cannabidiol and Fibrosis

Cannabidiol (CBD) is a non-intoxicating compound of Cannabis with anti-fibrotic properties. Pulmonary hypertension (PH) is a disease that can lead to right ventricular (RV) failure and premature death. There is evidence that CBD reduces monocrotaline (MCT)-induced PH, including reducing right ventricular systolic pressure (RVSP), vasorelaxant effect on pulmonary arteries, and decreasing expression of profibrotic markers in the lungs. The aim of our study was to investigate the effect of chronic administration of CBD (10 mg/kg daily for 21 days) on profibrotic parameters in the RVs of MCT-induced PH rats. In MCT-induced PH, we found an increase in profibrotic parameters and parameters related to RV dysfunction, i.e. plasma pro-B-type natriuretic peptide (NT-proBNP), cardiomyocyte width, interstitial and perivascular fibrosis area, amount of fibroblasts and fibronectin, as well as overexpression of the transforming growth of factor β1 (TGF-β1), galectin-3 (Gal-3), suppressor of mothers against decapentaplegic 2 (SMAD2), phosphorylated SMAD2 (pSMAD2) and alpha-smooth muscle actin (α-SMA). In contrast, vascular endothelial cadherin (VE-cadherin) levels were decreased in the RVs of MCT-induced PH rats. Administration of CBD reduced the amount of plasma NT-proBNP, the width of cardiomyocytes, the amount of fibrosis area, fibronectin and fibroblast expression, as well as decreased the expression of TGF-β1, Gal-3, SMAD2, pSMAD2, and increased the level of VE-cadherin. Overall, CBD has been found to have the anti-fibrotic potential in MCT-induced PH. As such, CBD may act as an adjuvant therapy for PH, however, further detailed investigations are recommended to confirm our promising results.

Topics: Animals; Cannabidiol; Fibronectins; Fibrosis; Heart Failure; Hypertension, Pulmonary; Monocrotaline; Rats; Transforming Growth Factor beta; Transforming Growth Factor beta1

As a new type of persistent organic pollutant, perfluorooctane sulphonate (PFOS) has received extensive attention worldwide. Cannabidiol (CBD) is a non-psychoactive natural cannabinoid extract that has been proved to have antioxidation, regulation of inflammation and other functions. However, the effects of PFOS on liver injury and whether CBD can alleviate PFOS-induced liver injury are still unclear. Therefore, in this study, we used CBD (10 mg/kg) and/or PFOS (5 mg/kg) to intraperitoneally inject mice for 30 days. We found that PFOS exposure led to inflammatory infiltration in the liver of mice, increased the formation of macrophage extracellular trap (MET), and promoted fibrosis. In vitro, we established a coculture system of RAW264.7, AML12 and LX-2 cells, and treated them with CBD (10 μM) and/or PFOS (200 μM). The results showed that PFOS could also induce the expression of MET, inflammation and fibrosis marker genes in vitro. Coiled-coil domain containing protein 25 (CCD25), as a MET-DNA sensor, was used to investigate its ability to regulate inflammation and fibrosis, we knocked down CCDC25 and its downstream proteins (integrin-linked kinase, ILK) by siRNA technology, and used QNZ to inhibit NF-κB pathway. The results showed that the knockdown of CCDC25 and ILK and the inhibition of NF-κB pathway could inhibit MET-induced inflammation and fibrosis marker gene expression. In summary, we found that PFOS-induced MET can promote inflammation and fibrosis through the CCDC25-ILK-NF-κB signaling axis, while the treatment of CBD showed a protective effect, and it is proved by Macromolecular docking that this protective effect is achieved by combining CBD with peptidylarginine deiminase 4 (PAD4) to alleviate the release of MET. Therefore, regulating the formation of MET and the CCDC25-ILK-NF-κB signaling axis is an innovative treatment option that can effectively reduce hepatotoxicity. Our study reveals the mechanism of PFOS-induced hepatotoxicity and provides promising insights into the protective role of CBD in this process.

Topics: Animals; Cannabidiol; Chemical and Drug Induced Liver Injury; Extracellular Traps; Fibrosis; Inflammation; Macrophages; Mice; NF-kappa B

Some cannabinoids showed anti-inflammatory and antifibrotic activities. EHP-101 is an oral lipidic formulation of the novel non-psychotropic cannabidiol aminoquinone VCE-004.8, which showed antifibrotic activity in murine models of systemic sclerosis induced by bleomycin. We herein examined the effect of EHP-101 on cardiac and other organ fibrosis in a mouse model induced by Angiotensin II. VCE-004.8 inhibited TGFβ- and Ang II-induced myofibroblast differentiation in cardiac fibroblasts detected by α-SMA expression. VCE-004.8 also inhibited Ang II-induced ERK 1 + 2 phosphorylation, NFAT activation and mRNA expression of IL1β, IL6, Col1A2 and CCL2 in cardiac fibroblasts. Mice infused with Ang II resulted in collagen accumulation in left ventricle, aortic, dermal, renal and pulmonary tissues; oral administration of EHP-101, Ajulemic acid and Losartan improved these phenotypes. In myocardial tissue, Ang II induced infiltration of T cells and macrophages together with the accumulation of collagen and Tenascin C; those were all reduced by either EHP-101 or Losartan treatment. Cardiac tissue RNA-Seq analyses revealed a similar transcriptomic signature for both treatments for inflammatory and fibrotic pathways. However, the gene set enrichment analysis comparing data from EHP-101 vs Losartan showed specific hallmarks modified only by EHP-101. Specifically, EHP-101 inhibited the expression of genes such as CDK1, TOP2A and MKi67 that are regulated to the E2 factor family of transcription factors. This study suggests that the oral administration of EHP-101 prevents and inhibits cardiac inflammation and fibrosis. Furthermore, EHP-101 inhibits renal, pulmonary and dermal fibrosis. EHP-101 could offer new opportunities in the treatment of cardiac fibrosis and other fibrotic diseases.

Topics: Administration, Oral; Angiotensin II; Animals; Anti-Inflammatory Agents; Cannabidiol; Fibroblasts; Fibrosis; Gene Expression Regulation; Inflammation; Losartan; Male; Mice; Mice, Inbred C57BL; Myocardium; Myofibroblasts

The endocannabinoid system and PPARγ are important targets for the development of novel compounds against fibrotic diseases such as systemic sclerosis (SSc), also called scleroderma. The aim of this study was to characterize VCE-004.3, a novel cannabidiol derivative, and study its anti-inflammatory and anti-fibrotic activities.. VCE-004.3 is a novel semisynthetic cannabidiol derivative that behaves as a dual PPARγ/CB

Topics: Animals; Bleomycin; Cannabidiol; Cell Differentiation; Cell Movement; Cells, Cultured; Dose-Response Relationship, Drug; Female; Fibrosis; Humans; Inflammation; Mice; Mice, Inbred BALB C; Molecular Docking Simulation; Molecular Structure; NIH 3T3 Cells; PPAR gamma; Quinones; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Skin; Structure-Activity Relationship

Systemic sclerosis (SSc) or scleroderma is a chronic multi-organ autoimmune disease characterized by vascular, immunological, and fibrotic abnormalities. The etiology of SSc is unknown, but there is growing evidence that dysfunction of the endocannabinoid system (ECS) plays a critical role in its development. Since the semi-synthetic cannabinoquinoid VCE-004.8 could alleviate bleomycin (BLM)-induced skin fibrosis, we have investigated an oral lipid formulation (EHP-101) of this dual PPARγ/CB

Topics: Administration, Oral; Animals; Bleomycin; Blood Vessels; Cannabidiol; Collagen; Female; Fibrosis; Lung; Mice, Inbred BALB C; Phenotype; Quinones; Skin; Transcriptome

In this study, we have investigated the effects of cannabidiol (CBD) on myocardial dysfunction, inflammation, oxidative/nitrative stress, cell death, and interrelated signaling pathways, using a mouse model of type I diabetic cardiomyopathy and primary human cardiomyocytes exposed to high glucose.. Cannabidiol, the most abundant nonpsychoactive constituent of Cannabis sativa (marijuana) plant, exerts anti-inflammatory effects in various disease models and alleviates pain and spasticity associated with multiple sclerosis in humans.. Left ventricular function was measured by the pressure-volume system. Oxidative stress, cell death, and fibrosis markers were evaluated by molecular biology/biochemical techniques, electron spin resonance spectroscopy, and flow cytometry.. Diabetic cardiomyopathy was characterized by declined diastolic and systolic myocardial performance associated with increased oxidative-nitrative stress, nuclear factor-κB and mitogen-activated protein kinase (c-Jun N-terminal kinase, p-38, p38α) activation, enhanced expression of adhesion molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1), tumor necrosis factor-α, markers of fibrosis (transforming growth factor-β, connective tissue growth factor, fibronectin, collagen-1, matrix metalloproteinase-2 and -9), enhanced cell death (caspase 3/7 and poly[adenosine diphosphate-ribose] polymerase activity, chromatin fragmentation, and terminal deoxynucleotidyl transferase dUTP nick end labeling), and diminished Akt phosphorylation. Remarkably, CBD attenuated myocardial dysfunction, cardiac fibrosis, oxidative/nitrative stress, inflammation, cell death, and interrelated signaling pathways. Furthermore, CBD also attenuated the high glucose-induced increased reactive oxygen species generation, nuclear factor-κB activation, and cell death in primary human cardiomyocytes.. Collectively, these results coupled with the excellent safety and tolerability profile of CBD in humans, strongly suggest that it may have great therapeutic potential in the treatment of diabetic complications, and perhaps other cardiovascular disorders, by attenuating oxidative/nitrative stress, inflammation, cell death and fibrosis.

Topics: Animals; Apoptosis; Blood Glucose; Body Weight; Cannabidiol; Cells, Cultured; Diabetic Cardiomyopathies; Disease Models, Animal; Drug Evaluation, Preclinical; Fibrosis; Glucose; Hemodynamics; Humans; Insulin; Male; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Myocardium; Myocytes, Cardiac; NF-kappa B; Oxidative Stress; Pancreas; Reactive Oxygen Species