CBD, PPARS and Gene Expression

Medical scientists are increasingly drawn to cannabidiol (CBD) gene-regulating characteristics. Scientists at the California Pacific Medical Center have revealed that by inhibiting ID-1 gene expression, CBD decreases brain cancer, breast cancer, cell proliferation and metastasis. There are several types of aggressive cancer involving ID-1 expression.

Israeli researchers recognized more than 1,200 CBD-affected genes in 2012: cannabidiol switched on 680 gene transcripts and cannabidiol turned off 524 in a study focusing on the role of CBD in zinc homeostasis. THC was discovered to control 94 genes in the same test. The findings suggest that CBD, but less so THC, impacts the gene expression engaged in zinc homeostasis and indicate that regulation of zinc concentrations could play a significant role by which CBD can impose its antioxidant and anti-inflammatory impacts.

CBD and regulation of gene expression

CBD has little binding quality for either CB1 or CB2, the canonical cannabinoid receptors, both of which are triggered by THC and this well recognized among cannabinoid researchers. Rather than, cannabidiol operates its charm mainly by connecting with multiple non-cannabinoid receptors through receptor-independent channels.

Recent research shows that CBD affects the development of certain genes by activating directly PPAR-gamma, a non-cannabinoid receptor located on the nucleus of the cell. The capacity of CBD to enable PPAR-gamma has possible medicinal potential for cancer and metabolic disorders in particular.

PPARs and their agonists

PPARs (peroxisome proliferator activated receptors) is a set of three nuclear cells — PPAR-alpha, PPAR-gamma, and PPAR-delta (the latter is not yet well defined). Hormones, endogenous fatty acids and different dietary compounds trigger PPARs. When initiated, PPARs tie to certain DNA sections to encourage or discourage particular gene transcription.

Many of the PPAR-regulated genes involve energy homeostasis, lipid absorption and metabolism, insulin levels, and other metabolic processes. The significance of these nuclear receptors is recognized by the pharmaceutical industry. Up to now, the U.S. has endorsed two classes of pharmaceutical PPAR activators – fibrates and thiazolidinediones, approved by the Food and Drug Administration.

Several types of research identified the function of CBD as an agonist of PPAR-gamma.  By preventing fatty acid amide hydrolase (FAAH), cannabidiol also encourages PPAR-alpha action. FAAH is a metabolic enzyme that decomposes many substances of endogenous fatty acids called N-acylethanolamines. This significant endogenous fatty acid molecules family involves anandamide, the endocannabinoid directly binding to the CB1 receptors (located in the mammalian brain and nervous system).

Two other N-acylethanolamines — N-palmitoylethanolamide (PEA) and N-oleoylethanolamide (OEA) — connect straight to PPAR alpha.  Cannabidiol indirectly triggers PPAR-alpha by inhibiting the FAAH enzyme and thus raising PEA and OEA concentrations. Improved PPAR-alpha transmission results in higher concentrations of PEA and OEA.  Inadequate signals of PPAR-alpha have been associated with schizophrenia.

CBD and O3s

Dietary variables also affect the signaling of PPAR.  PPAR-gamma is activated straight by the fatty acid derivatives omega-3 docosahexaenoyl ethanolamine (DHEA) and eicosapentaenoic ethanolamine (EPEA).  DHEA and EPEA can be made from docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) components of fish oil in the body.

A 2013 meeting in Vancouver showed that DHEA functions as a COX-2 enzyme inhibitor, and so does CBD. This is one of the main reasons why cannabidiol has powerful anti-inflammatory characteristics. COX-2 is an enzyme that is a class of inflammatory substances that produces prostaglandins. Aspirin and other anti-inflammatory medicines that are non-steroidal are COX inhibitors.

The process of angiogenesis

Both PPAR-alpha and PPAR-gamma agonists control angiogenesis, which involves the creation of new blood vessels, especially capillaries, according to a 2008 study.  Dysregulated angiogenesis in cancerous cells leads to new blood vessels that provide nutrients to tumors and allow them to develop and metastasize.  CBD may inhibit tumor angiogenesis by directly activating PPAR-gamma and by indirectly encouraging PPAR-alpha function.

Three significant Diabetes Mellitus-related complications — retinopathy, neuropathy, and nephropathy — are all aggravated by abnormal angiogenesis. The use of PPAR agonists to avoid many diabetic complications is of major concern between medical researchers. Conflicting information on the impact of PPAR signaling on angiogenesis, however, exist.  Although various PPAR agonists have demonstrated effectiveness in the prevention of retinal angiogenesis, some studies indicate that angiogenesis may be amplified by activating PPARs. Yet the general scientific consensus appears to be that angiogenesis is prevented by PPAR-alpha and PPAR-gamma agonists.

Clinical applications for obesity, cancer, Alzheimer’s  and schizophrenia

Most PPAR-controlled genes involve lipid metabolism and conservation of energy. Usually, PPAR activity encourages glycolysis (glucose breakdown), lipolysis (lipid breakdown) and insulin sensitivity, making PPAR activation a viable therapy for type II diabetes and obesity. For the treatment of dyslipidemia (obesity) and insulin insensitivity in type II diabetics, PPAR-activating medications fibrates and thiazolidinediones (PPAR-alpha agonists and PPAR-gamma agonists, respectively) have been introduced.

Activation of PPAR-gamma has proved both an anti-proliferative impact and a capacity to induce tumor regression in lines of human lung cancer cells. But activation of PPAR may also have an inverse outcome in some instances. In clinical studies, fibrates and thiazolidinediones, as well as certain drugs that trigger various PPARs, often have a side effect that increases cancer risk. It is necessary to further examine these conflicting results.

An Italian study group revealed in 2011 that the initiation of PPAR-gamma diminishes amyloid-beta plaque, a main molecule in Alzheimer’s disease growth. This is one of the factors why Alzheimer’s patients may find cannabidiol, a PPAR-gamma agonist, a helpful cure.

PPAR-alpha agonists are stated as an additional schizophrenia therapy. Schizophrenia is connected with polymorphisms or mutations in the PPAR-alpha biosynthetic pathway. In addition, activation of PPAR-alpha is both anti-inflammatory and can reduce the release of dopamine, reducing the symptoms of schizophrenia. This can assist clarify why and how the impacts of CBD are anti-psychotic.



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