and osteoarthritis phenotype in knee joint, but the underlying mechanisms is unknown. Here, we report that high-fat diet induces aberrant bone formation and cartilage degeneration in knee joint. Mechanistically, a high-fat diet increases the number of macrophages and the secretion of prostaglandins in subchondral bone, promoting bone formation. Metformin treatment is able to decrease the number of macrophages and also the level of prostaglandins induced by high-fat diet in subchondral bone. Importantly, metformin rescues aberrant bone formation and cartilage lesions by decreasing the number of osteoprogenitors and type-H vessels, which also results in relief of osteoarthritis pain response. Thus, we demonstrate prostaglandins secreted by macrophages may be a key reason for high-fat diet induced aberrant bone formation and metformin is a promising therapy for high-fat diet induced osteoarthritis.

Interventions for patent ductus arteriosus (PDA) in preterm infants: an overview of Cochrane Systematic Reviews.

Interventions for patent ductus arteriosus (PDA) in preterm infants: an overview of Cochrane Systematic Reviews.

The impact of propolis on clinical manifestations and specific IgE levels against salsola in perennial-allergic rhinitis patients.

Objectives: Propolis has an anti-inflammatory effect induced by inhibiting cyclooxygenase, subsequent inhibition of prostaglandin and nitric oxide synthesis, reduction of inflammatory cytokines, and eventually immunosuppressive activity [1-3]. This study aims to evaluate the impact of propolis on clinical features and specific IgE levels against salsola in perennial allergic rhinitis patients. Methods: Thirty patients diagnosed with perennial allergic rhinitis with salsola-positive skin prick test were enrolled in this randomized controlled clinical trial and divided into two groups. The intervention group received the propolis (200 mg per day), and the control group received a placebo for four months, besides intranasal corticosteroids. At baseline and the end of the intervention, the level of Salsola-specific IgE was measured by the RAST method. To assess the propolis effect on the quality of life and disease severity, miniRQLQ and SNOT22 questionnaires were completed by patients before and after the intervention. Results: According to Table 1, Serum IgE level showed decreasing changes (-0.057) despite increasing changes in the control group (1.039). However, these differences were not statistically significant (P = 0.967). Based on the miniRQLQ questionnaire, quality of life improved in both groups without any significant difference (P = 0.930). According to the SNOT-22 questionnaire, both groups' nasal and sinus problems decreased significantly. However, the intervention type did not affect this decrease and was observed over time in both groups (P> 0.05). Conclusion: Propolis supplementation did not significantly affect various laboratory parameters, clinical symptoms, and quality of life of patients with allergic rhinitis.