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Despite the clear roles played by peroxisome proliferators-activated receptor alpha (PPAR-alpha) in lipid metabolism, inflammation and feeding, the effects of its activation in the central nervous system (CNS) are largely unknown. Palmitoylethanolamide (PEA), a member of the fatty-acid ethanolamide family, acts peripherally as an endogenous PPAR-alpha agonist, exerting analgesic and anti-inflammatory effects. Both PPAR-alpha and PEA are present in the CNS, but the specific functions of this lipid and its receptor remain to be clarified. Using the carrageenan-induced paw model of hyperalgesia in mice, we report here that intracerebroventricular administration of PEA (0.1-1 microg) 30 min before carrageenan injection markedly reduced mechanical hyperalgesia up to 24 h following inflammatory insult. This effect was mimicked by GW7647 (1 microg), a synthetic PPAR-alpha agonist. The obligatory role of PPAR-alpha in mediating PEA's actions was confirmed by the lack of anti-hyperalgesic effects in mutant mice lacking PPAR-alpha. PEA significantly reduced the expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in sciatic nerves and restored carrageenan-induced reductions of PPAR-alpha in the L4-L6 dorsal root ganglia (DRG). To investigate the mechanism by which PEA attenuated hyperalgesia, we evaluated inhibitory kB-alpha (IkB-alpha) degradation and p65 nuclear factor kB (NF-kappaB) activation in DRG. PEA prevented IkB-alpha degradation and p65 NF-kappaB nuclear translocation, confirming the involvement of this transcriptional factor in the control of peripheral hyperalgesia. These results add further support to the broad-spectrum of biological and pharmacological effects induced by PPAR-alpha agonists, suggesting a centrally mediated component for these drugs in controlling inflammatory pain.

Despite the clear roles played by peroxisome proliferators-activated receptor alpha (PPAR-alpha) in lipid metabolism, inflammation and feeding, the effects of its activation in the central nervous system (CNS) are largely unknown. Palmitoylethanolamide (PEA), a member of the fatty-acid ethanolamide family, acts peripherally as an endogenous PPAR-alpha agonist, exerting analgesic and anti-inflammatory effects. Both PPAR-alpha and PEA are present in the CNS, but the specific functions of this lipid and its receptor remain to be clarified. Using the carrageenan-induced paw model of hyperalgesia in mice, we report here that intracerebroventricular administration of PEA (0.1-1 microg) 30 min before carrageenan injection markedly reduced mechanical hyperalgesia up to 24 h following inflammatory insult. This effect was mimicked by GW7647 (1 microg), a synthetic PPAR-alpha agonist. The obligatory role of PPAR-alpha in mediating PEA's actions was confirmed by the lack of anti-hyperalgesic effects in mutant mice lacking PPAR-alpha. PEA significantly reduced the expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in sciatic nerves and restored carrageenan-induced reductions of PPAR-alpha in the L4-L6 dorsal root ganglia (DRG). To investigate the mechanism by which PEA attenuated hyperalgesia, we evaluated inhibitory kB-alpha (IkB-alpha) degradation and p65 nuclear factor kB (NF-kappaB) activation in DRG. PEA prevented IkB-alpha degradation and p65 NF-kappaB nuclear translocation, confirming the involvement of this transcriptional factor in the control of peripheral hyperalgesia. These results add further support to the broad-spectrum of biological and pharmacological effects induced by PPAR-alpha agonists, suggesting a centrally mediated component for these drugs in controlling inflammatory pain.

Piperine is a natural alkaloid that possesses a variety of therapeutic properties, including anti-inflammatory, antioxidant, antibacterial, and anticarcinogenic activities. The present study aims to assess the medicinal benefits of piperine as an anti-diarrheal agent in a chick model by utilizing in vivo and in silico techniques. For this, castor oil was administered orally to 2-day-old chicks to cause diarrhea. Bismuth subsalicylate (10 mg/kg), loperamide (3 mg/kg), and nifedipine (2.5 mg/kg) were used as positive controls, while the vehicle was utilized as a negative control. Two different doses (25 and 50 mg/kg b.w.) of the test sample (piperine) were administered orally, and the highest dose was tested with standards to investigate the synergistic activity of the test sample. In our findings, piperine prolonged the latent period while reducing the number of diarrheal feces in the experimental chicks during the monitoring period (4 h). At higher doses, piperine appears to reduce diarrheal secretion while increasing latency in chicks. Throughout the combined pharmacotherapy, piperine outperformed bismuth subsalicylate and nifedipine in terms of anti-diarrheal effects with loperamide. In molecular docking, piperine exhibited higher binding affinities towards different inflammatory enzymes such as cyclooxygenase 1 (−7.9 kcal/mol), cyclooxygenase 2 (−8.4 kcal/mol), nitric oxide synthases (−8.9 kcal/mol), and L-type calcium channel (−8.8 kcal/mol), indicating better interaction of PP with these proteins. In conclusion, piperine showed a potent anti-diarrheal effect in castor oil-induced diarrheal chicks by suppressing the inflammation and calcium ion influx induced by castor oil. [ABSTRACT FROM AUTHOR]

Anticancer angiogenesis inhibitors cause hypertension and renal injury. Previously we observed in rats that high-dose aspirin (capable of blocking cyclooxygenase (COX)-1 and-2) was superior to low-dose aspirin (blocking COX-1 only) to prevent these side-effects during treatment with the angiogenesis inhibitor sunitinib, suggesting a role for COX-2. High-dose aspirin additionally prevented the rise in COX-derived prostacyclin (PGI 2). Therefore, we studied the preventive effects of selective COX-2 inhibition and the hypothesized contributing role of PGI 2 during angiogenesis inhibition. Male WKY rats received vehicle, sunitinib ((SU), 14 mg/kg/day) alone or combined with COX-2 inhibition (celecoxib, 10 mg/kg/day) or a PGI 2 analogue (iloprost, 100 μg/kg/day) for 8 days (n = 8–9 per group). Mean arterial pressure (MAP) was measured via radiotelemetry, biochemical measurements were performed via ELISA and vascular function was assessed via wire myography. SU increased MAP (17±1mmHg versus 3±1mmHg after vehicle on day 4, P < 0.002), which could not be significantly blunted by celecoxib (+12±3mmHg on day 4, P = 0.247), but was temporarily attenuated by iloprost (treatment days 1 + 2 only). Urinary PGI 2 (996 ± 112 versus 51 ± 11ng/24h after vehicle, P < 0.001), but not circulating PGI 2 increased during SU, which remained unaffected by celecoxib and iloprost. Celecoxib reduced sunitinib-induced albuminuria (0.36 ± 0.05 versus 0.58 ± 0.05mg/24h after SU, P = 0.005). Wire myography demonstrated increased vasoconstriction to endothelin-1 after SU (Emax P = 0.005 versus vehicle), which remained unaffected by celecoxib or iloprost. Selective COX-2 inhibition ameliorates albuminuria during angiogenesis inhibition with sunitinib, which most likely acts independently of PGI 2. To combat angiogenesis inhibitor-induced hypertension, dual rather than selective COX-1/2 blockade seems preferential. [ABSTRACT FROM AUTHOR]

Abstract The effects on the vasculature produced by ethanol withdrawal include both vasodilatation and hypocontractility, although a detailed biochemical understanding of these processes is yet to be accomplished. Here, we sought to investigate some of the mechanisms underlying vascular hypocontractility induced by ethanol withdrawal. Male Wistar rats were treated with increasing doses of 3–9% ethanol (v/v) for 21 days and the impact of ethanol withdrawal on the vascular function was assessed 48 h after immediate ethanol suspension. Endothelium-denuded rat aortic rings showed a reduced contractile response to phenylephrine, angiotensin II, serotonin and KCl after ethanol withdrawal, but the same phenomenon was not observed in endothelium-intact rings. Indomethacin, but not L-NAME, tiron, PEG-catalase and SC560, restored the contractile response to phenylephrine of endothelium-denuded aortas from abstinent rats. Hyporeactivity to phenylephrine induced by ethanol withdrawal was reversed by SC236, a selective cyclooxygenase (COX)-2 inhibitor. Similarly, Ro1138452, a selective prostacyclin IP receptor antagonist, reversed vascular hypocontractility induced by ethanol withdrawal. Increased concentrations of 6-keto-prostaglandin (PG)F 1α , a stable product of PGI 2 , was detected in endothelium-denuded aortas from abstinent rats, and this response was prevented by indomethacin. However, no changes in aortic PGE 2 levels were detected after ethanol withdrawal. In situ quantification of hydrogen peroxide (H 2 O 2) and nitric oxide (NO) using fluorescent dyes revealed that ethanol withdrawal decreased the levels of these two compounds in the tunica media. Our studies show that the vascular hypocontractility induced by ethanol withdrawal is independent of the endothelium and it is mediated by PGI 2 derived from COX-2. [ABSTRACT FROM AUTHOR]

Abstract Parecoxib, a prodrug of valdecoxib, is a selective inhibitor of cyclooxygenase-2 and widely used for traumatic and postoperative patients to avoid opioid-induced side effects. It is a potent analgesic and has a role in multimodal analgesic and enhanced recovery after surgery. Whether parecoxib exerts any actions on these types of ionic currents remains unclear. In this study, we investigated whether it exerts any effects on ion currents in differentiated NG108-15 neuronal cells. Cell exposure to parecoxib (1–30 μM) caused a reversible reduction in the amplitude of I K(DR) with an IC 50 value of 9.7 μM. The time course for the I K(DR) inactivation in response to a long-lasting pulse was changed to the biexponential process during cell exposure to 3 μM parecoxib. Other agents known to inhibit the cyclooxygenase activity have minimal effects on I K(DR). Parecoxib enhanced the degree of excessive accumulative inhibition of I K(DR) inactivation evoked by a train of brief repetitive stimuli. This compound suppressed the amplitude of M-type K+ current. It depressed the peak amplitude of voltage-gated Na+ current with no change in the current-voltage relationship of this current. However, it did not have any effect on hyperpolarization-activated cation current. No change in the expression level of K V 3.1 mRNA was detected in the presence of parecoxib. The effects of parecoxib on ion currents are direct and unrelated to its inhibition of the enzymatic activity of cyclooxygenase-2. The inhibition of these ion channels by parecoxib may partly contribute to the underlying mechanisms by which it affects neuronal function in vivo. [ABSTRACT FROM AUTHOR]

The current investigation aimed to explore the potential of etoricoxib nanostructured lipid carriers (ET-NLCs) as an anti-inflammatory drug in radiation-exposed rats, with a focus on assessing its efficacy in reducing inflammation while minimizing cardiac toxicity compared to conventional etoricoxib (ET) treatment. The ET-NLCs were prepared by the low-temperature melt emulsification solidification technique. Various techniques were employed to characterize the NLCs. Rats were exposed to gamma-irradiation (6 Gy) to induce cardiac inflammation and injury, followed by oral administration of ET or ET-NLCs (10 mg/kg b.w.) for 14 consecutive days. Results demonstrated a significant increase in the levels of malondialdehyde (MDA), cyclooxygenase-2 (COX-2), nuclear factor kappa-B p65 (NF-κB-p65), and poly ADP-ribose polymerase (PARP-1) in the heart tissues of gamma-irradiated rats compared to the control group. This increase was accompanied by a reduction in the activity of antioxidant enzymes. However, treatment with ET and ET-NLCs exhibited a positive impact on these levels. Interestingly, the efficacy of ET-NLCs in mitigating radiation-induced inflammation in heart tissue was found to be superior to that of ET. In conclusion, the study suggests that the utilization of NLCs as a drug delivery system for ET may not only enhance its therapeutic efficacy but also help reduce the cardiovascular risks associated with ET, specifically focused on individuals who had been exposed to gamma radiation. These findings open new avenues for further research in the development of effective and safer therapeutic strategies for managing inflammatory diseases and their impact on cardiovascular health. [ABSTRACT FROM AUTHOR]

Progressive up-regulation of β-catenin signaling is very common in the transformation of colorectal epithelium to colorectal cancer (CRC). Practical measures for opposing such signaling hence have potential for preventing or slowing such transformation. cAMP/PKA activity in colon epithelium, as stimulated by COX-2-generated prostaglandins and β2-adrenergic signaling, boosts β-catenin activity, whereas cGMP/PKG signaling has the opposite effect. Bacterial generation of short-chain fatty acids (as supported by unrefined high-carbohydrate diets, berberine, and probiotics), dietary calcium, daily aspirin, antioxidants opposing cox-2 induction, and nicotine avoidance, can suppress cAMP production in colonic epithelium, whereas cGMP can be boosted via linaclotides, PDE5 inhibitors such as sildenafil or icariin, and likely high-dose biotin. Selective activation of estrogen receptor-β by soy isoflavones, support of adequate vitamin D receptor activity with UV exposure or supplemental vitamin D, and inhibition of CK2 activity with flavanols such as quercetin, can also oppose β-catenin signaling in colorectal epithelium. Secondary bile acids, the colonic production of which can be diminished by low-fat diets and berberine, can up-regulate β-catenin activity by down-regulating farnesoid X receptor expression. Stimulation of PI3K/Akt via insulin, IGF-I, TLR4, and EGFR receptors boosts β-catenin levels via inhibition of glycogen synthase-3β; plant-based diets can down-regulate insulin and IGF-I levels, exercise training and leanness can keep insulin low, anthocyanins and their key metabolite ferulic acid have potential for opposing TLR4 signaling, and silibinin is a direct antagonist for EGFR. Partially hydrolyzed phytate can oppose growth factor-mediated down-regulation of β-catenin by inhibiting Akt activation. Multifactorial strategies for safely opposing β-catenin signaling can be complemented with measures that diminish colonic mutagenesis and DNA hypomethylation - such as avoidance of heme-rich meat and charred or processed meats, consumption of phase II-inductive foods and nutraceuticals (e.g., Crucifera), and assurance of adequate folate status., Competing Interests: Declaration of competing interest Mark F. McCarty is co-inventor and co-owner of a US patent on nutraceutical uses of phycocyanobilin-containing oligopeptides derived from spirulina. The other authors have no conflicts of interest to declare., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Parkinson's disease (PD) is a dopaminergic neurodegenerative disorder, which presents motor and non-motor symptoms. 7-Fluoro-1,3-diphenylisoquinoline (FDPI) is an isoquinoline compound with antioxidant and antidepressant properties. This study investigated whether FDPI reverses motor and non-motor symptoms in an acute mouse model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). It was also assessed the anti-inflammatory mechanisms in FDPI pharmacological action. C57Bl/6 male adult mice received four MPTP (20 mg/kg, intraperitoneal) or saline (vehicle) injections to induce an acute PD model. FDPI (10 mg/kg, intragastric) was daily administered to mice from the 2nd to 9th day after the induction and mice performed the behavioral tests on the 8th and 9th days. Striatum samples were collected for biochemical and molecular analyses. The results of the rotarod and challenging beam tests demonstrated that the administration of FDPI attenuated the impairments in balance and coordination of mice induced by MPTP. The FDPI reversed the short-term memory deficit and depressive-like behavior induced by MPTP in mice. FDPI attenuated the reduction in the striatal tyrosine hydroxylase levels, and it reversed the increase in the cyclooxygenase-2 levels and myeloperoxidase activity caused by MPTP in mice. Therefore, FDPI reversed motor and non-motor symptoms induced by an acute PD model and its restorative effects seem to be mediated by an anti-inflammatory action associated with a modulation of the striatal cyclooxygenase-2 levels and myeloperoxidase activity. [ABSTRACT FROM AUTHOR]

Asthma is a persistent respiratory ailment that displays periodicity and is linked to the equilibrium of T cells. Several compounds obtained from Chinese herbal medicines display beneficial impacts on T cell regulation and the attenuation of inflammatory mediator synthesis. Schisandrin A, an active lignan derived from the Schisandra fruit, exhibits anti-inflammatory characteristics. In the present study, the network analysis conducted revealed that the nuclear factor-kappaB (NF-κB) signaling pathway is likely a prominent contributor to the anti-asthmatic effects of schisandrin A. In addition, it has been established that the inhibition of cyclooxygenase 2 (COX-2/PTGS2) is likely a significant factor in this process. The results of in vitro experiments have substantiated that schisandrin A can effectively lower the expression of COX-2 and inducible nitric oxide synthase (iNOS) in 16 HBE cells and RAW264.7 cells in a manner that is dependent on the dosage administered. It was able to effectively reduce the activation of the NF-κB signaling pathway while simultaneously improving the injury to the epithelial barrier function. Furthermore, an investigation utilizing immune infiltration as a metric revealed an inequity in Th1/Th2 cells and a surge in Th2 cytokines in asthma patients. In the OVA-induced asthma mice model, it was observed that schisandrin A treatment effectively suppressed inflammatory cell infiltration, reduced the Th2 cell ratio, inhibited mucus secretion, and prevented airway remodeling. To summarize, the administration of schisandrin A has been found to effectively alleviate the symptoms of asthma by impeding the production of inflammation, which includes reducing the Th2 cell ratio and improving the integrity of the epithelial barrier function. These findings offer valuable insights into the potential therapeutic applications of schisandrin A for the treatment of asthma. [Display omitted] [ABSTRACT FROM AUTHOR]

The effects on blood pressure produced byethanol consumption include both vasoconstriction and activation of the renin-angiotensin-aldosterone system (RAAS), although the detailed relationship between these processes is yet to be accomplished. Here, we sought to investigate the contribution of mineralocorticoid receptors (MR) to ethanol-induced hypertension and vascular hypercontractility. We analyzed blood pressure and vascular function of male Wistar Hannover rats treated with ethanol for five weeks. The contribution of the MR pathway to the cardiovascular effects of ethanol was evaluated with potassium canrenoate, a MR antagonist (MRA). Blockade of MR prevented ethanol-induced hypertension and hypercontractility of endothelium-intact and -denuded aortic rings. Ethanol up-regulated cyclooxygenase (COX)2 and augmented vascular levels of both reactive oxygen species (ROS) and thromboxane (TX)B 2 , a stable metabolite of TXA 2. These responses were abrogated by MR blockade. Hyperreactivity to phenylephrine induced by ethanol consumption was reversed by tiron [a scavenger of superoxide (O 2 ∙–)], SC236 (a selective COX2 inhibitor) or SQ29548 (an antagonist of TP receptors). Treatment with the antioxidant apocynin prevented the vascular hypercontractility, as well as the increases in COX2 expression and TXA 2 production induced by ethanol consumption. Our study has identified novel mechanisms through which ethanol consumption promotes its deleterious effects in the cardiovascular system. We provided evidence for a role of MR in the vascular hypercontractility and hypertension associated with ethanol consumption. The MR pathway triggers vascular hypercontractility through ROS generation, up-regulation of COX2 and overproduction of TXA 2 , which will ultimately induce vascular contraction. [Display omitted] [ABSTRACT FROM AUTHOR]

Exploring the importance of nanofibrous scaffold with traditionally important medicine as a wound dressing material prevents infection and aids in faster healing of wounds. In the present study, the Collagen (COL) from the marine fish skin was extracted and employed for coating the Poly(3-hydroxybutyric acid) (P)–Gelatin (G) nanofibrous scaffold with a bioactive Coccinia grandis extract (CPE) fabricated through electrospinning. Further, the fabricated collagen coated nanofibrous scaffold (PG-CPE-COL) applied to the experimental wound of rats and the wound healing was analyzed with by physiochemical and biological techniques. The increased level of hydroxyproline, hexosamine and uronic acid was observed in PG-CPE-COL treated than the other groups. The CPE and collagen in the nanofibrous scaffold accelerates the wound healing and thereby reduced the inflammation caused by the cyclooxygenase-2 (COX-2) and inducible nitric oxide synthases (iNOS) in wound healing. The nanofibrous scaffold has influenced the expression of various growth factors such as vascular endothelial growth factor (VEGF), epidermal growth factor (EGF) and transforming growth factor (TGF-β). In addition, the PG-CPE-COL nanofibrous scaffold increases the deposition of collagen synthesis and accelerates reepithelialization. Thus, the results suggest that the collagen coated nanofibrous scaffold with bioactive traditional medicine enhanced the faster healing of wound. [ABSTRACT FROM AUTHOR]

Acute lung injury (ALI) represents an unmet medical need with an urgency to develop effective pharmacotherapies. Compound edaravone, a combination of edaravone and borneol, has been developed for treatment of ischemia stroke in clinical phase III study. The purpose of the present study is to investigate the anti-inflammatory effect of compound edaravone on lipopolysaccharide (LPS)-induced inflammatory response in RAW264.7 cells and the therapeutic efficacy on LPS-induced ALI in mice. Edaravone and compound edaravone concentration-dependently decreased LPS-induced interleukin-6 (IL-6) production and cyclooxygenase-2 (COX-2) expression in RAW264.7 cells. The efficiency of compound edaravone was stronger than edaravone alone. In the animal study, compound edaravone was injected intravenously to mice after intratracheal instillation of LPS. It remarkably alleviated LPS-induced lung injury including pulmonary histological abnormalities, polymorphonuclear leukocyte (PMN) infiltration and extravasation. Further study demonstrated that compound edaravone suppressed LPS-induced TNF-α and IL-6 increase in mouse serum and bronchoalveolar lavage (BAL) fluid, and inhibited LPS-induced nuclear factor-κB (NF-κB) activation and COX-2 expression in mice lung tissues. Importantly, our findings demonstrated that the compound edaravone showed a stronger protective effect against mouse ALI than edaravone alone, which suggested the synergies between edaravone and borneol. In conclusion, compound edaravone could be a potential novel therapeutic drug for ALI treatment and borneol might produce a synergism with edaravone. [ABSTRACT FROM AUTHOR]

Phosphorylation and activation of p38 MAPK and NFκB pathways, along with the resulting overproduction of interleukin IL-1β, IL-6, and tumor necrosis factor a (TNFα) is a hallmark of inflammatory disorders. Omega-3 polyunsaturated fatty acid (n-3 PUFA) supplementations are known to exert anti-inflammatory properties by reduction of keys cytokines and enzymes involved in inflammation. Here, we investigated the anti-inflammatory pathways and mediators modulated by eicosapentaenoic acid monoglyceride (MAG-EPA) on human peripheral blood mononuclear cells (PBMCs) from healthy donors and stimulated, ex vivo, with lipopolysaccharide (LPS). LPS stimulation increased p38 MAPK and NFκB phosphorylation, which was abolished by MAG-EPA treatments. Concomitantly, MAG-EPA also abolished LPS-induced inflammation in PBMCs by reducing IL-1β, IL-6, and TNFα cytokines at protein and transcript levels. Moreover, MAG-EPA decreased the levels of HIF1α in LPS-induced human PBMCs. Results also revealed a decreased of pro-inflammatory enzymes such as Cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) in LPS-induced PBMCs. Altogether, the present data suggest that MAG-EPA, represents a new potential therapeutic strategy for resolving inflammation in inflammatory disorders including autoimmune diseases, allergies, asthma, arthritis and cancer. [ABSTRACT FROM AUTHOR]

Previous researches indicated that cyclooxygenase-2 (Cox-2) might be involved in P-glycoprotein (P-gp)-mediated multidrug resistance in hepatocellular carcinoma cells. Doxorubicin-resistant hepatocellular carcinoma PLC/PRF/5 cells (PLC/PRF/5R) and HepG2 (HepG2R) cells were developed in the present study. The modulatory effect of guggulsterone on Cox-2 and P-gp in PLC/PRF/5R and HepG2R cells was investigated. Cells proliferation, Cox-2 and P-gp expression, and prostaglandin E 2 release were examined using MTT, flow cytometry, western blot and ELISA assays. Small interfering RNA (siRNA) targeted against Cox-2 and multidrug resistance protein (Mdr-1) was used to regulate the expression of Cox-2 and P-gp. The results showed that co-administration of guggulsterone resulted in a significant increase in chemo-sensitivity of PLC/PRF/5R cells to doxorubicin, as compared with doxorubicin treatment alone. When doxorubicin (10 µM) was combined with guggulsterone (50 µM), the mean apoptotic population of PLC/PRF/5R cells was 20.16%. It was increased by 1.5 times, as compared with doxorubicin (10 µM) treatment alone. Furthermore, guggulsterone had significantly inhibitory effect on the levels of Cox-2, P-gp and prostaglandin E 2 . However, guggulsterone did not show significantly inhibitory effect on the expression of prostaglandin E receptors. In addition, Cox-2 siRNA simultaneously reduced the expression of Cox-2 and P-gp in PLC/PRF/5R cells. Mdr-1 siRNA had no influence on Cox-2, but inhibited P-gp expression. The present study suggested that guggulsterone might enhance the cytotoxic effect of doxorubicin to PLC/PRF/5R cells through a Cox-2/P-gp dependent pathway. [ABSTRACT FROM AUTHOR]

High on-aspirin platelet reactivity (HAPR) has been associated with compromised aspirin efficacy in patients with diabetes suffering from acute cardiovascular events, but the key mechanisms remain elusive. The objective of this study was to uncover the potential link between pathogenic accumulation of salicylic acid (SA), the major metabolite of aspirin, and HAPR in diabetic state. Aspirin failed to inhibit platelet CD62P expression and thromboxane (TX) B 2 /6-keto-prostaglandin（PG）F 1α ratio in a type 2 diabetes mellitus (T2DM) mice model, particularly in the female, which were unanimously accompanied by significantly higher plasma SA concentrations. Pre-administration with SA increased both platelet CD62P expression and TXB 2 /6-keto-PGF 1α ratio in female T2DM mice, while pretreatment with NaHCO 3 caused the opposite effect. On the in vitro human umbilical vein endothelial cells (HUVECs)-platelet interaction assay, SA suppressed inflammation-induced cyclooxygenase-2 upregulation on HUVECs and attenuated their inhibitory effect on platelet aggregation in a dose-dependent manner. The prolonged retention of SA in diabetes may be partially explained by the downregulation of various SA efflux transporters in the kidney and the decreased urine pH. Importantly, in female aspirin non-responsive patients, the trough plasma concentration of SA are markedly increased with T2DM treated with long-term aspirin, and TXB 2 /6-keto-PGF 1α ratio and uric acid level in plasma are positively correlated with SA concentration. Our findings support that the accumulation of SA represents an important factor in causing HAPR in diabetes, and that targeting impaired SA excretion may become a novel intervention strategy to diabetes-associated HAPR. [ABSTRACT FROM AUTHOR]

Polyunsaturated fatty acids (PUFAs) are vital for normal growth and development and physiological function of various tissues in humans. PUFAs have immunomodulatory actions in addition to their ability to modulate inflammation, vascular reactivity, neurotransmission and stem cell biology. PUFAs and their metabolites possess both pro- and anti-inflammatory properties that underlie their actions and involvement in several diseases. Aspirin, a non-steroidal anti-inflammatory drug (NSAID), possesses both cyclo-oxygenase (COX) and lipoxygenase (LOX) inhibitory action and enhances the production of anti-inflammatory lipoxin A4 {(called as epi-lipoxin A4, aspirin-triggered lipoxins (ATLs))}. In addition, at low doses aspirin may not interfere with the production of prostacyclin (PGI2). Both lipoxin A4 and PGI2 have vasodilator, platelet anti-aggregator and anti-inflammatory actions that may underlie the beneficial actions of aspirin. Paradoxically, other NSAIDs may not have the same actions as that of aspirin on PUFA metabolism. Similar anti-inflammatory compounds are formed from eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) by the action of aspirin termed as resolvins (from EPA and DHA) and protectins and maresins from DHA. PUFAs: arachidonic acid (AA), EPA and DHA and their various products modulate not only inflammation and immune response but also possess actions on various genes, nuclear factors, cyclic AMP and GMP, G-protein coupled receptors (GPRs), hypothalamic neurotransmitters, hormones, cytokines and enzymes, and interact with nitric oxide, carbon monoxide, and hydrogen sulfide to regulate their formation and action and to form new compounds that have several biological actions. These pleiotropic actions of PUFAs and their metabolites may explain their ability to play a role in several physiological actions and diseases. The big challenge is to harness these actions to prevent and manage clinical conditions. [ABSTRACT FROM AUTHOR]

Our previous study suggested that co-administration of celecoxib increased chemo-sensitivity of multidrug-resistant human gastric cancer SGC-7901/DDP cells to cisplatin (DDP) in vitro . The present study was designed to investigate whether celecoxib had the similar activities in vivo . SGC-7901/DDP and SGC-7901 xenograft mouse models were established. At the end of the experiment, cisplatin treatment alone significantly inhibited tumor growth in SGC-7901 xenograft, as compared with that in SGC-7901/DDP xenograft, suggesting that it maintained cisplatin sensitivity. When cisplatin and celecoxib were co-administrated, their antitumor activities were augmented in SGC-7901/DDP xenograft. The levels of Ki67 and PCNA after combination therapy were significantly decreased in SGC-7901/DDP xenograft, as compared with those of cisplatin treatment alone. Moreover, examining the apoptotic index by TUNEL assay showed similar results. Further studies demonstrated the inhibitory effect of celecoxib on cyclooxygenase-2 and P-glycoprotein expression was the possible reason to increase sensitivity of SGC-7901/DDP cells to cisplatin in vivo . However, the ratio of thromboxane B 2 and prostaglandin F 1α was elevated after celecoxib treatment in mice. This has been proposed to increase the risk of thrombogenesis. Further studies are required to evaluate the efficacy and safety of celecoxib for reducing chemo-resistance in gastric cancer. [ABSTRACT FROM AUTHOR]

Recently studies indicated that cyclooxygenase-2 might induce P-glycoprotein expression, and was involved in the development of drug resistance phenotype in human gastric cancer cells. The present study was to explore the correlation of celecoxib, a cyclooxygenase-2 specific inhibitor, and P-glycoprotein in drug-resistant gastric cancer cells. The results showed the over-expression of cyclooxygenase-2 and P-glycoprotein in cisplatin-resistant gastric cancer SGC-7901 cells (SGC-7901/DDP), suggesting the possible involvement of cyclooxygenase-2 in the development of P-glycoprotein-mediated drug resistance. Celecoxib was more effective in SGC-7901/DDP cells with a lower inhibitory concentration compared to that in SGC-7901 cells, supporting such a cyclooxygenase-2-dependent drug resistance in SGC-7901/DDP cells. Further studies revealed down-regulation of cyclooxygenase-2 and P-glycoprotein expression by celecoxib, and a decline in prostaglandin E 2 release and protein kinase A level. Celecoxib-induced apoptosis of SGC-7901/DDP cells led to increased p53 expression, decreased Bcl-2/Bax ratio and up-regulated caspase-3 level. Also, celecoxib induced apoptosis in SGC-7901/DDP cells synergistically with cisplatin. Our study suggested that celecoxib might enhance the cytotoxic effect of chemotherapeutic agents in drug-resistant human gastric cancer cells through a cyclooxygenase-2-dependent manner. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA), a chronic degenerative joint disease, is a leading cause of disability among elderly patients. Taraxasterol, a pentacyclic-triterpene isolated from Taraxacum officinale , has been shown to have anti-inflammatory effects. However, the protective effect of taraxasterol on OA remains unclear. In order to provide a scientific basis for the applicability of taraxasterol in OA, the anti-inflammatory effects of taraxasterol on IL-1β-stimulated osteoarthritic chondrocytes were investigated. Chondrocytes were pretreated with taraxasterol 1 h before IL-1β treatment. The productions of MMP-1, MMP3, MMP13, PGE 2 and NO were measured by ELISA and Griess reaction. The expression of COX-2, iNOS, and NF-κB was detected by western blot analysis. Our results demonstrated that taraxasterol dose-dependently suppressed MMP-1, MMP3, MMP13, PGE 2 and NO production induced by IL-1β. The expression of COX-2 and iNOS was also inhibited by taraxasterol. Western blot analysis showed that taraxasterol suppressed IL-1β-induced NF-κB activation in a dose-dependent manner. Taken together, we found that taraxasterol protected human chondrocytes by inhibiting MMPs, NO and PGE 2 production. Taraxasterol may be a useful agent for prevention and treatment of OA. [ABSTRACT FROM AUTHOR]

The major effects of Angiotensin II (AngII) in vascular tissue are mediated by AngII AT 1A receptor activation. Certain effects initiated by AT 1A receptor activation require receptor internalization. In rat aortic vascular smooth muscle cells (RASMC), AngII stimulates cyclooxygenase 2 protein expression. We have previously shown this is mediated by β-arrestin-dependent receptor internalization and NF-κB activation. In this study, a specific inhibitor of clathrin-mediated endocytosis (CME), pitstop-2, was used to test the hypothesis that clathrin-dependent internalization of activated AT 1A receptor mediates NF-κB activation and subsequent cyclooxygenase 2 expression. Radioligand binding assays, real time qt-PCR and immunoblotting were used to document the effects of pitstop-2 on AngII binding and signaling in RASMC. Laser scanning confocal microscopy (LSCM) was used to image pitstop-2׳s effects on AT 1 receptor/GFP internalization in HEK-293 cells and p65 NF-κB nuclear localization in RASMC. Pitstop-2 significantly inhibited internalization of AT 1A receptor (44.7%±3.1% Control vs. 13.2%±8.3% Pitstop-2; n =3) as determined by radioligand binding studies in RASMC. Studies utilizing AT 1A receptor/GFP expressed in HEK 293 cells and LSCM confirmed these findings. Pitstop-2 significantly inhibited AngII-induced p65 NF-κB phosphorylation and nuclear localization, COX-2 message and protein expression in RASMC without altering activation of p42/44 ERK or TNFα signaling. Pitstop-2, a specific inhibitor of clathrin-mediated endocytosis, confirms that internalization of activated AT 1A receptor mediates AngII activation of cyclooxygenase 2 expression in RASMC. These data provide support for additional intracellular signaling pathways activated through β-arrestin mediated internalization of G protein-coupled receptors, such as AT 1A receptors. [ABSTRACT FROM AUTHOR]

The pathophysiological processes of inflammation can lead to a host of diseases, such as periodontitis, atherosclerosis, rheumatoid arthritis, and even cancer. The dysregulated inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) activation play important roles in the development of certain inflammatory diseases. Here, we investigated the effects of CDr10b which is originally developed for a microglia staining probe on inflammation, by modulating NF-κB activation and iNOS and COX-2 expression induced by lipopolysaccharide (LPS) in murine macrophages. The CDr10b suppressed NF-κB activation and iNOS and COX-2 expression induced by LPS. All the results suggest that CDr10b is a promising novel agent for the treatment of inflammatory diseases. [ABSTRACT FROM AUTHOR]

Abstract: Increased expressions of cyclooxygenase-2 (COX-2) and its downstream metabolite, prostaglandin E2 (PGE2), are well documented events in the development of colorectal cancer. Interestingly, PGE2 itself can induce the expression of COX-2 thereby creating the potential for positive feedback. Although evidence for such a positive feedback has been previously described, the specific E-type prostanoid (EP) receptor subtype that mediates this response, as well as the relevant signaling pathways, remain unclear. We now report that the PGE2 stimulated induction of COX-2 expression in human colon cancer HCA-7 cells is mediated by activation of the prostanoid EP4 receptor subtype and is followed by coupling of the receptor to Gαi and the activation of phosphatidylinositol 3-kinase. Subsequent activation of metalloproteinases releases membrane bound heparin-binding epidermal growth factor-like growth factor resulting in the transactivation of epidermal growth factor receptors and the activation of the extracellular signal-regulated kinases and induction of COX-2 expression. This induction of COX-2 expression by PGE2 stimulation of the prostanoid EP4 receptor may underlie the upregulation of COX-2 during colorectal cancer and appears to be an early event in the process of tumorigenesis. [Copyright &y& Elsevier]

Abstract: Metabolites from arachidonic acids play the pivotal roles in inflammatory arthritis. Arachidonic acid could be metabolized by cyclooxygenase (COX) and lipoxygenase (LOX) to produce the bioactive eicosanoids. Although the down-stream products of COX including prostaglandin E2 are well-known inflammatory stimulators, the role of LOX products in inflammatory arthritis is still unclear. Here we found that the downstream product of 15-LOX, 15-S-hydroxyeicosatetraenoic acid (15-(S)–HETE), can enhance the expression of placenta growth factor (PLGF), which is recently considered to play an important role in rheumatoid arthritis. 15-(S)-HETE increased the expression of PLGF in human rheumatoid arthritis synovial fibroblasts in a time-dependent and concentration-dependent manner. PI3K-Akt, NF-κB signaling pathways were involved in the potentiation effects of 15-(S)–HETE. In addition, COX-2 was up-regulated by the treatment of 15-(S)-HETE and the increase of COX-2 expression participated in 15-(S)-HETE-induced PLGF expression, which was confirmed by COX-2 shRNA or pharmacological COX-2 inhibitor. Moreover, it was found that treatment of prostaglandin E2 (PGE2), which was the main down-stream metabolite of COX-2, increased the expression of PLGF. EP1, EP2, EP3 and EP4 agonists could up-regulate PLGF as well. In animal studies, we found that the adjuvant-induced expression of PLGF and COX-2 was inhibited in 15-LOX knockout mice. These results indicated that PLGF up-regulation by 15-LOX downstream product may be involved in inflammatory arthritis. [Copyright &y& Elsevier]

Abstract: The effects of a snake venom Lys-49 phospholipase A2 (PLA2) homolog named MT-II, devoid of enzymatic activity, on the biosynthesis of prostaglandins and protein expression of cyclooxygenase-2 (COX-2) and signaling pathways involved were evaluated in mouse macrophages in culture and in peritoneal cells ex vivo. Stimulation of macrophages with MT-II leads to production of prostaglandin D2 (PGD2) and prostaglandin E2 (PGE2) and protein expression of COX-2 and microsomal prostaglandin E synthase-1 (mPGES-1). Inhibition of cytosolic PLA2 (cPLA2), but not Ca2+ independent PLA2 (iPLA2) reduced release of PGD2 and PGE2 and expression of COX-2 induced by MT-II. Inhibition of nuclear factor κB (NF-κB) significantly reduced MT-II-induced PGE2, but not PGD2 production and COX-2 expression. Inhibitors of either protein kinase C (PKC), protein tyrosine kinase (PTK), or extracellular signal-regulated kinase (ERK) pathways abrogated MT-II-induced NF-κB activation and reduced COX-2 expression and PGE2 release, whereas the p38 mitogen-activated protein kinase (MAPK) inhibitor reduced MT-II-induced COX-2 expression and PGD2 production. Inhibition of phosphatidylinositol-3-kinase (PI3K) pathway abrogated MT-II-induced NF-κB activation, but affected neither prostaglandins production nor COX-2 expression. MT-II-induced production of PGD2 and PGE2 and COX-2 expression were also observed in vivo after intraperitoneal injection into mice. Collectively, our data demonstrate that a catalytically-inactive PLA2 homolog is capable of inducing prostaglandins biosynthesis and COX-2 expression in macrophages in both in vitro and in vivo models, indicating that the enzymatic activity of PLA2 is not necessary to trigger these effects. MT-II-activated NF-κB, cPLA2 and distinct protein kinases are the principal steps involved in these cellular events. [Copyright &y& Elsevier]

Abstract: Overexpression of matrix metalloproteinases (MMPs), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) have long been suggested to play crucial roles in the progression of osteoarthritis. Studies have showed that selective MMPs, iNOS and COX-2 inhibitors possess great potential as chondroprotective agents for osteoarthritis. Therefore, there have been intensive efforts to develop novel natural compounds that target MMPs, iNOS and COX-2 activation. As interleukin-1β (IL-1β) is one of the key proinflammatory cytokines contributing to the progression in osteoarthritis, we investigated the effect of celastrol, a triterpenoid compound extracted from the Chinese herb Tript erygium wilfordii Hook F, in neutralizing the inflammatory effects of IL-1β on MMPs, iNOS and COX-2 expression as well as nitric oxide (NO) and prostaglandin E2 (PGE2) production. Protein expression was detected by Western blotting or by enzyme-linked immunosorbent assay (ELISA); messenger RNA (mRNA) expression was examined by real-time reverse transcription-polymerase chain reaction analysis and the involvement of signal pathway was assessed by transient transfection and luciferase activity assay. We found that treatment of primary human osteoarthritic chondrocytes with various concentrations of celastrol resulted in striking decrease in the expression of MMP-1, MMP-3, MMP-13, iNOS-2 and COX-2. In addition, celastrol treatment of cells also inhibited the activation of nuclear factor-kappa B (NF-kappaB). Taken together, we provide evidence that celastrol can protect human chondrocytes by downregulating the expression of MMPs, iNOS and COX-2. We suggest that celastrol could be a useful agent for prevention and treatment of osteoarthritis. [Copyright &y& Elsevier]

Abstract: Intestinal subepithelial myofibroblasts (ISMFs) are crucial for barrier formation against inflammatory stimuli. Physical injury induces cyclooxygenase-2 (COX-2) expression, which accelerates wound healing by ISMFs. However, the mechanism of COX-2 induction remains unclear. Physically damaged cells release ATP. Here, we investigate the role of ATP-purinergic signaling in wound-induced COX-2 induction in ISMFs. By 24h post-injury, bovine ISMFs had migrated to and closed the wounded area. A COX inhibitor, indomethacin or a purinergic P2 receptor antagonist, suramin, inhibited wound healing. However, additional treatment with indomethacin did not influence wound healing in suramin-treated ISMFs. RT-PCR showed an increase in COX-2 mRNA expression 2h post-injury, which was inhibited by suramin. These results suggest that ATP mediates wound-induced COX-2 elevation. We next assessed the contribution of various purinergic receptors in COX-2 induction. An ATP analog, ATPγS and a purinergic P2Y1, 11–13 receptors agonist, ADP, were among the agents tested which increased COX-2 expression. ATPγS-induced COX-2 mRNA expression was suppressed by suramin or a purinergic P2Xs, P2Y1, 4, 6, and 13 receptors antagonist, PPADS. These data suggest the involvement of Gq-coupled purinergic P2Y1 receptor or Gi-coupled purinergic P2Y13 receptor in COX-2 induction. U73122, an inhibitor of phospholipase C, which is a downstream signal of Gq protein, showed suppression of COX-2 mRNA expression. However, pertussis toxin, a Gi inhibitor, did not show suppression. We also revealed that inhibitors of p38 MAPK and PKC inhibited ATPγS-induced COX-2 mRNA expression. Collectively, purinergic P2Y1 receptor signaling mediates wound-induced COX-2 expression through p38 MAPK and PKC pathways in ISMFs. [Copyright &y& Elsevier]

Abstract: The role of cyclooxygenase-2 (COX-2) in restoring the functions of impaired endothelium is attracting considerable attention, notably the function of COX-2-derived vasodilatory prostaglandins is disputed in the context of the regulation function in the impaired vascular beds. We have examined the hypothesis that COX-2 activity contributes more to vasodilation in hyperglycemic animals than in healthy counterparts, and that COX-2 derived vasodilatory prostaglandins (PGI2 and PGE2) are responsible for this effect. Using the Langendorff heart perfusion system, the effects of COX-2 inhibition were monitored on both basal and bradykinin-induced coronary flows in Sprague–Dawley rats given 8-week streptozotocin-induced diabetes and in age-matched controls (n=15). Secretions of PGI2 and PGE2, both total and the COX-2 dependent pools, have also been compared. The selective COX-2 inhibitor, N-[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide (NS-398), had no effect on coronary flow in the diabetic group of animals. Thus, the compensatory role of COX-2 in regulation of vascular tone in experimental diabetes found in other experimental models was not confirmed. However, COX-2 activity significantly contributed to PGI2 synthesis in healthy rats, with prostacyclin secretion being two-fold decreased by NS-398. Contrary to our hypothesis, neither prostacyclin nor PGE2 production differed between the experimental groups under the basal conditions. Bradykinin had no effect on the secretion of PGI2 in either group, but increased PGE2 synthesis in healthy animals, although not in the streptozotocin group. PGE2 production in response to bradykinin was COX-2-dependent in control animals. We conclude that, in rats with 8-week streptozotocin-induced diabetes, the activity of COX-2 in coronary vasculature is not significantly enhanced. [Copyright &y& Elsevier]

Abstract: Carvacrol, a phenolic monoterpene, has been reported to possess anti-inflammatory properties. However, the mechanisms involved in its pharmacological properties are currently not well understood. In the present study, the contribution of cytokine modulation to the anti-inflammatory effects of carvacrol was investigated in a classical inflammation model: the complete Freund’s adjuvant (CFA)-induced paw inflammation in mice. The paw edema was measured using a plesthismometer. Paw tissue was removed 2h after the inflammatory stimulus to determine the levels of prostaglandin E2 (PGE2) by enzyme immunoassay, the levels of interleukin-1 β (IL-1β), tumor necrosis factor-α (TNF-α), and interleukin-10 (IL-10) by ELISA or the mRNA expression of cyclooxygenase-2 (COX-2), IL-1β, TNF-α, and IL-10 by real-time PCR. Administration of carvacrol produced anti-inflammatory effects against CFA-induced inflammation in mice. Treatment of mice with carvacrol at 50 and 100mg/kg attenuated the paw edema and reduced the IL-1β and PGE2, but not TNF-α, local levels. Similarly, carvacrol (100mg/kg) reduced the COX-2 and IL-1β mRNA expression. The levels of IL-10, an anti-inflammatory cytokine, and the IL-10 mRNA expression in the inflamed paw were enhanced by carvacrol. In addition, the treatment with carvacrol did not reduce the CFA-induced paw edema in IL-10 knockout mice. The present results suggest that carvacrol causes anti-inflammatory effects by reducing the production of inflammatory mediators, such as IL-1β and prostanoids, possibly through the induction of IL-10 release. [Copyright &y& Elsevier]

Abstract: Inflammation underlies the development and progression of a number of skin disorders including psoriasis, atopic dermatitis and cancer. Therefore, novel antiinflammatory agents are of great clinical interest for prevention and treatment of these conditions. Herein, we demonstrated the underlying molecular mechanisms of the antiinflammatory activity of euphol, a tetracyclic triterpene isolated from the sap of Euphorbia tirucalli, in skin inflammation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in mice. Topical application of euphol (100μg/ear) significantly inhibited TPA-induced ear edema and leukocyte influx through the reduction of keratinocyte-derived chemokine (CXCL1/KC) and macrophage inflammatory protein (MIP)-2 levels. At the intracellular level, euphol reduced TPA-induced extracellular signal-regulated protein kinase (ERK) activation and cyclooxygenase-2 (COX-2) upregulation. These effects were associated with euphol''s ability to prevent TPA-induced protein kinase C (PKC) activation, namely PKCα and PKCδ isozymes. Our data indicate that topical application of euphol markedly inhibits the inflammatory response induced by TPA. Thus, euphol represents a promising agent for the management of skin diseases with an inflammatory component. [Copyright &y& Elsevier]

Abstract: Anandamide, an endocannabinoid, prostaglandins derived from cyclooxygenase-2 and nitric oxide synthesized by nitric oxide synthase (NOS), are relevant mediators of embryo implantation. We adopted a pharmacological approach to investigate if anandamide modulated NOS activity in the receptive rat uterus and if prostaglandins mediated this effect. As we were interested in studying the changes that occur at the maternal side of the fetal–maternal interface, we worked with uteri obtained from pseudopregnant rats. Females were sacrificed on day 5 of pseudopregnancy, the day in which implantation would occur, and the uterus was obtained. Anandamide (2ng/kg, i.p.) inhibited NOS activity (P<0.001) and increased the levels of prostaglandin E2 (P<0.001) and prostaglandin F2α (P<0.01). These effects were mediated via cannabinoid receptor type 2, as the pre-treatment with SR144528 (10mg/kg, i.p.), a selective cannabinoid receptor type 2 antagonist, completely reverted anandamide effect on NOS activity and prostaglandin levels. The pre-treatment with a non-selective cyclooxygenase inhibitor (indomethacin 2.5mg/kg, i.p.) or with selective cyclooxygenase-2 inhibitors (meloxicam 4mg/kg, celecoxib 3mg/kg, i.p.) reverted anandamide inhibition on NOS, suggesting that prostaglandins are derived from cyclooxygenase-2 mediated anandamide effect. Thus, anandamide levels seemed to modulate NOS activity, fundamental for implantation, via cannabinoid receptor type 2 receptors, in the receptive uterus. This modulation depends on the production of cyclooxygenase-2 derivatives. These data establish cannabinoid receptors and cyclooxygenase enzymes as an interesting target for the treatment of implantation deficiencies. [Copyright &y& Elsevier]

Abstract: Both mycelium and fruiting body of Antrodia camphorate, a traditional medicinal fungus of the family Polyporaceae in Taiwan, have been suggested to possess multiple biological functions. However, there is little information on the anticancer components and actions of mycelium of Antrodia camphorate. In the present study, the anticancer potential of synthesized maleimide derivatives, which have been isolated from mycelium of Antrodia camphorate, is examined. Comparing the cytotoxicity of two synthesized maleimide derivatives in four human cancer cell lines, camphorataimide B displayed potent efficacy. Then we investigated the impact of camphorataimide B on cell survival and cell cycle progression in vitro, and tumor growth in vivo in MDA-MB-231 breast cancer cells. Camphorataimide B decreased the cell viability and foci formation of MDA-MB-231 breast cancer cells. Further, camphorataimide B triggered apoptosis and blocked cell cycle progression of MDA-MB-231 breast cancer cells. Using immunoblotting analysis, camphorataimide B decrease the expression of cyclin-A and cyclin-B1. Moreover, we demonstrated for the first time that camphorataimide B inhibited cyclooxygenase-2 (COX-2) activity and protein expression in MDA-MB-231 cells. In nude mice study, camphorataimide B administration retarded the xenograft tumor growth of MDA-MB-231 cells. By immunohistochemical analysis, camphorataimide B decreased the expression of Ki-67 in xenograft tumor in vivo. It implied that camphorataimide B blocked cell cycle progression. Consistent with the cell culture investigation, camphorataimide B also reduced the expression of cyclin-A, cyclin-B1 and COX-2 in xenograft tumor. Thus, camphorataimide B may play a crucial role in prevention and therapy of malignant breast cancer. [Copyright &y& Elsevier]

Abstract: Increases in the level of cyclooxygenase (COX)-2 and prostanoids such as prostaglandin E2 (PGE2) are considered biomarkers of colorectal cancer. Therefore, non-steroidal anti-inflammatory drugs (NSAID) have been used to reduce the risk of cancer development by reducing prostanoid biosynthesis as COX inhibitors. Along with their activity as COX inhibitors, NSAID have been reported to have other effects. One major NSAID, indomethacin, has been shown to have several effects independent of COX inhibition. To further examine the COX-inhibition-independent effects of indomethacin on colorectal cancer, we used human colon cancer LS174T cells, known to have express little COX-2 and have no detectable PGE2 production. Here we show that indomethacin has a potential antagonizing effect on human EP2 receptors. We believe this study raises the reasons to use indomethacin as a lead-compound for setting up another EP2 receptor-specific antagonist as a relatively cost-efficient strategy for anti-cancer medication in the future. [Copyright &y& Elsevier]

Abstract: The molecular basis for the anti-inflammatory effects of lindenenyl acetate (LA) was investigated in the lipopolysaccharide (LPS)-stimulated human periodontal ligament (HPDL) cell model. LA concentration-dependently inhibited LPS-induced inducible nitric oxide synthase (iNOS) derived nitric oxide (NO) and cyclooxygenase-2 (COX-2) derived prostaglandin E2 (PGE2) production in HPDL cells. LA also attenuated the production of LPS-induced tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6 and IL-12. LA stimulated heme oxygenase-1 (HO-1) protein expression and enzyme activity of HPDL cells in a dose-dependent manner. Pretreatment with the HO-1 inhibitor, tin protoporphyrin (SnPP), attenuated the inhibitory activities of LA on LPS-induced inflammatory NO, PGE2, IL-1β, TNF-α, IL-6 and IL-12 production. LA induced translocation of Nrf-2. Furthermore, an inhibitor of JNK MAPK abolished LA-induced HO-1 expression. LA exposure up-regulated the levels of phosphorylated adenosine monophosphate-activated protein kinase (AMPK) and its upstream kinase activators, including LKB1 and Ca2+/calmodulin-dependent protein kinase kinase-II. Furthermore, compound C, a specific AMPK inhibitor, partially blocked the LA-induced anti-inflammatory effect. Taken together, these results indicate that LA has anti-inflammatory activity in HPDL cells that might be mediated by the HO-1, AMPK, JNK MAPK, and Nrf-2 pathways. Thus, LA may serve as a potential therapeutic agent in periodontal disease. [Copyright &y& Elsevier]