The Endocannabinoid, Anandamide, Induces Cannabinoid Receptor-Independent Cell Death in Renal Proximal Tubule Cells

Monika Schlosser, Heike Löser, Sören V. Siegmund, Manuel Montesinos-Rongen, Laura Bindila, Beat Lutz, David A. Barrett, Sarir Sarmad, Catharine A. Ortori, Veronika Grau, Melanie von Brandenstein, Jochen W.U. Fries  (Decemeber 2017)

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The endocannabinoid anandamide induces cell death in renal proximal tubule cell in a time- and dose-dependent manner. This pathway is mediated via ROS and is independent of cannabinoid receptors, membrane cholesterol or FAAH activity.

Hepatic expression of cannabinoid receptors CB1 and CB2 correlate with fibrogenesis in patients with chronic hepatitis B

Erhei Dai, Lianshan Zhang, Lihong Ye, Shiging Wan, Lulu Feng, Qi Qi, Fang Yao, Zhen Li  (June 2017)

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The roles of cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2) in hepatofibrosis in patients with chronic hepatitis B (CHB) have not been studied fully. This study aimed to explore the relationship between liver fibrosis and the expression of CB1 and CB2 in patients with CHB. The hepatic expression of CB1 and CB2 plays an important role during the progression of fibrosis induced by CHB. Endogenous activation of CB1 receptors in patients with CHB enhances fibrogenesis by direct effect on activated HSCs.

The Endocannabinoid/CB1R System Is Overactive in Hermansky-Pudlak Syndrome Associated Pulmonary Fibrosis in Humans

Nathan J. Coffey , Bernadette R. Gochuico , Tony Jourdan , Joshua K. Park , Kevin J. O’Brien , William A. Gahl ,George Kunos , Resat Cinar  (May 2017)

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We identified that HPS-PF patients displayed a higher endocannabinoid tone compared to healthy patients. Given the established pro-fibrotic role of CB1R in other tissues, CB1R antagonism could represent a therapeutic target in HPS-PF.

Novel Treatment Strategy for Pulmonary Fibrosis by a Hybrid Inhibitor of Peripheral Cannabinoid-1-Receptors (CB1R) and Inducible NO Synthase (iNOS)

R. Cinar, B.R. Gochuico, M.R. Iyer, J.K. Park, W.A. Gahl, G. Kunos  (May 2017)

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We have identified CB1R as a novel therapeutic target in IPF. Moreover, simultaneous inhibition of CB1R and iNOS by peripherally restricted, orally bioavailable hybrid CB1R/iNOS inhibitors may offer a novel form of pharmacotherapy with improved efficacy and safety.

Design, Synthesis, and Biological Evaluation of Novel, Non-Brain-Penetrant, Hybrid Cannabinoid CB1R Inverse Agonist/Inducible Nitric Oxide Synthase (iNOS) Inhibitors for the Treatment of Liver Fibrosis

Malliga R. Iyer, Resat Cinar, Alexis Katz, Michael Gao, Katalin Erdelyi, Tony Jourdan, Nathan J. Coffey, Pal Pacher, and George Kunos  (January 2017)

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We report the design, synthesis, and structure–activity relationships of novel dual-target compounds with antagonist/inverse agonist activity at cannabinoid receptor type 1 (CB1R) and inhibitory effect on inducible nitric oxide synthase (iNOS). A series of 3,4-diarylpyrazolinecarboximidamides were synthesized and evaluated in CB1 receptor (CB1R) binding assays and iNOS activity assays. The novel compounds, designed to have limited brain penetrance, elicited potent in vitro CB1R antagonist activities and iNOS inhibitory activities. Some key compounds displayed high CB1R binding affinities. Compound 7 demonstrated potent in vivo pharmacological activities such as reduction of food intake mediated by the antagonism of the CB1Rs and antifibrotic effect in the animal models of fibrosis mediated by iNOS inhibition and CB1R antagonism.

Serum levels of endocannabinoids are independently associated with nonalcoholic fatty liver disease

Shira Zelber‐Sagi, Shahar Azar, Alina Nemirovski, Muriel Webb, Zamir Halpern, Oren Shibolet, Joseph Tam  (November 2016)
To evaluate the association between circulating levels of endocannabinoids (eCBs) and non‐alcoholic fatty liver disease (NAFLD). This study is the first to show high circulating levels of 2‐AG and AA in NAFLD patients compared with controls, independent of obesity. The findings may suggest an independent role of eCBs in the pathogenesis of NAFLD.

The direct profibrotic and indirect immune antifibrotic balance of blocking the cannabinoid 2 receptor

Yosefa Avraham, Johnny Amer, Sarit Doron, Lina Abu-Tair, Mahmud Mahamid, Areej Khatib, Elliot M. Berry, and Rifaat Safadi  (June 2012)
Cannabinoid 2 (CB2) receptors expressed on immune cells are considered to be antifibrogenic. Hepatic stellate cells (HSCs) directly interact with phagocytosis lymphocytes, but the nature of this interaction is obscure. We aimed to study the effects of CB2 receptors on hepatic fibrosis via their role in mediating immunity.