The Role of Cannabinoids in the Setting of Cirrhosis.

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“Although the mortality rates of cirrhosis are underestimated, its socioeconomic burden has demonstrated a significant global impact. Cirrhosis is defined by the disruption of normal liver architecture after years of chronic insult by different etiologies. Treatment modalities are recommended primarily in decompensated cirrhosis and specifically tailored to the different manifestations of hepatic decompensation. Antifibrogenic therapies are within an active area of investigation.

The endocannabinoid system has been shown to play a role in liver disease, and cirrhosis specifically, with intriguing possible therapeutic benefits. The endocannabinoid system comprises cannabinoid receptors 1 (CB1) and cannabinoid receptor 2 (CB2) and their ligands, endocannabinoids and exocannabinoids.

CB1 activation enhances fibrogenesis, whereas CB2 activation counteracts progression to fibrosis. Conversely, deletion of CB1 is associated with an improvement of hepatic fibrosis and steatosis, and deletion of CB2 results in increased collagen deposition, steatosis, and enhanced inflammation.

CB1 antagonism has also demonstrated vascular effects in patients with cirrhosis, causing an increase in arterial pressure and vascular resistance as well as a decrease in mesenteric blood flow and portal pressure, thereby preventing ascites. In mice with hepatic encephalopathy, CB1 blockade and activation of CB2 demonstrated improved neurologic score and cognitive function.

Endocannabinoids, themselves also have mechanistic roles in cirrhosis. Arachidonoyl ethanolamide (AEA) exhibits antifibrogenic properties by inhibition of HSC proliferation and induction of necrotic death. AEA induces mesenteric vasodilation and hypotension via CB1 induction. 2-arachidonoyl glycerol (2-AG) is a fibrogenic mediator independent of CB receptors, but in higher doses induces apoptosis of HSCs, which may actually show antifibrotic properties. 2-AG has also demonstrated growth-inhibitory and cytotoxic effects.

The exocannabinoid, THC, suppresses proliferation of hepatic myofibroblasts and stellate cells and induces apoptosis, which may reveal antifibrotic and hepatoprotective mechanisms. Thus, several components of the endocannabinoid system have therapeutic potential in cirrhosis.”

https://www.ncbi.nlm.nih.gov/pubmed/29890719

http://www.mdpi.com/2305-6320/5/2/52

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Mechanistic Potential and Therapeutic Implications of Cannabinoids in Nonalcoholic Fatty Liver Disease.

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“Nonalcoholic fatty liver disease (NAFLD) is comprised of nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). It is defined by histologic or radiographic evidence of steatosis in the absence of alternative etiologies, including significant alcohol consumption, steatogenic medication use, or hereditary disorders.

NAFLD is now the most common liver disease, and when NASH is present it can progress to fibrosis and hepatocellular carcinoma. Different mechanisms have been identified as contributors to the physiology of NAFLD; insulin resistance and related metabolic derangements have been the hallmark of physiology associated with NAFLD.

The mainstay of treatment has classically involved lifestyle modifications focused on the reduction of insulin resistance. However, emerging evidence suggests that the endocannabinoid system and its associated cannabinoid receptors and ligands have mechanistic and therapeutic implications in metabolic derangements and specifically in NAFLD.

Cannabinoid receptor 1 antagonism has demonstrated promising effects with increased resistance to hepatic steatosis, reversal of hepatic steatosis, and improvements in glycemic control, insulin resistance, and dyslipidemia. Literature regarding the role of cannabinoid receptor 2 in NAFLD is controversial.

Exocannabinoids and endocannabinoids have demonstrated some therapeutic impact on metabolic derangements associated with NAFLD, although literature regarding direct therapeutic use in NAFLD is limited. Nonetheless, the properties of the endocannabinoid system, its receptors, substrates, and ligands remain a significant arena warranting further research, with potential for a pharmacologic intervention for a disease with an anticipated increase in economic and clinical burden.”

https://www.ncbi.nlm.nih.gov/pubmed/29843404

http://www.mdpi.com/2305-6320/5/2/47

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Cannabis, cannabinoids, and health.

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“Cannabis does have therapeutic properties for certain indications.”   https://www.ncbi.nlm.nih.gov/pubmed/29302228

“The legislative policies that have been established to reduce the risks in relation to cannabis have long represented an obstacle to research concerning medical cannabis use. Improved knowledge of the endocannabinoid system and of exocannabinoids has proven that cannabis may have significant therapeutic effects.”  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5741114/

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Exocannabinoids effect on in vitro bovine oocyte maturation via activation of AKT and ERK1/2.

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“Endocannabinoids are known to mediate practically all reproductive events in mammals; however, little is known about their role in oocyte maturation. Through RT-PCR and immunocytochemistry, this study confirms the presence of CB1 and CB2 cannabinoidreceptors in bovine oocytes and shows how exposure to the exogenous cannabinoids HU-210 and THC during their in vitro maturation (IVM) activates the phosphorylation of AKT and ERK1/2 proteins associated with the resumption of meiosis. Although supplementation with HU-210 or THC during IVM did not increase blastocyst yields, the expression of interferon tau (IFNτ) and gap junction alpha-1 protein (GJA1) was enhanced at the blastocyst stage. Our data suggest that cannabinoid agonists may be useful IVM supplements as their presence during oocyte maturation upregulates the expression in blastocysts of key genes for embryo quality.”

https://www.ncbi.nlm.nih.gov/pubmed/27798282

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