Cannabidiol (CBD) is considered a non-psychoactive, antioxidant, and anti-inflammatory compound derived from the Cannabis sativa plant. There are various reports on the versatile function of CBD, including ameliorating chronic inflammation and fibrosis formation in several tissue types. However, only a hand full of studies have proposed or provided a molecular justification for the beneficial properties of this Phyto-compound. This review focused on the anti-inflammation and anti-fibrotic effects of CBD based on modulating the associated chemokines/cytokines and receptor-mediated pathways. We also highlighted the regulatory impact of CBD on reactive oxygen species (ROS) producing-NADPH oxidase (Nox), and ROS scavenging-superoxide dismutase (SOD) enzymes. Although CBD has a low affinity to Cannabinoid receptors 1 and 2 (CB 1 and CB 2), we reported on the activation of these receptors by other CBD analogs, and CBD on non-CBD receptors. CBD downregulates pro-inflammatory and pro-fibrotic chemokines/cytokines by acting as direct or indirect agonists of Adenosine A 2A /equilibrative nucleoside transporter receptors, Peroxisome proliferator-activated receptor gamma, and Transient receptor potential vanilloid receptors or channels, and as an antagonist of GPR55 receptors. CBD also caused the reduction and enhancement of the ROS producing, Nox and ROSscavenging, SOD enzyme activities, respectively. This review thus recommends the continued study of CBD's molecular mechanism in treating established and emerging inflammatory and fibrosis-related diseases. K E Y W O R D S cannabidiol (CBD), fibrosis, inflammation, reactive oxygen species (ROS) How to cite this article: Sunda F, Arowolo A. A molecular basis for the anti-inflammatory and anti-fibrosis properties of cannabidiol.

Hereditary fibrosing poikiloderma with tendon contractures, myopathy and pulmonary fibrosis (POIKTMP) is a unique multi-systemic fibrosing and autosomal dominant genetic syndrome. The development of poikiloderma is one of the earliest signs of this disorder. 1 Consequently, this disease is often misdiagnosed in infants and neonates as Rothmund-Thomson syndrome (RTS), Bloom syndrome, dyskeratosis congenita, Baller-Gerold syndrome, poikiloderma neutropenia, Weary syndrome and Kindler syndrome. 1 Clinical features in POIKTMP include poikiloderma, myopathy, hypohidrosis, alopecia, tendon/muscle contractures, papules and epidermal atrophy, growth retardation, liver impairment, exocrine pancreatic insufficiency, cataracts and haematological abnormalities. [2][3][4][5][6] The affected individuals may also experience progressive weakness of proximal and distal muscles. 7 Furthermore, some patients develop fibrosis of the lungs in later life, causing recurrent bronchitis and abnormal lung function. 3 Pulmonary fibrosis, however, occurs around the second decade of life and is life-threatening, 3,4 with some earlier case reports also mentioning fibrosis of the oesophagus

Angiotensin-converting enzyme (ACE) is a zinc metalloprotease best known for its role in blood pressure regulation. ACE consists of two homologous catalytic domains, the N- and C-domain, that display distinct but overlapping catalytic functions in vivo owing to subtle differences in substrate specificity. While current generation ACE inhibitors target both ACE domains, domain-selective ACE inhibitors may be clinically advantageous, either reducing side effects or having utility in new indications. Here, we used site-directed mutagenesis, an ACE chimera and X-ray crystallography to unveil the molecular basis for C-domain-selective ACE inhibition by the bradykinin-potentiating peptide b (BPPb), naturally present in Brazilian pit viper venom. We present the BPPb N-domain structure in comparison with the previously reported BPPb C-domain structure and highlight key differences in peptide interactions with the S4 to S9 subsites. This suggests the involvement of these subsites in conferring C-domain-selective BPPb binding, in agreement with the mutagenesis results where unique residues governing differences in active site exposure, lid structure and dynamics between the two domains were the major drivers for C-domain-selective BPPb binding. Mere disruption of BPPb interactions with unique S2 and S4 subsite residues, which synergistically assist in BPPb binding, was insufficient to abolish C-domain selectivity. The combination of unique S9–S4 and S2′ subsite C-domain residues was required for the favourable entry, orientation and thus, selective binding of the peptide. This emphasizes the need to consider factors other than direct protein–inhibitor interactions to guide the design of domain-selective ACE inhibitors, especially in the case of larger peptides.