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.

Maternal obesity and gestational diabetes mellitus (GDM) are associated with insulin resistance and health risks for mother and offspring. Obesity is also characterized by low‐grade inflammation, which in turn, impacts insulin sensitivity. The placenta secretes inflammatory cytokines and hormones that influence maternal glucose and insulin handling. However, little is known about the effect of maternal obesity, GDM and their interaction, on placental morphology, hormones and inflammatory cytokines. In a South African cohort of non‐obese and obese pregnant women with and without GDM, this study examined placental morphology using stereology, placental hormone and cytokine expression using real‐time PCR, western blotting and immunohistochemistry, and circulating TNFα and IL‐6 concentrations using ELISA. Placental expression of endocrine and growth factor genes was not altered by obesity or GDM. However, LEPTIN gene expression was diminished, syncytiotrophoblast TNFα immunostaining elevated and stromal and fetal vessel IL‐6 staining reduced in the placenta of obese women in a manner that was partly influenced by GDM status. Placental TNFα protein abundance and maternal circulating TNFα concentrations were reduced in GDM. Both maternal obesity and, to a lesser extent, GDM were accompanied by specific changes in placental morphometry. Maternal blood pressure and weight gain and infant ponderal index were also modified by obesity and/or GDM. Thus, obesity and GDM have specific impacts on placental morphology and endocrine and inflammatory states that may relate to pregnancy outcomes. These findings may contribute to developing placenta‐targeted treatments that improve mother and offspring outcomes, which is particularly relevant given increasing rates of obesity and GDM worldwide. Key points Rates of maternal obesity and gestational diabetes (GDM) are increasing worldwide, including in low‐middle income countries (LMIC). Despite this, much of the work in the field is conducted in higher‐income countries. In a well‐characterised cohort of South African women, this study shows that obesity and GDM have specific impacts on placental structure, hormone production and inflammatory profile. Moreover, such placental changes were associated with pregnancy and neonatal outcomes in women who were obese and/or with GDM. The identification of specific changes in the placenta may help in the design of diagnostic and therapeutic approaches to improve pregnancy and neonatal outcomes with particular significant benefit in LMICs.

Background: Androgenetic alopecia (AGA) is the most common form of non-scarring alopecia in humans. Several studies have used different laboratory models to study the pathogenesis and interventions for AGA. These study models have proved beneficial and have led to the approval of two drugs. However, the need to build on existing knowledge remains by examining the relevance of study models to the disease. Objective: We sought to appraise laboratory or pre-clinical models of AGA. Method: We searched through databases (PubMed, ScienceDirect, Web of Science, World CAT, Scopus and Google Scholar) for articles on AGArelated studies from 1942 to March 2019 with a focus on study models. Results: The search rendered 101 studies after screening and deduplication. Several studies (70) used in vitro models, mostly consisting of twodimensional monolayer cells for experiments involving the characterization of androgen and 5-alpha reductase (5AR) and inhibition thereof, the effects of dihydrotestosterone (DHT) and biomarker(s) of AGA. Twenty-seven studies used in vivo models of mice and monkeys to investigate DHT synthesis, the expression and inhibition of 5AR and hair growth. Only four studies used AGA-related or healthy excisional/punch biopsy explants as ex vivo models to study the action of 5AR inhibitors and AGA-associated genes. No study used three-dimensional [3-D] organoids or organotypic human skin culture models. Conclusion:We recommend clinically relevant laboratory models like human or patient-derived 3-D organoids or organotypic skin in AGA-related studies. These models are closer to human scalp tissue and minimize the use of laboratory animals and could ultimately facilitate novel therapeutics. | BACKGROUNDAndrogenetic alopecia (AGA) is the most common form of non-scarring hair loss in humans. [1][2][3] The prevalence of AGA varies between races and ethnicities. 1 This disparity is attributed to the different methods of measuring prevalence, making it difficult to compare studies. 1,2 Nonetheless, about 50% of men of European descent are affected by the age of 50 years; this proportion increases to 90% with age. 1,4,5 Furthermore, AGA is estimated to affect about 19% of women of European ancestry, while the prevalence and severity of AGA are considered low in Asian and African men. 1,4,6 In the early 1940s, Hamilton proved that genetic predisposition and male hormone stimulation are prerequisites in AGA development. 7 After this discovery, several AGA models were created to delineate the pathophysiology and evaluate the effectiveness of novel therapeutics using both laboratory (in vitro, in vivo and ex vivo) and non-laboratory models. These models,This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

The use of noninvasive human substrates to interrogate pathophysiological conditions has become essential in the post- Human Genome Project era. Due to its high turnover rate, and its long term capability to incorporate exogenous and endogenous substances from the circulation, hair testing is emerging as a key player in monitoring long term drug compliance, chronic alcohol abuse, forensic toxicology, and biomarker discovery, among other things. Novel high-throughput 'omics based approaches like proteomics have been underutilized globally in comprehending human hair morphology and its evolving use as a diagnostic testing substrate in the era of precision medicine. There is paucity of scientific evidence that evaluates the difference in drug incorporation into hair based on lipid content, and very few studies have addressed hair growth rates, hair forms, and the biological consequences of hair grooming or bleaching. It is apparent that protein-based identification using the human hair proteome would play a major role in understanding these parameters akin to DNA single nucleotide polymorphism profiling, up to single amino acid polymorphism resolution. Hence, this work seeks to identify and discuss the progress made thus far in the field of molecular hair testing using proteomic approaches, and identify ways in which proteomics would improve the field of hair research, considering that the human hair is mostly composed of proteins. Gaps in hair proteomics research are identified and the potential of hair proteomics in establishing a historic medical repository of normal and disease-specific proteome is also discussed.

FAM111B gene mutations are associated with a hereditary fibrosing poikiloderma known to cause poikiloderma, tendon contracture, myopathy, and pulmonary fibrosis (POIKTMP). In addition, the overexpression of FAM111B has been associated with cancer progression and poor prognosis. This review inferred the molecular function of this gene’s protein product and mutational dysfunction in fibrosis and cancer based on recent findings from studies on this gene. In conclusion, FAM111B represents an uncharacterized protease involved in DNA repair, cell cycle regulation, and apoptosis. The dysregulation of this protein ultimately leads to fibrotic diseases like POIKTMP and cancers via the disruption of these cellular processes by the mutation of the FAM111B gene. Hence, it should be studied in the context of these diseases as a possible therapeutic target.

The incubation of neuronal nitric oxide synthase with the five amyloid peptide fragments [Aβ17-21; Aβ25-29; Aβ29-33; Aβ33-37; Aβ25-37] catalyzed the formation of fibrils. The role of neuronal isomer (nNOS) involved the entrapment of free monomers and seed aggregates to initiate the events of nucleation and elongation, critical for the formation of fibrils. It was evident that the hydrophobic nature of Aβ17-21, the three glycine zipper peptides [Aβ25-29; Aβ29-33; Aβ33-37] and Aβ25-37 was a trigger in the formation of fibrils and was a force critical in the association of the peptides with the enzyme. Gold and silver nanoparticles (average 4.0 nm) inhibited fibril formation when added to the induced fibrils from nNOS-Aβ incubation. The addition of nNOS and/or Aβ to co-incubated solutions of nanoparticle-Aβ or nanoparticle-nNOS respectively did not prevent fibril formation but reversed it. Three mechanisms for this reversal were proposed: (1) depletion of free Aβ monomer in solution and blocking potential aggregation sites on the nNOS molecule due to large surface area of the nanoparticle (2) hydrophobic interaction between the Aβ peptide and nanoparticle (3) disruption of binary adducts between Aβ-peptides and nNOS by nanoparticles.