Prostaglandin D2 mediates the stimulation of glycogenolysis in the liver by phorbol ester.

The tumour-promoting phorbol ester, phorbol 12-myristate 13-acetate (PMA), when added to the perfused liver, stimulates glycogenolysis 2-fold. This stimulation is not seen when aspirin is present in the perfusion medium. In isolated parenchymal liver cells. PMA is not able to stimulate glycogenolysis, suggesting that its effect on glycogenolysis might be indirect and depends on the presence of the non-parenchymal liver cell types. To test the possible operation of an indirect mechanism, we measured the amount of prostaglandin (PG) D2 in liver perfusates. After addition of PMA, the amount of PGD2 is doubled, in parallel with the increase in glycogenolysis. Glycogenolysis in both isolated parenchymal liver cells and perfused liver could be stimulated by the addition of PGD2. Our data indicate that stimulation of glycogenolysis in the liver by PMA may be mediated by non-parenchymal liver cells, which produce PGD2 in response to PMA. Subsequently PGD2 activates glycogenolysis in the parenchymal liver cells. The intercellular communication inside the liver in response to PMA adds a new mechanism to the complex regulation of glucose homoeostasis by the liver.     

The PAR-1-activating peptide attenuates carrageenan-induced hyperalgesia in rats

We examined if thrombin or a receptor-activating peptide for protease-activated receptor-1 (PAR-1), a thrombin receptor, could modulate nociception at peripheral levels. Intraplantar administration of PAR-1 activators, thrombin or TFLLR-NH(2), but not its inactive control FTLLR-NH(2) or a PAR-2 activator SLIGRL-NH(2), significantly attenuated the hyperalgesia in rats treated with carrageenan, although they had no effect on nociception in na?ve rats. The thrombin-PAR-1 system might thus act to attenuate nociception during inflammatory hyperalgesia.     

Prostaglandin modulation of airway inflammation and hyperresponsiveness in mice sensitized without adjuvant

As adjuvant during sensitization may cause unspecific immune reactions, the aim of the present study was to define the role of cyclooxygenase (COX) activity on airway inflammation and airway hyperresponsiveness (AHR) in an adjuvant-free allergic mouse model.Administration of diclofenac and indomethacin (non-selective COX inhibitors), FR122047 (COX-1 inhibitor) and lumiracoxib (selective COX-2 inhibitor) enhanced AHR. Only diclofenac and lumiracoxib reduced the inflammatory cell content of bronchoalveolar lavage (BAL). Moreover, levels of prostaglandins in BAL were reduced by indomethacin and FR122047 but were unaffected by lumiracoxib. However, compared with antigen controls, none of the COX inhibitors displayed major effects on the production of cytokines, smooth muscle mass, number of goblet cells and eosinophils, or collagen deposition in the airways.These data in mice sensitized without adjuvant support the fact that COX products have a general bronchoprotective role in allergic airway inflammation. Furthermore, the data suggest that COX-1 activity predominantly generates prostanoids in BAL, whereas COX-2 activity is associated with the accumulation of inflammatory cells in BAL. This study further supports that AHR on the one hand, and the inflammatory response and generation of prostanoids on the other, are dissociated and, at least in part, uncoupled events.     

前列腺素D2与睡眠调节

前列腺素D2（PGD2）是目前已知最有潜力的内源性促睡眠物质之一。鼠脑脊液（CSF）中PGD2浓度与睡眠－觉醒周期一致,呈现节律性改变,并且随睡眠剥夺期间嗜睡倾向增加而增加,催化PGH2转变为PGD2的特生酶有两种：Lipocalin型前列腺素D合成酶（L－PGDS）和脾型PGDS。L－PGDS主要在大脑蛛网膜和脉络丛产生,并分泌入CSF。L－PGDS和PGD2在脑室系统、蛛网膜下腔及细胞外间隙中循环,循环中的PGD2可与前脑头端基底腹内侧面的化学感受器中的前列腺素D2受体（DPR）相互作用,通过活化具有腺苷A2a受体的元以产生促进睡眠的信号。PGD2敏感区内DPR的活化可导致腹侧视前区（VLPO）内神经元的活化,其可通过抑制结节乳头核（TMN）而促进睡眠。相反,PGE2在维持大脑清醒状态下起主要作用。PGD2和PGE2的平衡对正常睡眠－觉醒周期的维持十分关键。     

A comparison of chronic aspartame exposure to aspirin on inflammation, hyperalgesia and open field activity following carrageenan-induced monoarthritis.

The purpose of the present study was to investigate whether chronic aspartame exposure possesses analgesic and anti-inflammatory actions in the carrageenan-induced monoarthritis model similar to those properties of aspirin. Prior research demonstrated that aspartame can reduce second phase formalin pain and increase motor activity in arthritic patients. Fifty-eight male Sprague-Dawly rats were treated with aspartame (25, 50, 100 mg/kg) or saline for six days. An additional group of animals received daily injections of saline and on the sixth treatment day, received a 150-mg/kg dose of aspirin 30-minutes prior to behavioral testing. On Day 6, animals received an intra-articular (i.a.) injection of 2% lambda carrageenan (CARR) or an equal volume of saline and were tested four hours later on threshold to mechanical and thermal stimuli, open field activity, and knee joint diameter. Aspirin-treated arthritic animals exhibited significantly less mechanical hyperalgesia and knee joint inflammation compared with vehicle treated arthritic animals. However, aspirin did not reverse thermal hyperalgesia or increase motor activity to control levels. Aspartame did not reduce inflammation, increase motor activity, or attenuate thermal allodynia, but at 50 mg/kg did attenuate mechanical allodynia compared with vehicle treated arthritic animals. The anti-hyperalgesic effect on mechanical hyperalgesia was not seen at 25 mg/kg or 100 mg/kg aspartame. These results suggest that a certain amount of aspartame may provide relief of arthritic pain to a similar degree as aspirin in some individuals. The specific effect of aspartame and aspirin on mechanical hyperalgesia should be considered when these agents are used for the therapeutic treatment of arthritic conditions.     

Inhibition of lipoprotein-associated phospholipase A2 ameliorates inflammation and decreases atherosclerotic plaque formation in ApoE-deficient mice

Background

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is thought to play modulatory roles in the development of atherosclerosis. Here we evaluated the effects of a specific lp-PLA2 inhibitor on atherosclerosis in ApoE-deficient mice and its associated mechanisms.

Methodology/Principal Findings

ApoE-deficient mice fed an atherogenic high-fat diet for 17 weeks were divided into two groups. One group was administered the specific lp-PLA2 inhibitor, darapladib (50 mg/kg/day; p.o.) daily for 6 weeks, while the control group was administered saline. We observed no differences in body weight and serum lipids levels between the two groups at the end of the dietary period. Notably, serum lp-PLA2 activity as well as hs-CRP (C-reactive protein) and IL-6 (Interleukin-6) levels were significantly reduced in the darapladib group, compared with the vehicle group, while the serum PAF (platelet-activating factor) levels were similar between the two groups. Furthermore, the plaque area through the arch to the abdominal aorta was reduced in the darapladib group. Another finding of interest was that the macrophage content was decreased while collagen content was increased in atherosclerotic lesions at the aortic sinus in the darapladib group, compared with the vehicle group. Finally, quantitative RT-PCR performed to determine the expression patterns of specific inflammatory genes at atherosclerotic aortas revealed lower expression of MCP-1, VCAM-1 and TNF-α in the darapladib group.

Conclusions/Significance

Inhibition of lp-PLA2 by darapladib leads to attenuation of in vivo inflammation and decreased plaque formation in ApoE-deficient mice, supporting an anti-atherogenic role during the progression of atherosclerosis.     

Prostaglandin D2 plays an essential role in chronic allergic inflammation of the skin via CRTH2 receptor

PGD(2) plays roles in allergic inflammation via specific receptors, the PGD receptor designated DP and CRTH2 (chemoattractant receptor homologous molecule expressed on Th2 cells). We generated mutant mice carrying a targeted disruption of the CRTH2 gene to investigate the functional roles of CRTH2 in cutaneous inflammatory responses. CRTH2-deficent mice were fertile and grew normally. Ear-swelling responses induced by hapten-specific IgE were less pronounced in mutant mice, giving 35-55% of the responses of normal mice. Similar results were seen in mice treated with a hemopoietic PGD synthase inhibitor, HQL-79, or a CRTH2 antagonist, ramatroban. The reduction in cutaneous responses was associated with decreased infiltration of lymphocytes, eosinophils, and basophils and decreased production of macrophage-derived chemokine and RANTES at inflammatory sites. In models of chronic contact hypersensitivity induced by repeated hapten application, CRTH2 deficiency resulted in a reduction by approximately half of skin responses and low levels (63% of control) of serum IgE production, although in vivo migration of Langerhans cells and dendritic cells to regional lymph nodes was not impaired in CRTH2-deficient mice. In contrast, delayed-type hypersensitivity to SRBC and irritation dermatitis in mutant mice were the same as in wild-type mice. These findings indicate that the PGD(2)-CRTH2 system plays a significant role in chronic allergic skin inflammation. CRTH2 may represent a novel therapeutic target for treatment of human allergic disorders, including atopic dermatitis.     

美普他酚及其同分异构体对角叉菜胶引起的炎症大鼠具有抗热痛敏作用

实验以清醒大鼠的缩腿潜伏期为指标,观察了腹腔注射美普他酚及其同分异构体112824和112825对角叉菜胶引起的热痛敏的影响.外周炎症由单侧足底注射角叉菜胶(2 mg/100 μl)引起.注射角叉菜胶3 h后,注射侧后肢局部红肿及热痛过敏反应达到高峰,持续数小时.腹腔注射0.1 mg/kg美普他酚对炎症和非炎症侧后肢的缩腿潜伏期无明显影响(P＞0.05,n=8).腹腔注射1mg/kg和10 mg/kg美普他酚对炎症和非炎症侧后肢产生明显的抗痛敏和抗伤害效应,且对炎症侧缩腿反应的抑制(抗痛敏)作用明显强于非炎症侧(抗伤害)(P＜0.05,n=8～11).预先腹腔注射1.5 mg/kg纳洛酮明显阻断美普他酚引起的抗伤害和抗痛敏效应.腹腔注射美普他酚的同分异构体112824(1 mg/kg)和112825(1.5 ms/kg)可产生与美普他酚类似的抗痛敏作用,该效应可被预先腹腔注射1.5 mg/kg纳洛酮完全阻断.提示美普他酚及其同分异构体具有明显抗伤害和抗痛敏作用,且以后者为强.该作用主要通过mu阿片受体介导.本研究为扩展美普他酚及其同分异构体在临床上的应用提供了依据.     

Exercise accelerates cutaneous wound healing and decreases wound inflammation in aged mice

The purpose of this study was to determine the effect of exercise on wound healing and inflammation in young (3 mo) and old (18 mo) female BALB/cByJ mice. Mice were assigned to either exercise or sedentary control (control) groups. The exercise group mice were run on a motorized treadmill at a moderate intensity 30 min/day for 8 days. All mice were given four full-thickness dermal wounds, and the rate of wound closure was assessed daily for 10 days. Four months later, the aged mice were rerandomized to treatment, wounded again in different locations, and wounds were harvested at 1, 3, or 5 days postwounding. Wound tissue was analyzed for IL-1beta, IL-6, keratinocyte chemoattractant (KC), monocyte chemoattractant protein-1 (MCP-1), and TNF-alpha protein. Myeloperoxidase (MPO) activity and F4/80 mRNA were assessed as an indirect measure of neutrophil and macrophage content, respectively. There was a trend (P = 0.10) for exercise to reduce wound size in young mice, and exercise significantly (P < 0.05) decreased wound size in old mice. TNF-alpha, KC, and MCP-1 were significantly (P < 0.05) lower in wounds from exercised old mice compared with control. No group differences were found for wound IL-1beta or IL-6, MPO activity, or F4/80 mRNA. Our data suggest that exercise accelerates the wound healing process in old mice. This improved healing response in the old mice may be the result of an exercise-induced anti-inflammatory response in the wound.     

Inhibitory effect of ginsenoside-Rd on carrageenan-induced inflammation in rats

A previous study reported that ginsenoside-Rd reduced the production of tumor necrosis factor-α by inhibiting nuclear factor-κB in lipopolysaccharide-activated N9 microglia in vitro. The aim of the present study was to confirm the anti-inflammatory effects and mechanisms of ginsenoside-Rd in animal experiments involving acute inflammation. The results indicated that ginsenoside-Rd at doses ranging from 12.5 to 50?mg/kg i.m. significantly inhibited the swelling of hind paws in rats for 1-6?h after the carrageenan injection. The levels of proinflammatory cytokines and proinflammatory mediators were markedly reduced by ginsenoside-Rd. Ginsenoside-Rd, when administered intramuscularly at 12.5, 25, and 50?mg/kg doses, showed signicant inhibition of carrageenan-induced production of interleukin-1β (6.91%, 45.75%, and 55.18%, respectively), tumor necrosis factor-α (37.99%, 56.39%, and 47.38%, respectively), prostaglandin E(2) (22.92%, 30.12%, and 36.36%, respectively), and nitric oxide (28.27%, 44.53%, and 53.42%, respectively). In addition, ginsenoside-Rd (12.5, 25, and 50?mg/kg i.m.) effectively decreased the levels of nuclear factor-κB (6.77%, 20.28%, and 41.03%, respectively) and phosphorylation of IκBα (13.23%, 26.92%, and 41.80%, respectively) in the carrageenan-inflamed paw tissues. These results suggest that ginsenoside-Rd has significant anti-inflammatory effects in vivo, which might be due to its blocking of the nuclear factor-κB signaling pathway. Thus, it may be possible to develop ginsenoside-Rd as a useful agent for inflammatory diseases.     

Inhibitory effect of quercetin on carrageenan-induced inflammation in rats

We examined the effect of quercetin on the inflammatory response induced by carrageenan in the rat. Air pouches were induced subcutaneously on the backs of rats and injected with carrageenan. The rats were treated with either vehicle or quercetin at a dose of 10 mg/kg one hour before carrageenan challenge. Fourty-eight hour after carrageenan challenge, the air pouches were removed and analyzed. The volume, protein amounts and cell counts in the exudation obtained from the quercetin-treated animals were significantly reduced compared to those from vehicle-treated animals. The contents of PGE(2), TNF-alpha, RANTES, MIP-2 and the mRNA for cyclooxygenase-2 were also suppressed in these rats. The histological examination displayed the suppression of the inflammatory response in the pouch tissues from quercetin-treated rats. As the anti-inflammatory effect of the flavonols was more or less at the similar level among the quercetin-, isoquercitrin- or rutin-treated rats, it appeared that the sugar parts did not influence on the anti-inflammatory effect.Our study indicated that the flavonols modulated the inflammatory response, at least in part, by modulating the prostanoid synthesis as well as cytokine production.     

Prostaglandin D2 and adenosine as endogenous somnogens

Sleep and Biological Rhythms -     

Ebselen enhances insulin sensitivity and decreases oxidative stress by inhibiting SHIP2 and protects from inflammation in diabetic mice

Ebselen, a multifunctional organoselenium compound, has been recognized as a potential treatment for diabetes-related disorders. However, the underlying mechanisms whereby ebselen regulates metabolic pathways remain elusive. We discovered that ebselen inhibits lipid phosphatase SHIP2 (Src homology 2 domain-containing inositol-5-phosphatase 2), an emerging drug target to ameliorate insulin resistance in diabetes. We found that ebselen directly binds to and inhibits the catalytic activity of the recombinant SHIP2 phosphatase domain and SHIP2 in cultured cells, the skeletal muscle and liver of the diabetic db/db mice, and the liver of the SHIP2 overexpressing (SHIP2-Tg) mice. Ebselen increased insulin-induced Akt phosphorylation in cultured myotubes, enhanced insulin sensitivity and protected liver tissue from lipid peroxidation and inflammation in the db/db mice, and improved glucose tolerance more efficiently than metformin in the SHIP2-Tg mice. SHIP2 overexpression abrogated the ability of ebselen to induce glucose uptake and reduce ROS production in myotubes and blunted the effect of ebselen to inhibit SHIP2 in the skeletal muscle of the SHIP2-Tg mice. Our data reveal ebselen as a potent SHIP2 inhibitor and demonstrate that the ability of ebselen to ameliorate insulin resistance and act as an antioxidant is at least in part mediated by the reduction of SHIP2 activity.     

Polyamine deprivation alters formalin-induced hyperalgesia and decreases morphine efficacy

Although the exact functions of polyamines in the nervous system remain still unclear, they are thought to have a physiological role in intracellular signal processing and neurotransmission. Polyamine deprivation which consists in the reduction of both the endogenous and exogenous sources of polyamines is a promising treatment for cancer. In a previous study we have shown that this treatment provokes an analgesic effect in rats submitted to brief phasic nociceptive tests. The present study examined the effect of polyamine deprivation on pain-related behaviors and spinal c-fos expression evoked in the formalin test presumed to better reflect clinical pain, using morphine as analgesia control. Polyamine deprivation per se altered the characteristic pain-related behaviors, reducing the interphase depression of pain, without inducing changes in the spinal Fos staining. In addition this treatment prevented the antinociceptive effect of morphine both on behavioral responses and on spinal c-fos expression. In polyamine-deprived rats, despite morphine injection, nociceptive scores remained dramatically high during the intermediate and the late phases of the response and the number of Fos immunoreactive neurons remained largely higher in deeper layers than in morphine control rats. Altogether these data support a modulatory role of polyamines both on the neuronal circuitry mediating sensory information, and on mechanisms underlying morphine analgesia.     

前列腺素D2及其受体与哺乳动物生殖

前列腺素D2(PGD2)是前列腺素(PGs)家族成员之一,广泛分布于各种哺乳动物组织中,并发挥多种生理功能。PGD,可以促进睡眠、诱导过敏反应、抑制血小板凝集及松弛平滑肌等,并且在生殖系统中起重要作用。机体中存在生化和免疫功能截然不同的两类前列腺素D合成酶(PGDs)：脑型PGDS(L-PGDS)和生血型PGDS(hPGDS)。生殖系统中,L-PGDS主要存在于雄性生殖道,可能在睾丸发育、精子发生、精子成熟以及血一睾和血一附睾屏障等方面发挥重要作用。hPGDS在妊娠时期的子宫内膜和胚胎滋养层中表达,由其产生的PGD2可能通过DP和CRTH2两种受体来维持妊娠。此外,PGD2还可能与女性不孕以及精子在雌性生殖道内的运输等有关。     

I - Prostaglandin hyperalgesia, a cAMP/Ca2+ dependent process.

Prostaglandins stimulate cAMP increase in several biological systems including CNS. The possible participation of a cAMP/Ca2+ related mechanism in prostaglandin induced hyperalgesia in the rat paw, as measured by a modification of the Randall-Selitto method was investigated. A serie of agents was administered in the paw in an attempt to change either Ca2+ or cyclic AMP concentration at the nociceptive terminations. PGE2, dibutyryl cyclic AMP, isoprenaline, noradrenaline, adrenaline, Ca2+ionophore (A23187), BaCl2 caused a dose dependent hyperalgesia. The hyperalgesic effect of these substances was enhanced by methyl-xanthines. Cyclic GMP as well as agents which interfere with Ca2+ influx (verapamil and lanthanum) were local analgesics in normal and hyperalgesic paws.     

HGF can reduce accumulation of inflammation and regulate glucose homeostasis in T2D mice

Journal of Physiology and Biochemistry - Hepatocyte growth factor (HGF) has been studied as a protective factor for the survival of islet β cells and regulatory glucose transport and...     

Prostaglandin D2, a potential antineoplastic agent

Cytotoxic actions of various prostaglandins were examined on L1210 mouse leukemia and several human leukemia cell lines, and prostaglandin D₂ (PGD₂) was found most active. PGD₂ exerted a dose dependent inhibition of L1210 cell growth over 3.6 μ$\text{M}$. At 14.3 μ$\text{M}$ growth was completely inhibited, and the number of viable cells remarkably decreased during culture. Microscopically the remaining cells showed degenerative changes with many vacuoles in their cytoplasm. The IC₅₀ value of PGD₂ on L1210 cell growth was calculated to be 6.9 μ$\text{M}$ (2.4 μg/ml), and at this concentration the DNA synthesis in 24 hr cultured cells was also decreased to a half of the level in the control cells. Such growth inhibition by PGD₂ was also found at similar concentrations with several human leukemia cell lines such as NALL-1, RPMI-8226, RPMI-8402, and Sk-Ly-16. Among other prostaglandins tested, PGA₂ showed a comparable, and PGE₂ a less but significant growth inhibitory activity, while PGB₂, PGF_2α and PGI₂ had no such effects on cell proliferation at 14.3 μ$\text{M}$ concentration. These results suggest a potential antineoplastic activity of PGD₂.     

Prostaglandin I2 as a potentiator of acute inflammation in rats.

Prostaglandin I2 potentiated the paw swelling induced by carrageenin in rats. Prostaglandin I2 (0.1 microgram) showed similar activity to PGE1 (0.01 microgram). This potentiating property disappeared in 60 minutes and was completely abolished by diphenhydramine (25 mg kg-1, i.p.). In vascular permeability tests, PGI2 itself (2.5 X 10(-10) mol, 88 ng) caused no dye leakage reaction, but PGE1 (2.5 X 10(-10) mol, 88.5 ng) caused a significant dye leakage. This effect of PGE1 was statistically significant compared with vehicle- or PGI2-treated groups (p less than 0.05). Prostaglandin I2 potentiated the increased vascular permeability induced by 5-hydroxytriptamine (2.5 X 10(-10) mol), bradykinin (5 X 10(-10) mol) and histamine (2 X 10(-10) to 2 X 10(-8) mol). The potentiation was the most evident in the case of histamine.