<scp>VCE</scp>‐004.3, a cannabidiol aminoquinone derivative, prevents bleomycin‐induced skin fibrosis and inflammation through PPARγ‐ and CB<sub>2</sub> receptor‐dependent pathways

Río, Carmen del; Cantarero, Irene; Palomares, Belén; Gómez‐Cañas, María; Fernández‐Ruiz, Javier; Pavicic, Carolina; García‐Martín, Adela; Bellido, M. Luz; Ortega‐Castro, Rafaela; Pérez-Sánchez, C.; López‐Pedrera, Chary; Appendino, Giovanni; Calzado, Marco A.; Muñóz, Eduardo

doi:10.1111/bph.14450

Cited by 30 publications

(29 citation statements)

References 65 publications

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“…Approved drugs and clinical trials). In addition, CB2/PPARγ agonist with CB1 antagonistic property, VCE-004.3, was proposed for the treatment of SSc, based on promising in vitro results [211]. Dual CB1/iNOS inhibitor, MRI-1867 (10 mg/kg), exhibited antifibrotic activity in the rodent model of pulmonary fibrosis [212].…”

Section: Inflammatory and Autoimmune Diseasesmentioning

confidence: 99%

A Guide to Targeting the Endocannabinoid System in Drug Design

Stasiulewicz

Znajdek

Grudzień

et al. 2020

IJMS

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The endocannabinoid system (ECS) is one of the most crucial systems in the human organism, exhibiting multi-purpose regulatory character. It is engaged in a vast array of physiological processes, including nociception, mood regulation, cognitive functions, neurogenesis and neuroprotection, appetite, lipid metabolism, as well as cell growth and proliferation. Thus, ECS proteins, including cannabinoid receptors and their endogenous ligands’ synthesizing and degrading enzymes, are promising therapeutic targets. Their modulation has been employed in or extensively studied as a treatment of multiple diseases. However, due to a complex nature of ECS and its crosstalk with other biological systems, the development of novel drugs turned out to be a challenging task. In this review, we summarize potential therapeutic applications for ECS-targeting drugs, especially focusing on promising synthetic compounds and preclinical studies. We put emphasis on modulation of specific proteins of ECS in different pathophysiological areas. In addition, we stress possible difficulties and risks and highlight proposed solutions. By presenting this review, we point out information pivotal in the spotlight of ECS-targeting drug design, as well as provide an overview of the current state of knowledge on ECS-related pharmacodynamics and show possible directions for needed research.

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Section: Inflammatory and Autoimmune Diseasesmentioning

confidence: 99%

A Guide to Targeting the Endocannabinoid System in Drug Design

Stasiulewicz

Znajdek

Grudzień

et al. 2020

IJMS

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“…Higher numbers of total mast cells and/or numbers of degranulating mast cells have been reported in the dermis with the bleomycin model [ 96 , 97 , 98 , 99 ]. In experiments where bleomycin-induced skin fibrosis was alleviated due to various treatments or genetic ablation of specific mediators that reduce fibrosis, reduced mast cell density or degranulation was evident [ 97 , 100 , 101 , 102 , 103 , 104 , 105 ]. Despite the clear correlation between mast cell density and activity in bleomycin-induced fibrosis, studies in mast-cell deficient mice have yielded mixed results.…”

Section: Mast Cells In Cutaneous Fibrosismentioning

confidence: 99%

A Review of the Evidence for and against a Role for Mast Cells in Cutaneous Scarring and Fibrosis

Wilgus

Uddin

Bayat

2020

IJMS

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Scars are generated in mature skin as a result of the normal repair process, but the replacement of normal tissue with scar tissue can lead to biomechanical and functional deficiencies in the skin as well as psychological and social issues for patients that negatively affect quality of life. Abnormal scars, such as hypertrophic scars and keloids, and cutaneous fibrosis that develops in diseases such as systemic sclerosis and graft-versus-host disease can be even more challenging for patients. There is a large body of literature suggesting that inflammation promotes the deposition of scar tissue by fibroblasts. Mast cells represent one inflammatory cell type in particular that has been implicated in skin scarring and fibrosis. Most published studies in this area support a pro-fibrotic role for mast cells in the skin, as many mast cell-derived mediators stimulate fibroblast activity and studies generally indicate higher numbers of mast cells and/or mast cell activation in scars and fibrotic skin. However, some studies in mast cell-deficient mice have suggested that these cells may not play a critical role in cutaneous scarring/fibrosis. Here, we will review the data for and against mast cells as key regulators of skin fibrosis and discuss scientific gaps in the field.

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“…In contrast to the above data, 30 μM WIN55,212-2 was found to CB 2 -dependently prevent degranulation of LAD2 cells induced by the supernatant of human HPV18-positive SW756 cervical carcinoma cells [ 240 ]. Moreover, AEA inhibited FcεRI-dependent degranulation and cytokine synthesis in murine bone marrow-derived MCs via the activation of CB 2 /GPR55 receptor heteromers [ 241 ], and VCE-004.3, as well as VCE-004.8, two PPARγ and CB 2 receptor activating derivatives of CBD, could also reduce MC degranulation in bleomycin-induced murine fibrosis [ 242 , 243 ].…”

Section: Translational Potential Of the Cutaneous Cannabinoid Signmentioning

confidence: 99%

“…Besides AJA, certain CBD-derivatives also exhibited promising potential in SSc. Indeed, another PPARγ and CB 2 co-activator (and CB 1 antagonist), namely “VCE-004.3” (a semi-synthetic CBD quinol derivative) was also found to alleviate bleomycin-induced scleroderma as well as exerting potent anti-fibrotic effects via activating PPARγ and CB 2 [ 242 ]. Similarly, another PPARγ- and CB 2 -activating CBD aminoquinone (VCE-004.8) could inhibit TGFβ-induced Col1A2 gene transcription and collagen synthesis, as well as TGFβ-induced myofibroblast differentiation, and it also impaired wound-healing.…”

Section: Translational Potential Of the Cutaneous Cannabinoid Signmentioning

confidence: 99%

Cannabinoid Signaling in the Skin: Therapeutic Potential of the “C(ut)annabinoid” System

et al. 2019

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The endocannabinoid system (ECS) has lately been proven to be an important, multifaceted homeostatic regulator, which influences a wide-variety of physiological processes all over the body. Its members, the endocannabinoids (eCBs; e.g., anandamide), the eCB-responsive receptors (e.g., CB1, CB2), as well as the complex enzyme and transporter apparatus involved in the metabolism of the ligands were shown to be expressed in several tissues, including the skin. Although the best studied functions over the ECS are related to the central nervous system and to immune processes, experimental efforts over the last two decades have unambiguously confirmed that cutaneous cannabinoid (“c[ut]annabinoid”) signaling is deeply involved in the maintenance of skin homeostasis, barrier formation and regeneration, and its dysregulation was implicated to contribute to several highly prevalent diseases and disorders, e.g., atopic dermatitis, psoriasis, scleroderma, acne, hair growth and pigmentation disorders, keratin diseases, various tumors, and itch. The current review aims to give an overview of the available skin-relevant endo- and phytocannabinoid literature with a special emphasis on the putative translational potential, and to highlight promising future research directions as well as existing challenges.

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VCE‐004.3, a cannabidiol aminoquinone derivative, prevents bleomycin‐induced skin fibrosis and inflammation through PPARγ‐ and CB₂ receptor‐dependent pathways

Abstract: VCE-004.3 is a novel semisynthetic cannabidiol derivative that behaves as a dual PPARγ/CB agonist and CB receptor modulator that could be considered for the development of novel therapies against different forms of scleroderma.

Cited by 30 publications

References 65 publications

A Guide to Targeting the Endocannabinoid System in Drug Design

A Guide to Targeting the Endocannabinoid System in Drug Design

A Review of the Evidence for and against a Role for Mast Cells in Cutaneous Scarring and Fibrosis

Cannabinoid Signaling in the Skin: Therapeutic Potential of the “C(ut)annabinoid” System

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VCE‐004.3, a cannabidiol aminoquinone derivative, prevents bleomycin‐induced skin fibrosis and inflammation through PPARγ‐ and CB2 receptor‐dependent pathways

Abstract: VCE-004.3 is a novel semisynthetic cannabidiol derivative that behaves as a dual PPARγ/CB agonist and CB receptor modulator that could be considered for the development of novel therapies against different forms of scleroderma.

Cited by 30 publications

References 65 publications

A Guide to Targeting the Endocannabinoid System in Drug Design

A Guide to Targeting the Endocannabinoid System in Drug Design

A Review of the Evidence for and against a Role for Mast Cells in Cutaneous Scarring and Fibrosis

Cannabinoid Signaling in the Skin: Therapeutic Potential of the “C(ut)annabinoid” System

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VCE‐004.3, a cannabidiol aminoquinone derivative, prevents bleomycin‐induced skin fibrosis and inflammation through PPARγ‐ and CB₂ receptor‐dependent pathways