Cannabinoids Ameliorate Pain and Reduce Disease Pathology in Cerulein-Induced Acute Pancreatitis

Michalski, Christoph; Laukert, Tamara; Sauliunaite, Danguole; Pacher, Pál; Bergmann, Frank; Agarwal, Nitin; Su, Yun; Giese, Thomas; Giese, Nathalia A.; Bátkai, Sándor; Friess, Helmut; Kuner, Rohini

doi:10.1053/j.gastro.2007.02.035

Cited by 95 publications

(89 citation statements)

References 22 publications

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“…The mRNA extraction, cDNA synthesis and QRT-PCR were performed as described previously (specimens used: normal n ¼ 19; PDAC n ¼ 57) (Michalski et al, 2007a). Data are presented as relative expression fold.…”

Section: Qrt-pcrmentioning

confidence: 99%

AZGP1 is a tumor suppressor in pancreatic cancer inducing mesenchymal-to-epithelial transdifferentiation by inhibiting TGF-β-mediated ERK signaling

et al. 2010

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Epithelial-to-mesenchymal transdifferentiation (EMT) mediated by transforming growth factor-b (TGF-b) signaling leads to aggressive cancer progression. In this study, we identified zinc-a2-glycoprotein (AZGP1, ZAG) as a tumor suppressor in pancreatic ductal adenocarcinoma whose expression is lost due to histone deacetylation. In vitro, ZAG silencing strikingly increased invasiveness of pancreatic cancer cells accompanied by the induction of a mesenchymal phenotype. Expression analysis of a set of EMT markers showed an increase in the expression of mesenchymal markers (vimentin (VIM) and integrin-a5) and a concomitant reduction in the expression of epithelial markers (cadherin 1 (CDH1), desmoplakin and keratin-19). Blockade of endogenous TGF-b signaling inhibited these morphological changes and the downregulation of CDH1, as elicited by ZAG silencing. In a ZAG-negative cell line, human recombinant ZAG (rZAG) specifically inhibited exogenous TGF-b-mediated tumor cell invasion and VIM expression. Furthermore, rZAG blocked TGF-b-mediated ERK2 phosphorylation. PCR array analysis revealed that ZAG-induced epithelial transdifferentiation was accompanied by a series of concerted cellular events including a shift in the energy metabolism and prosurvival signals. Thus, epigenetically regulated ZAG is a novel tumor suppressor essential for maintaining an epithelial phenotype.

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Section: Qrt-pcrmentioning

confidence: 99%

AZGP1 is a tumor suppressor in pancreatic cancer inducing mesenchymal-to-epithelial transdifferentiation by inhibiting TGF-β-mediated ERK signaling

et al. 2010

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“…p38 and JNK have been described to become activated by CB 1 and CB 2 in cells of hippocampus in mice (11,13). Recently, a study showed that CB 1 and CB 2 are also expressed on pancreatic cells and that the relatively nonselective CB 1 /CB 2 agonist HU210 ameliorates acute experimental pancreatitis (42). Anti-inflammatory effects of cannabinoids and components of the endocannabinoid system (ECS) have also been described in other models.…”

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confidence: 99%

Activation of cannabinoid receptor 2 reduces inflammation in acute experimental pancreatitis via intra-acinar activation of p38 and MK2-dependent mechanisms

Michler

Storr

Krämer

et al. 2013

American Journal of Physiology-Gastrointestinal and Liver Physi

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. Activation of cannabinoid receptor 2 reduces inflammation in acute experimental pancreatitis via intra-acinar activation of p38 and MK2-dependent mechanisms. Am J Physiol Gastrointest Liver Physiol 304: G181-G192, 2013. First published November 8, 2012 doi:10.1152/ajpgi.00133.2012.-The endocannabinoid system has been shown to mediate beneficial effects on gastrointestinal inflammation via cannabinoid receptors 1 (CB 1) and 2 (CB2). These receptors have also been reported to activate the MAP kinases p38 and c-Jun NH 2-terminal kinase (JNK), which are involved in early acinar events leading to acute pancreatitis and induction of proinflammatory cytokines. Our aim was to examine the role of cannabinoid receptor activation in an experimental model of acute pancreatitis and the potential involvement of MAP kinases. Cerulein pancreatitis was induced in wild-type, CB 1Ϫ/Ϫ, and MK2Ϫ/Ϫ mice pretreated with selective cannabinoid receptor agonists or antagonists. Severity of pancreatitis was determined by serum amylase and IL-6 levels, intracellular activation of pancreatic trypsinogen, lung myeloperoxidase activity, pancreatic edema, and histological examinations. Pancreatic lysates were investigated by Western blotting using phospho-specific antibodies against p38 and JNK. Quantitative PCR data, Western blotting experiments, and immunohistochemistry clearly show that CB 1 and CB2 are expressed in mouse pancreatic acini. During acute pancreatitis, an upregulation especially of CB 2 on apoptotic cells occurred. The unselective CB 1/CB2 agonist HU210 ameliorated pancreatitis in wild-type and CB 1Ϫ/Ϫ mice, indicating that this effect is mediated by CB 2. Furthermore, blockade of CB2, not CB1, with selective antagonists engraved pathology. Stimulation with a selective CB 2 agonist attenuated acute pancreatitis and an increased activation of p38 was observed in the acini. With use of MK2Ϫ/Ϫ mice, it could be demonstrated that this attenuation is dependent on MK2. Hence, using the MK2Ϫ/Ϫ mouse model we reveal a novel CB 2-activated and MAP kinase-dependent pathway that modulates cytokine expression and reduces pancreatic injury and affiliated complications. cannabinoids; CB 2; p38; MK2; experimental pancreatitis ACUTE PANCREATITIS HAS BEEN the subject of investigations for many years, and cytokines have become a new focus in the investigation of the pathophysiology of pancreatitis. Although the exact underlying mechanisms only begin to emerge, cytokines play a crucial role in the process of pancreatitis. Since multiple organ dysfunction syndrome is the primary cause for morbidity and mortality in acute pancreatitis (6, 64), there is a great need to understand the pathophysiological processes leading to this fatal complication. Here, TNF-␣ and IL-6 as proinflammatory cytokines play a predominant role (5, 6, 23). As a consequence of an inflammatory cascade triggered by induction of proinflammatory cytokines in acinar cells (39,45), neutrophil granulocytes immigrate into lung tissue (5, 49). This constitutes a key event in gene...

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“…Our study might suggest that compounds capable to prolong the lifespan of anandamide by inhibiting its inactivation, and that have proved useful in several animal models of pain, inflammation, and itch (15,16,(41)(42)(43)(44)(45)(46)(47)(48), might not be necessarily suitable for the symptomatic treatment of candidiasis, as they might also promote the formation of 3-HAEA, a likely algogenic compound. Furthermore, our data provide an unusual example of the typical capability of pathogenic microorganisms to control, or even exploit, innate defense mechanisms to facilitate infection (49,50).…”

Section: Discussionmentioning

confidence: 98%

“…TRPV1 sensitization likely occurs during candidiasis, because increased expression of vulvar TRPV1 receptors is observed during vulvodynia, a condition similar to that caused by candidiasis (14), and clotrimazole, a widely used antimycotic agent, was suggested to owe its inflamma- tory and algogenic side effects to its capability to activate TRPV1 receptors (40). On the other hand, several peripheral inflammatory conditions causing pain and/or itch are known to be accompanied by elevated levels of anandamide as an adaptive reaction to counteract these symptoms, as suggested by the observation that compounds that prolong the life span of anandamide by inhibiting its inactivation exert anti-inflammatory effects (15,16,(41)(42)(43)(44)(45)(46)(47). Thus, it seems reasonable to hypothesize that, during candidiasisinduced inflammation, on the one hand TRPV1 is sensitized, and, on the other hand, anandamide is produced by host or neighboring cells.…”

Section: Discussionmentioning

confidence: 99%

Chemical synthesis, pharmacological characterization, and possible formation in unicellular fungi of 3-hydroxy-anandamide

Petrocellis

Deva

Mainieri

et al. 2009

Journal of Lipid Research

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The fungal pathogen Candida albicans transforms arachidonic acid (AA) into 3-hydroxyarachidonic acid [3(R)-HETE], and we investigated if its nonpathogenic and 3(R)-HETE-producing close relative, Dipodascopsis uninucleata, could similarly transform the endocannabinoid/endovanilloid anandamide into 3-hydroxyanandamide (3-HAEA). We found that D. uninucleata converts anandamide into 3-HAEA, and we therefore developed an enantiodivergent synthesis for this compound to study its pharmacological activity. Both enantiomers of 3-HAEA were as active as anandamide at ele- Supplementary key words cannabinoidFungi belonging to the Candida species (Ascomycetes; class Saccharomycetes) are among the most abundant fungal pathogens and cause of infections (candidiasis) in humans. They colonize a wide range of micro environments in the human body, and not only cause damage of the skin, nails, oral, or vaginal epithelium, but are also frequently involved in life-threatening infections. Candida species are opportunistic pathogens and cause nosocomial infections (disseminated candidiasis) that are particularly severe in cancer patients under chemotherapy or in immunocompromised individuals (1-6). They also cause mucocutaneous infections, such as vulvovaginal candidiasis, the most prevalent superficial fungal infection in women with acquired immunodeficiency syndrome (AIDS) and diabetes mellitus, or assuming oral contraceptives, antibiotics, and corticosteroids. The symptoms of vaginal candidiasis include itching, burning, soreness, abnormal vaginal discharge, dysparunia, as well as vaginal and vulvar erythema (7). C. albicans is the most prevalent pathogenic fungal species, and accounts for approximately 75% of all infections in women during the child-bearing period (8). Although C. albicans exists in the vagina of most of the women as an innocuous commensal organism with no apparent symptoms or clinical signs (9), it can also cause untreatable problems. Thus, due to its incomplete clearance by therapy with antimycotics, several women diagnosed with an episode of sporadic vulvovaginal infection experience subsequent recurrent episodes of acute vulvovaginitis.When looking at the major symptoms of candidiasis, particularly vulvar itching, burning, soreness, and erythema, it is possible to hypothesize that at least some of them

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Cannabinoids Ameliorate Pain and Reduce Disease Pathology in Cerulein-Induced Acute Pancreatitis

Abstract: Background & Aims-The functional involvement of the endocannabinoid system in modulation of pancreatic inflammation, such as acute pancreatitis, has not been studied to date. Moreover, the therapeutic potential of cannabinoids in pancreatitis has not been addressed.

Cited by 95 publications

References 22 publications

AZGP1 is a tumor suppressor in pancreatic cancer inducing mesenchymal-to-epithelial transdifferentiation by inhibiting TGF-β-mediated ERK signaling

AZGP1 is a tumor suppressor in pancreatic cancer inducing mesenchymal-to-epithelial transdifferentiation by inhibiting TGF-β-mediated ERK signaling

Activation of cannabinoid receptor 2 reduces inflammation in acute experimental pancreatitis via intra-acinar activation of p38 and MK2-dependent mechanisms

Chemical synthesis, pharmacological characterization, and possible formation in unicellular fungi of 3-hydroxy-anandamide

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