Prostaglandin Biosynthesis Research Articles

Anti-inflammatory biomolecular activity of chlorinated-phenyldiazenyl-naphthalene-2-sulfonic acid derivatives: perception from DFT, molecular docking, and molecular dynamic simulation

In this study, two novel derivatives of naphthalene-2-sulfonic acid: 6-(((1S,5R)-3,5-dichloro-2,4,6-triazabicyclo [z3.1.0]hex-3-en-1-yl)amino)-5-((E)-phenyldiazenyl)naphthalene-2-sulfonic acid (DTPS1) and (E)-6-((4,6-dichloro-1,3,5-triazine2-yl)amino)-4-hydroxy-3-(phenyldiazenyl)naphthalene-2-sulfonic acid (DTPS2) have been synthesized and characterized using FT-IR, UV-vis, and NMR spectroscopic techniques. Applying density functional theory (DFT) at the B3LYP, APFD, PBEPBE, HCTH, TPSSTPSS, and ωB97XD/aug-cc-pVDZ level of theories for the electronic structural properties. In-vitro analysis, molecular docking, molecular dynamic (MD) simulation of the compounds was conducted to investigate the anti-inflammatory potential using COXs enzymes. Docking indicates binding affinity of −9.57, −9.60, −6.77 and −7.37 kcal/mol for DTPS1, DTPS2, Ibuprofen and Diclofenac which agrees with in-vitro assay. Results of MD simulation, indicates sulphonic group in DTPS1 has > 30% interaction with the hydroxyl and oxygen atoms in amino acid residues, but > 35% interaction with the DTPS2. It can be said that the DTPS1 and DTPS2 can induce inhibitory effect on COXs to halt biosynthesis of prostaglandins (PGs), a chief mediator of inflammation and pain in mammals. Communicated by Ramaswamy H. Sarma

The Sequence of Prostaglandin-Endoperoxide Synthase 2 Gene in Women with Cervicitis

Cervicitis is a clinical syndrome characterized by inflammation of primarily the columnar epithelium of the uterine endocervix. It can be acute or chronic. Prostaglandin endo peroxide synthase2 (Cyclooxygenase-2) is a key enzyme in prostaglandin synthesis, which is coded by the PTGS2 gene, and recognized as the master switch that activates the inflammatory response; its induction leads to the biosynthesis of prostaglandins. The current study aims to determine the CA125, CA 19.9, and, CA 15.3 markers level and their relationship with the COX-2 gene. Venous blood samples were obtained from 100 women with cervicitis whose ages ranged from 18 to 60 years, and 100 healthy women as a control group. Detection of CA19-9, CA- 125 and CA 15-3 markers was performed by using Cobas E411 analyzer while the CRP test was detected by using Afias CRP instrument. The conventional PCR was used for gene detection and DNA sequencing. The mean± SD of Ca125, CA15.3 and CRP showed a highly significant differences between patient (30.33±1.09), (22.82±1.07), (88.06±5.88) respectively and the healthy control (19.40±0.68), (18.34±0.77), (6.73±0.12) respectively-value >0.001. The mutation in PTGS2 gene with highly CA125 marker 100(100%) and CRP levels 20(80%), while in CA15.3 marker 3(15%) and CA19.9 marker 1(5%). The mutation occurrence in analysis of rs20417 NSP of PTGS2 gene with wild CC GG and the variation C>G G>C.

The Effect of Aspirin on the Prevention of Pro-thrombotic States in Hospitalized COVID-19 Patients: Systematic Review.

Thromboembolic events are one of the important complications in COVID-19 patients, especially in severe cases. Aspirin affects platelet function by irreversibly inhibiting cyclooxygenase activity, reducing the risk of thrombosis. The current systematic review aimed to evaluate aspirin's effectiveness in preventing pro-thrombotic states in COVID-19 hospitalized patients. The systematic search was done in PubMed/Medline, EMBASE, and Medrxiv until September 27, 2021. The following keywords were used: "COVID-19", "SARS-CoV-2", "2019 Novel Coronavirus", "Aspirin," and "Acetylsalicylic Acid." Twelve studies were included. In COVID-19 patients, aspirin can reduce CRP, IL-6 levels, and platelet aggregation by inhibiting thromboxane A2. It can also improve antiviral immunity by hindering the biosynthesis of prostaglandins and lipoxin. Eight out of twelve articles indicated that aspirin provided a beneficial effect on COVID-19. Most studies consider lowered mechanical ventilation needs, ICU admission, illness severity, overt thrombosis, and clinical outcomes in COVID-19 patients receiving aspirin. Aspirin as an antiplatelet and anti-inflammatory agent may reduce the mortality rates in hospitalized patients with severe COVID-19. Further observational studies are necessary to determine the effect of aspirin on the prevention of pro-thrombotic states in hospitalized COVID- 19 patients.

The specific deletion of cyclooxygenase-1 in megakaryocytes/platelets reduces intestinal polyposis in ApcMin/+ mice

Clinical and experimental evidence sustain the role of cyclooxygenase (COX)−1 in intestinal tumorigenesis. However, the cell type expressing the enzyme involved and molecular mechanism(s) have not been clarified yet. We aimed to elucidate the role of platelet COX-1 (the target of low-dose aspirin in humans) in intestinal tumorigenesis of ApcMin/+ mice, considered a clinically relevant model. To realize this objective, we generated an ApcMin/+ mouse with a specific deletion of Ptgs1(COX-1 gene name) in megakaryocytes/platelets (ApcMin/+;pPtgs1-/-mice) characterized by profound inhibition of thromboxane(TX)A2 biosynthesis ex vivo (serum TXB2; by 99%) and in vivo [urinary 2,3-dinor-TXB2(TXM), by 79%]. ApcMin/+ mice with the deletion of platelet COX-1 showed a significantly reduced number (67%) and size (32%) of tumors in the small intestine. The intestinal adenomas of these mice had decreased proliferative index associated with reduced COX-2 expression and systemic prostaglandin(PG)E2 biosynthesis (urinary PGEM) vs. ApcMin/+mice. Extravasated platelets were detected in the intestine of ApcMin/+mice. Thus, we explored their contribution to COX-2 induction in fibroblasts, considered the primary polyp cell type expressing the protein. In the coculture of human platelets and myofibroblasts, platelet-derived TXA2 was involved in the induction of COX-2-dependent PGE2 in myofibroblasts since it was prevented by the selective inhibition of platelet COX-1 by aspirin or by a specific antagonist of TXA2 receptors. In conclusion, our results support the platelet hypothesis of intestinal tumorigenesis and provide experimental evidence that selective inhibition of platelet COX-1 can mitigate early events of intestinal tumorigenesis by restraining COX-2 induction.

In Vitro Effects of Short-Term and Long-Term Heat Exposures on the Immune Response and Prostaglandin Biosynthesis in Bovine Endometrial Cells.

Worldwide heat stress (HS) conditions have a negative impact on dairy cow fertility. However, understanding of the effect of heat stress on endometrial functions is still unclear. The present study aimed to investigate the effects of differential heat exposure conditions on the immune response and prostaglandin biosynthesis of bovine endometrium challenged with bacterial lipopolysaccharide (LPS). Cultures of endometrial cells were grown to confluence at 37 °C (control) and 40.4 °C for 24 h after confluence (short-term heat exposure) and 40.4 °C for 8 days from the beginning of the culture (long-term heat exposure), prior to a challenge by 100 ng/mL LPS for 12 h. LPS altered ALOX12, IL8, IL1B, S100A8, PTGES and AKR1B1 expressions, as well as secretory IL8 and PGF2α. Short-term heat exposure decreased S100A8, IL8 and PGF2α compared with the control temperature, while long-term heat exposure decreased S100A8 and PGF2α. In contrast, HSPA5 expression was not altered by heat exposure or LPS. Indeed, the short-term heat treatment was insufficient for accomplishing the responses of the endometrium to LPS treatment for IL8, S100A8 and PTGES expressions when compared with other temperature conditions. Our findings showed that heat exposure could compromise endometrium immune response and prostaglandin biosynthesis in different ways based on elevated temperature duration, which could reduce subsequent fertility.

Synergistic prostaglandin E synthesis by myeloid and endothelial cells promotes fetal hematopoietic stem cell expansion in vertebrates

During development, hematopoietic stem cells (HSCs) are produced from the hemogenic endothelium and will expand in a transient hematopoietic niche. Prostaglandin E2 (PGE2) is essential during vertebrate development and HSC specification, but its precise source in the embryo remains elusive. Here, we show that in the zebrafish embryo, PGE2 synthesis genes are expressed by distinct stromal cell populations, myeloid (neutrophils, macrophages), and endothelial cells of the caudal hematopoietic tissue. Ablation of myeloid cells, which produce the PGE2 precursor prostaglandin H2 (PGH2), results in loss of HSCs in the caudal hematopoietic tissue, which could be rescued by exogeneous PGE2 or PGH2 supplementation. Endothelial cells contribute by expressing the PGH2 import transporter slco2b1 and ptges3, the enzyme converting PGH2 into PGE2. Of note, differential niche cell expression of PGE2 biosynthesis enzymes is also observed in the mouse fetal liver. Taken altogether, our data suggest that the triad composed of neutrophils, macrophages, and endothelial cells sequentially and synergistically contributes to blood stem cell expansion during vertebrate development.

Oral exposure to DEHP may stimulate prostatic hyperplasia associated with upregulation of COX-2 and L-PGDS expressions in male adult rats

Di-(2-ethylhexyl) phthalate (DEHP), a typical environmental endocrine disruptor (EED), can disrupt estrogen and androgen secretion and metabolism process, thus inducing dysfunctional reproduction such as impaired gonadal development and spermatogenesis disorder. Prostaglandin synthases (PGS) catalyze various prostaglandins biosynthesis, involved in inflammatory cascade and tumorigenesis. Yet, little is known about how PGS may impact prostatic hyperplasia development and progression. This study concentrates predominantly on the potential prostatic toxicity of DEHP exposure and the mediating role of PGS. In vivo study, adult male rats were administered via oral gavage 30 μg/kg/d, 90 μg/kg/d, 270 μg/kg/d, 810 μg/kg/d DEHP or vehicle for four weeks. The results elucidated that low-dose DEHP may cause the proliferation of the prostate with an increased PCNA/TUNEL ratio. Given the importance of estrogens and androgens in prostatic hyperplasia, our first objective was to evaluate the levels of sex hormones. DEHP improved the ratio of estradiol (E2)/testosterone (T) in a dose-dependent manner and upregulated estrogen receptor alpha (ERα) and androgen receptor (AR) expressions. Prostaglandin synthases, including cyclooxygenase-2 (COX-2) and lipocalin-type prostaglandin D synthase (L-PGDS), were significantly upregulated in the ventral prostate. COX-2 and L-PGDS might mediate the tendency of prostatic hyperplasia induced by low-dose DEHP through estradiol/androgen regulation and imbalance between proliferation and apoptosis in vivo. These findings provide the first evidence that prostaglandin synthases contribute to the tendency toward benign prostatic hyperplasia induced by DEHP. Further investigations will have to be performed to facilitate an improved understanding of the role of prostaglandin synthases in DEHP-induced prostatic lesions.

PENGARUH SUHU TERHADAP PERURAIAN KADAR ASETOSAL PADA TABLET GENERIK DAN PATEN SECARA SPEKTROFOTOMETRI UV

Acetosal has many properties or broad therapeutic effects, including analgesic, antipyretic, non-steroidal anti-inflammatory, antifibrinolysis, inhibition of prostaglandin biosynthesis, pain relief, and cardiovascular disorders. The purpose of this study was to determine the effect of storage temperature on acetosal content and acetosal decomposition in generic and patent tablets. Acetosal tablets were stored at 250C, 500C and 750C, then weighed 50.0 mg and dissolved with 5.0 mL of ethanol and aquabidestilata to 100.0 mL, then diluted and read with the maximum wavelength. The results were calculated as percent acetosal content and percent decomposition and were analyzed using the Two Way Anova statistical test. The levels of generic acetosal tablets at 250C, 500C and 750C respectively yielded 94.3% (± 0.64) ; 91.53% (±1.19) ; 81.43% (± 0.73). Acetosal levels in patent tablets at temperatures of 250C, 500C and 750C respectively yielded 96.06% (± 0.68) ; 92.74% (±0.53) ; 87.15% (± 0.67). Acetosal decomposition results in generic tablets at temperatures of 250C, 500C and 750C respectively yielded 5.07% (± 0.64) ; 8.47 %(± 1.19); 18.57% (± 0.73). The levels of acetosal decomposition products in patent tablets at temperatures of 250C, 500C and 750C respectively yielded 3.94% (± 0.68) ; 7,26 %(± 0,53) ; 12.85% (± 0.67). The results of the two-way ANOVA showed that there was a significant difference in the levels of acetosal and decomposition products between generic tablets and patented tablets which were affected by storage temperature.

PPARβ/δ Augments IL-1β-Induced COX-2 Expression and PGE2 Biosynthesis in Human Mesangial Cells via the Activation of SIRT1.

Peroxisome proliferator-activated receptor β/δ (PPARβ/δ), a ligand-activated nuclear receptor, regulates lipid and glucose metabolism and inflammation. PPARβ/δ can exert an anti-inflammatory effect by suppressing proinflammatory cytokine production. Cyclooxygenase-2 (COX-2)-triggered inflammation plays a crucial role in the development of many inflammatory diseases, including glomerulonephritis. However, the effect of PPARβ/δ on the expression of COX-2 in the kidney has not been fully elucidated. The present study showed that PPARβ/δ was functionally expressed in human mesangial cells (hMCs), where its expression was increased by interleukin-1β (IL-1β) treatment concomitant with enhanced COX-2 expression and prostaglandin E2 (PGE2) biosynthesis. The treatment of hMCs with GW0742, a selective agonist of PPARβ/δ, or the overexpression of PPARβ/δ via an adenovirus-mediated approach significantly increased COX-2 expression and PGE2 production. PPARβ/δ could further augment the IL-1β-induced COX-2 expression and PGE2 production in hMCs. Moreover, both PPARβ/δ activation and overexpression markedly increased sirtuin 1 (SIRT1) expression. The inhibition or knockdown of SIRT1 significantly attenuated the effects of PPARβ/δ on the IL-1β-induced expression of COX-2 and PGE2 biosynthesis. Taken together, PPARβ/δ could augment the IL-1β-induced COX-2 expression and PGE2 production in hMCs via the SIRT1 pathway. Given the critical role of COX-2 in glomerulonephritis, PPARβ/δ may represent a novel target for the treatment of renal inflammatory diseases.

PGE2 mediation of egg development in Western flower thrip, Frankliniella occidentalis.

Eicosanoids mediate various insect physiological processes, including reproduction. Especially, the eicosanoid prostaglandin E2 (PGE2 ) is known to mediate oocyte development in some insects. The explosive reproductive potential of the Western flower thrips, Frankliniella occidentalis, damages various agricultural crops. However, little is known about the underlying physiological processes of egg development in this pest. This study found that treatment with aspirin (ASP) (a specific cyclooxygenase (COX) inhibitor) used to inhibit PGE2 biosynthesis during ovarian development significantly suppressed the reproduction of female F. occidentalis. However, the addition of PGE2 to ASP-treated females significantly rescued the suppressed reproduction. PGE2 was detected in growing ovarian follicles in an immunofluorescence assay. The hypothetical biosynthetic machinery of PGE2 was predicted from the F. occidentalis genome and included phospholipase A2 (PLA2 ), COX-like peroxidase (POX), and PGE2 synthase (PGES). Three specific PLA2 s were highly expressed in female adults during active oogenesis. Specific POX and PGES genes also showed high expression during active oogenesis. The adverse effect of ASP treatment on oogenesis was observed in follicle formation in the germarium where the follicle numbers in an ovariole were decreased, which resulted in hypotrophied ovaries. This impairment was rescued by the addition of PGE2 . ASP treatment also significantly inhibited chorion formation and suppressed gene expression associated with choriogenesis, which included chorion protein, mucin, and yellow while it did not inhibit vitellogenin gene expression. However, the addition of PGE2 induced the expression of the target genes suppressed by ASP treatment and rescued chorion formation. These results suggest that PGE2 mediated ovarian development by affecting follicle formation and choriogenesis in F. occidentalis.

Exploration of serum biomarkers in dogs with malignant melanoma receiving anti-PD-L1 therapy and potential of COX-2 inhibition for combination therapy

Immune checkpoint inhibitors (ICIs) such as anti-PD-L1 antibodies are widely used to treat human cancers, and growing evidence suggests that ICIs are promising treatments for canine malignancies. However, only some canine oral malignant melanoma (OMM) cases respond to ICIs. To explore biomarkers predictive of survival in dogs with pulmonary metastatic OMM receiving the anti-PD-L1 antibody c4G12 (n = 27), serum concentrations of prostaglandin E2 (PGE2), cytokines, chemokines, and growth factors were measured prior to treatment initiation. Among 12 factors tested, PGE2, interleukin (IL)-12p40, IL-8, monocyte chemotactic protein-1 (MCP-1), and stem cell factor (SCF) were higher in OMM dogs compared to healthy dogs (n = 8). Further, lower baseline serum PGE2, MCP-1, and vascular endothelial growth factor (VEGF)-A concentrations as well as higher IL-2, IL-12, and SCF concentrations predicted prolonged overall survival. These observations suggest that PGE2 confers resistance against anti-PD-L1 therapy through immunosuppression and thus is a candidate target for combination therapy. Indeed, PGE2 suppressed IL-2 and interferon (IFN)-γ production by stimulated canine peripheral blood mononuclear cells (PBMCs), while inhibition of PGE2 biosynthesis using the COX-2 inhibitor meloxicam in combination with c4G12 enhanced Th1 cytokine production by PBMCs. Thus, serum PGE2 may be predictive of c4G12 treatment response, and concomitant use of COX-2 inhibitors may enhance ICI antitumor efficacy.

Review on the Ethnobotany, Phytochemical and Pharmacological Profile of Senna occidentalis L. (Fabaceae): Potential Application as Remedy in the Treatment of Dysmenorrhea

Senna occidentalis L. has been used in several traditional medicines against various diseases and this is based on its botanical, ethnopharmacology, and phytochemistry profiles. This powerful herb is recognized for its antibacterial, antifungal, antidiabetic, anticancer, antimutagenic, protective, and inflammatory hepatic activity. Multiple chemical compounds, including achrosine, aloe-emodin, emodin, anthraquinones, etc., have been isolated from this plant. The results of this bibliographic research thus presented in this review have demonstrated the ability of certain extracts from S. occidentalis L. to lower the lipid peroxide content, the activity of gamma-glutamyl transpeptidase and phospholipase A2 in exudates of the granuloma of cotton pellets, thus resulting in a reduced availability of arachidonic acid, an important precursor in the biosynthesis of prostaglandins, which are the only likely source and/or cause of dysmenorrhea. Thus, based on its phytochemical profile and its pharmacological properties, it is therefore suggested that S. occidentalis would be a potential and effective remedy in the treatment of dysmenorrhea.

Lipocalin 2 Deficiency Alters Prostaglandin Biosynthesis and mTOR Signaling Regulation of Thermogenesis and Lipid Metabolism in Adipocytes.

Apart from a well-known role in the innate immune system, lipocalin 2 (Lcn2) has been recently characterized as a critical regulator of thermogenesis and lipid metabolism. However, the physiological mechanism through which Lcn2 regulates cellular metabolism and thermogenesis in adipocytes remains unknown. We found that Lcn2 expression and secretion are significantly upregulated by arachidonic acid (AA) and mTORC1 inhibition in differentiated inguinal adipocytes. AA-induced Lcn2 expression and secretion correlate with the inflammatory NFkB activation. Lcn2 deficiency leads to the upregulation of cyclooxygenase-2 (COX2) expression, as well as increased biosynthesis and secretion of prostaglandins (PGs), particularly PGE2 and PGD2, induced by AA in adipocytes. Furthermore, Lcn2 deficiency affects the mTOR signaling regulation of thermogenic gene expression, lipogenesis, and lipolysis. The loss of Lcn2 dismisses the effect of mTORC1 inhibition by rapamycin on COX2, thermogenesis genes, lipogenesis, and lipolysis, but has no impact on p70 S6Kinase-ULK1 activation in Lcn2-deficient adipocytes. We conclude that Lcn2 converges the COX2-PGE2 and mTOR signaling pathways in the regulation of thermogenesis and lipid metabolism in adipocytes.

Expression and characterization of a putative cyclooxygenase from the genome of Nitrosospira multiformis

Cyclooxygenases are dual‐function heme proteins critical for the biosynthesis of prostaglandins in mammals. Mammalian cyclooxygenases contain both dioxygenase activity (adding molecular oxygen to lipid substrates to form lipid hydroperoxides) and peroxidase activity (reducing the hydroperoxides to alcohols). Two open reading frames in the ammonia‐oxidizing betaproteobacterium Nitrosospira multiformis are annotated as cyclooxygenases by structural prediction of the protein product. We have attempted to express and characterize one of these open reading frames to test the structural prediction. DNA encoding the desired open reading frame was synthesized and inserted into several expression vectors with N‐terminal fusion partners (his6 tag, SUMO, thioredoxin). Protein expression yielded largely insoluble protein product under many different expression conditions. Recently, we have been able to express a thioredoxin‐Nitrosospira cyclooxygenase fusion partner in soluble form. Ongoing experiments to characterize the protein structurally and enzymatically will be reported.

Sinomenine increases the methylation level at specific GCG site in mPGES-1 promoter to facilitate its specific inhibitory effect on mPGES-1

Prostaglandin E2 (PGE2) in cancer and inflammatory diseases is a key mediator of disease progression. Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to inhibit the expression of PGE2 by depressing cyclooxygenase (COX) in inflammatory treatments. However, the inhibition to COXs may cause serious side effects. Thus, it is urgent to develop new anti-inflammatory drugs aiming new targets to inhibit PGE2 production. Microsomal prostaglandin E synthase 1 (mPGES-1) catalyzes the final step of PGE2 biosynthesis. Therefore, the selective inhibition of mPGES-1 has become a promising strategy in the treatments of cancer and inflammatory diseases. Our previous studies confirmed that sinomenine (SIN) is a specific mPGES-1 inhibitor. However, the exact mechanism by which SIN inhibits mPGES-1 remains unknown. This study aimed to explain the regulation effect of SIN to mPGES-1 gene expression by its DNA methylation induction effect. We found that the demethylating agent 5-azacytidine (5-AzaC) reversed the inhibitory effect of SIN to mPGES-1. Besides, SIN selectively increased the methylation level of the promoter region in the mPGES-1 gene while the pretreatment of 5-AzaC suppressed this effect. The results also shows that pretreatment with SIN increased the methylation level of specific GCG sites in the promoter region of mPGES-1. This specific methylation site may become a new biomarker for predicting and diagnosing RA and cancer with high expression of mPGES-1. Also, our research provides new ideas and solutions for clinical diagnosis and treatment of diseases related to mPGES-1 and for targeted methylation strategy in drug development.

Na+-Retaining Action of COX-2 (Cyclooxygenase-2)/EP1 Pathway in the Collecting Duct via Activation of Intrarenal Renin-Angiotensin-Aldosterone System and Epithelial Sodium Channel.

The collecting duct (CD) is a major site of both biosynthesis and action of prostaglandin E2 as highlighted by the predominant expression of COX-2 (cyclooxygenase-2) and some E-prostanoid (EP) subtypes at this nephron site. The purpose of this study was to determine the relevance and mechanism of CD COX-2/prostaglandin E2/EP1 signaling for the regulation of Na+ hemostasis during Na+ depletion. Mice with Aqp2Cre-driven deletion of COX-2 (COX-2fl/flAqp2Cre+) or the EP1 subtype (EP1fl/flAqp2Cre+) were generated and the Na+-wasting phenotype of these mice during low-salt (LS) intake was examined. EP subtypes responsible for prostaglandin E2-induced local renin response were analyzed in primary cultured mouse inner medullary CD cells. Following 28-day LS intake, COX-2fl/flAqp2Cre+ mice exhibited a higher urinary Na+ excretion and lower cumulative Na+ balance, accompanied with suppressed intrarenal renin, AngII (angiotensin II), and aldosterone, expression of CYP11B2 (cytochrome P450 family 11 subfamily B member 2), and blunted expression of epithelial sodium channel subunits compared to floxed controls (COX-2fl/flAqp2Cre-), whereas no differences were observed for indices of systemic renin-angiotensin-aldosterone system. In cultured CD cells, exposure to prostaglandin E2 stimulated release of soluble (pro)renin receptor, prorenin/renin and aldosterone and the stimulation was more sensitive to antagonism of EP1 as compared other EP subtypes. Subsequently, EP1fl/flAqp2Cre+ mice largely recapitulated Na+-wasting phenotype seen in COX-2fl/flAqp2Cre+ mice. The study for the first time reports that CD COX-2/EP1 pathway might play a key role in maintenance of Na+ homeostasis in the face of Na+ depletion, at least in part, through activation of intrarenal renin-angiotensin-aldosterone-system and epithelial sodium channel.

Inflammation and Cancer: From the Development of Personalized Indicators to Novel Therapeutic Strategies.

Colorectal (CRC) and hepatocellular carcinoma (HCC) are associated with chronic inflammation, which plays a role in tumor development and malignant progression. An unmet medical need in these settings is the availability of sensitive and specific noninvasive biomarkers. Their use will allow surveillance of high-risk populations, early detection, and monitoring of disease progression. Moreover, the characterization of specific fingerprints of patients with nonalcoholic fatty liver disease (NAFLD) without or with nonalcoholic steatohepatitis (NASH) at the early stages of liver fibrosis is necessary. Some lines of evidence show the contribution of platelets to intestinal and liver inflammation. Thus, low-dose Aspirin, an antiplatelet agent, reduces CRC and liver cancer incidence and mortality. Aspirin also produces antifibrotic effects in NAFLD. Activated platelets can trigger chronic inflammation and tissue fibrosis via the release of soluble mediators, such as thromboxane (TX) A2 and tumor growth factor (TGF)-β, and vesicles containing genetic material (including microRNA). These platelet-derived products contribute to cyclooxygenase (COX)-2 expression and prostaglandin (PG)E2 biosynthesis by tumor microenvironment cells, such as immune and endothelial cells and fibroblasts, alongside cancer cells. Enhanced COX-2-dependent PGE2 plays a crucial role in chronic inflammation and promotes tumor progression, angiogenesis, and metastasis. Antiplatelet agents can indirectly prevent the induction of COX-2 in target cells by inhibiting platelet activation. Differently, selective COX-2 inhibitors (coxibs) block the activity of COX-2 expressed in the tumor microenvironment and cancer cells. However, coxib chemopreventive effects are hampered by the interference with cardiovascular homeostasis via the coincident inhibition of vascular COX-2-dependent prostacyclin biosynthesis, resulting in enhanced risk of atherothrombosis. A strategy to improve anti-inflammatory agents’ use in cancer prevention could be to develop tissue-specific drug delivery systems. Platelet ability to interact with tumor cells and transfer their molecular cargo can be employed to design platelet-mediated drug delivery systems to enhance the efficacy and reduce toxicity associated with anti-inflammatory agents in these settings. Another peculiarity of platelets is their capability to uptake proteins and transcripts from the circulation. Thus, cancer patient platelets show specific proteomic and transcriptomic expression profiles that could be used as biomarkers for early cancer detection and disease monitoring.

Free Radical Scavenging and Analgesic Activities of 70% Ethanol Extract of Luvunga sarmentosa (BI.) Kurz from Central Kalimantan

Luvunga sarmentosa, commonly known as saluang belum, is widely used in Kalimantan to relieve pains, rheumatism, boost the immune system, and fever. The research on the free radical scavenging and analgesic effect of the L. sarmentosa stem extract has not been reported. This study aimed to evaluate the free radical scavenging and analgesic activity of the ethanol extract of L. sarmentosa. The L. sarmentosa stem was extracted using 70% ethanol and tested for free radical scavenging using the 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) and analgesic activity, acetic acid-induced writhing test, and hot plate test in an animal model. The results showed that the 70% ethanol extract of the L. sarmentosa had an anti-free radical scavenging and analgesic activity. The extract has weak free radical scavenging with an IC50 value of 293.45 µg/mL. Analgesic activity using the writhing test indicated that the extract significantly reduced the writhes count after oral administration in a dose-dependent manner compared to the negative control. Extract at a dose of 550 mg/kg BW can reduce the writhing test by 67.60% compared to others. In contrast, the diclofenac sodium reduced the number of writhes by 74.74%. While in a hot plate, the extract at a dose of 550 mg/kg BW produced a maximum possible analgesia (MPA) of 17.64%, lower than the MPA of diclofenac sodium (51.01%). Analgesic activity of the extract has higher inhibition on the writhing test than on the hot plate. The extract could be responsible for the peripheral mechanism by inhibiting the prostaglandin biosynthesis.

Aspirin‑induced asthma: a still evolving area of basic and clinical research.

The first modern description of respiratory syndrome of aspirin hypersensitivity was published over half of the century ago, but the pathogenesis of the disease is still elusive. Just a few years after discovery how aspirin works, Andrew Szczeklik and his co‑workers described that asthmatics with aspirin hypersensitivity cross‑react to the whole class of nonsteroidal anti‑inflammatory drugs. It took rest of his life to seek for an answer on how this disease, nowadays referred to as N ‑ERD, develops and how it can be treated. In the meantime, cysteinyl leukotrienes, leukotriene modifying drugs, and novel subpopulations of lymphocytes were discovered. This review on aspirin hypersensitivity documents a progress in our understanding of mechanisms of hypersensitivity to nonsteroidal anti‑inflammatory drugs. Current concepts about origin of the disease integrate advances in the field of allergology and inflammatory mechanisms of asthma. However, pharmacological inhibition of prostaglandin biosynthesis by nonsteroidal anti‑inflammatory drugs has a pivotal role in these investigations. Presented is a central role of prostaglandin E2 , a double‑faced lipid immunoregulatory mediator whose deficiency is related to the administration of an anti‑inflammatory drug. Discussed are cysteinyl leukotrienes, the most reliable biomarkers of aspirin hypersensitivity and cells of innate immunity capable of leukotrienes production. Involvement of blood platelets and recently described mucosal basophils are areas of ongoing studies in the disease. Aspirin hypersensitivity is an acquired condition; therefore, the search for genetic predisposition using classic association studies was inconclusive. There is a new hope to explain mechanisms of aspirin hypersensitivity by studies of innate lymphoid cells, which have a central role in the regulation of respiratory mucosa function in asthma.

Formulasi dan Uji Efektivitas Sediaan Sirup Ekstrak Daun Kacapiring (Gardenia jasminoides J. Ellis) Sebagai Antipiretik Terhadap Mencit (Mus musculus L) YANG DI INDUKSI VAKSIN DPT

Flavonoids in plate glass leaves (Gardenia jasminoides J. Ellis) can inhibit the cyclooxygenase enzyme, especially cyclooxygenase-2, which plays a role in prostaglandin biosynthesis so that the process of fever is inhibited. In addition, flavonoids and paracetamol have a similar structure. The aim of this research was to test the syrup extract of G. jasminoides leaves to have antipyretic effectiveness against male mice (Mus musculus) induced by DPT vaccine. The research method used was experimental research. The research stages were plant determination, the manufacture of G. jasminoides leaf extract using the maceration method with 96% ethanol solvent, phytochemical screening, syrup formulation with the active substance of G. jasminoides leaf extract and additives in the form of saccharose, citric acid, grape essence, propylene glycol and distilled water. Antipyretic testing was carried out in vivo, namely the male mice were measured at the initial oral temperature, then injected intramuscularly with the DPT HB vaccine in the thigh, two hours after experiencing optimum fever (above normal temperature), then each group was treated with oral method, namely negative control (syrup basis), positive control (paracetamol syrup), ethanol extract syrup from G. jasminoides leaves dose 1; 3 and 5 mg / 20gBW. The results showed that extract G. jasminoides could be formulated into syrup preparations with good physical quality in terms of organoleptic, density, volume transferred and pH. The dose of G. jasminoides leaf extract syrup 5 mg/20Gbb was the most effective dose as an antipyretic in male mice induced with DPT vaccine with a total temperature reduction of 2oC.
 Keywords: antipyretic, gardenia, syrup.