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Cannabis (Cannabis sativa, or hemp) and its constituents-in particular the cannabinoids-have been the focus of extensive chemical and biological research for almost half a century since the discovery of the chemical structure of its major active constituent, Δ 9 -tetrahydrocannabinol (Δ 9 -THC). The plant’s behavioral and psychotropic effects are attributed to its content of this class of compounds, the cannabinoids, primarily Δ 9 -THC, which is produced mainly in the leaves and flower buds of the plant. Besides Δ 9 -THC, there are also non-psychoactive cannabinoids with several medicinal functions, such as cannabidiol (CBD), cannabichromene (CBC), and cannabigerol (CBG), along with other non-cannabinoid constituents belonging to diverse classes of natural products. Today, more than 560 constituents have been identified in cannabis. The recent discoveries of the medicinal properties of cannabis and the cannabinoids in addition to their potential applications in the treatment of a number of serious illnesses, such as glaucoma, depression, neuralgia, multiple sclerosis, Alzheimer’s, and alleviation of symptoms of HIV/AIDS and cancer, have given momentum to the quest for further understanding the chemistry, biology, and medicinal properties of this plant.This contribution presents an overview of the botany, cultivation aspects, and the phytochemistry of cannabis and its chemical constituents. Particular emphasis is placed on the newly-identified/isolated compounds. In addition, techniques for isolation of cannabis constituents and analytical methods used for qualitative and quantitative analysis of cannabis and its products are also reviewed.

Keywords: Analytical methods; Biosynthesis; Botany of Cannabis sativa; Cannabinoids from C. sativa; Chemotaxonomy; Definitions of cannabis and cannabinoids; GC/FID; GC/MS; HPLC; HPTLC; Indoor cultivation; Micropropagation; Non-cannabinoids from C. sativa; Outdoor cultivation; Propagation; UPLC.

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However, one of the main points under debate is whether cannabinoids and CBD, in particular, are safe for consumers at the doses found to be active in the experimental conditions, by taking into account the fact that there is only limited knowledge about the long-term effects of chronic use and drug-drug interactions between CBD and other medications, although human studies have indicated that CBD is very well tolerated even at high doses. Another important issue is whether or not Cannabis extracts or CBD are simply a food supplement, a pharmaceutical product, or other. If on one hand this perplexity is justified by the need for a reliable evaluation of the balance between efficacy and side effects, on the other hand it must be recognized that, in some cases, an unconscious prejudice seems to hover on C. sativa, mainly because of its history of drug of abuse.

Cytokines may regulate the normal activity of the endocannabinoid system in different ways: for example, IL-4 and IL-10 are able to stimulate FAAH activity, whereas IFN-γ and IL-12 decrease FAAH expression, resulting in an increase of AEA levels [58, 59]. TNF-α and IL-6 are the major cytokines which can regulate CBr activity. Indeed, these cytokines have pro- and anti-inflammatory properties, depending on a variety of factors. Recent studies have shown that TNF-α provides a crucial signal for stem cells migration through CB1/CB2 signaling. The activation of TNF-α receptor then leads to 2AG synthesis, which may act on CB1 and CB2. This activity leads to a promotion of stem cells proliferation and migration that might have important implications for brain self-repairing processes [60].

The role of the endocannabinoid system in cancer biology is a controversial matter. Indeed, if on one hand an increase, although with a different pattern and extent, of endocannabinoid receptors CB1 and CB2 in various types of cancers has been observed, on the other hand the endocannabinoid system seems to play a tumor suppressing role on colon carcinoma in a genetic modified mouse model, carrying a knockdown of CB1 gene [93]. However, the majority of researches have reported an increase of CB1 and CB2 in different types of cancer. In particular, CB1 receptor has been found to be upregulated in cellular hepatocarcinoma [94] and in Hodgkin lymphoma cells [95], and its expression correlates with the severity of the disease in human epithelial ovarian cancer [96], whereas CB2 has been found to be overexpressed in human breast adenocarcinomas associated with HER2+ [97] and in glioma [98]. Moreover, CB1 and CB2 expression has been proposed to be a factor of bad prognosis following surgery in stage IV of colorectal cancer [99]. All these findings support the hypothesis that cannabinoids might interfere with cancer biology, acting on CB1 and CB2 receptors in a wide range of cancer types, in particular for Δ 9 -tetrahydrocannabivarin (Δ 9 -THCV), which is a homologue of Δ 9 -THC with a propyl side chain instead of a pentyl group. However, since nonpsychoactive cannabinoids, such as CBD, do not bind with high affinity to both CB1 and CB2, alternative pathways should be considered in order to analyze the molecular mechanisms of CBD anticancer activity ( Figure 3 ).

Cancer is the second leading cause of death worldwide, and it accounts for about 8.8 million deaths in 2015 (GHO 2018 data); nearly 1 of 6 deaths is due to cancer. Cancer is a multistep disease characterized by a formation of a preneoplastic lesion (initiation processes) which, by time, progresses into malignant tumor. Generally, cell transformation is a combination of intrinsic genetic factors and external exposure to physical, chemical, and biological carcinogens. However, it must be underlined that ageing and life style are others fundamental factors for the development of the disease. Indeed, the incidence of cancer rises dramatically with age, probably due to the decreased efficacy of cellular repair mechanisms, while tobacco, alcohol, unhealthy diet, and physical inactivity are the major global cancer risks. A number of evidences pointed out that chronic inflammation, independently of the triggering agent, could be responsible of almost 20% of human cancers [84]. As described above, inflammation per se is not dangerous, since it protects the body by increasing host defense and it is self-limiting. However, persistent and deregulated inflammation is associated with an increased risk of malignant diseases [85]. Cells and mediators of the innate immune system have been detected in many cancers, even when inflammation is not implicated in tumor development [85, 86]. This finding suggests that inflammatory conditions and carcinogenesis might share common pathways, such as proliferation, increased cell survival, and migration, where cytokines and growth factors play a pivotal and fundamental role. Therefore, not only can inflammation cause cancer, but also cancer causes inflammation [87]. Thus, in the tumor microenvironment, inflammatory mediators regulate a number of proinflammatory responses, acting in an autocrine and/or paracrine manner, leading to either an antiproliferative response or an increase of cancer promotion through the inhibition of protective immune response [88]. In this context, it has been shown that the activation of the proinflammatory NF-kB pathway has a tumor prosurvival effect, giving chemotherapy resistance to cancer cells in an Akt-independent pathway, but involving the epidermal growth factor (EGF) activating signaling [89]. This interesting link between inflammation and growth factors, such as EGF/EGFR, configures an intriguing perspective in the study of the possible correlation between inflammatory processes and aberrant cell growth. Studies carried out on liver cancer have shown that chronic tissue damage and inflammation in liver result in a sustained overexpression and overstimulation of the EGFR pathway and that the deregulated EGFR signaling has been reported to play an important role in the development of liver cancer [89]. Proinflammatory stimuli activated by EGFR promote the release of EGFR ligands, such as heparin-binding-EGF (HB-EGF), from liver cancer cells and endothelial cells, which stimulate the proliferation of initiated hepatocytes [89], and further potentiate their aggressive behavior [90]. Moreover, the finding that CBD suppresses the activation of EGF/EGFR signaling transduction pathway and its downstream targets Akt, ERK, and NF-kB suggests that the effect of C. sativa extract might play an important in the modulation on the intricate relationship between growth factors, inflammation, and cell growth [90]. Indeed, the ability to inhibit proinflammatory pathways, as described in the previous chapter, strongly indicates that cannabinoids are antiproliferative compounds by possibly interfering with NF-kB/EGF/EGFR pathway. This hypothesis has been further supported by Elbaz et al. [91], who have demonstrated that CBD, acting on its receptors, changes cytokine secretion, such as CCL3, GM-CSF, and MIP-2 proteins, from 4T1.2 tumor cells compared to vehicle-treated cells, thus decreasing the recruitment of macrophages to the tumor microenvironment and, therefore, suppressing both angiogenesis and the invasive potential of cancer cells. In addition, the presence of GPR55 receptor, which is able to bind CBD, on NK cells, represents a possible novel modulatory activity of NK cell responsiveness [92]. Noteworthy, the noncanonical cannabinoid receptor G coupled receptor GPR55-mediated NK cell stimulation and/or inhibition is of particular importance in tumor immune-surveillance, since these cells play a pivotal role in the recognition and elimination of malignant cells.

5.3. Cannabinoids and TRPVs

In another study, CBD has been demonstrated to improve Clostridium difficile toxin A-induced damage in Caco-2 cells, by inhibiting the apoptotic process and restoring the intestinal barrier integrity, through the involvement of CB1 receptors [53]. Clostridium difficile infection is the leading cause of hospital-acquired diarrhea and pseudomembranous colitis. Clostridium difficile toxin A significantly affects enterocytes permeability leading to apoptosis and colonic mucosal damage. Given the absence of any significant toxic effect in humans, CBD may ideally represent an effective adjuvant treatment for Clostridium difficile-associated colitis [53].

General representation of the signaling pathways involved in CBD anti-inflammatory effects. Cannabinoids reduce peripheral inflammation by acting at TRPV1, CB2, and GPR55 receptors; these interactions lead to downregulation of enzymes involved in the production of prostaglandins, reactive oxygen species, and cytokines. MAPK inhibition and NF-kB downregulation, together with PPARγ-mediated reduction of lipid peroxidation, are also involved in the anti-inflammatory effects of cannabinoids in the CNS. Abbreviations: CBD, cannabidiol; CNS, central nervous system, CB2, cannabinoid receptor 2; TRPV1, receptor potential channel subfamily V member 1; GPR55, orphan G-protein coupled receptor 55; Akt, protein kinase B; ERK, extracellular signal-regulated kinases; NF-kB nuclear factor kappa-light-chain-enhancer of activated B cells; iNOS, inducible nitric oxide synthase; COX2, cyclooxygenase 2; TNF-α, tumor necrosis factor alpha; PPARγ, peroxisome proliferator-activated receptor gamma.

In this context, this review is focused on the effects and the molecular mechanisms of CBD and related compounds on inflammation and cancer processes, highlighting also the role of other related nonpsychoactive cannabinoids and noncannabinoids constituents of fibre-type hemp. Although it has been reported that CBD is able to bind several protein complexes, such as PPARγ and 5HT1, their role in CBD-mediated anticancer activity is still poor documented. For this reason, the attention is focused mainly on the interaction between CBD and three putative molecular targets such CB2, GPR55, and TRPV1/2 protein receptors, where there is an extensive literature and several molecular mechanisms have been proposed.

4. Inflammation and Cancer

As regards cancer, CBD has exhibited antiproliferative and proapoptotic activities, thus demonstrating modulating the tumorigenesis in different types of cancer, including breast, lung, colon, brain, and others [21].

Many studies have expanded the concept that inflammation is a critical component of tumour progression [20]. Indeed, several cancers originate from infection, chronic irritation, and inflammation [20]. Tumour microenvironment, which is largely regulated by inflammatory cells, displays a key role in the neoplastic process, fostering proliferation, survival, and migration [20]. In addition, cancer cells have co-opted some of the signalling molecules of the innate immune system for invasion, migration, and metastasis [20].