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Cannabis sativa: From Plants to Humans

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (15 May 2024) | Viewed by 25117

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Dr. Daniela Trono

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Research Centre for Cereal and Industrial Crops, Council for Agricultural Research and Economics, Foggia, Italy
Interests: plant physiology and biochemistry; functional analysis of genes; abiotic stress; oxidative stress; secondary metabolites
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Dr. Beleggia Romina

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Council for Agricultural Research and Economics (CREA), Research Centre for Cereal and Industrial Crops, S.S. 673, 71122 Foggia, Italy
Interests: metabolomics, primary and secondary metabolites, evolutionary metabolomics, biodiversity and plant genetic resources, genotype by environment interaction, cereals
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

In the last several years, industrial hemp (Cannabis sativa L.) is experiencing renewed interest thanks to its multi-purpose application. Hemp plant is a natural source of fiber, and the hemp varieties grown for fiber are the most widely cultivated worldwide. Hemp fiber is the strongest and most durable form of natural fiber, and is useful for textiles, paper making or other industrial products, including construction materials and biofuels. More recent is the use of hemp derivatives in the food and pharmaceutical sectors. The beneficial effects of hemp seeds on human health are receiving growing interest and the hemp flour and oil obtained from seeds are used in several foods of high nutritional value due to their high levels of minerals, vitamins, proteins, and lipids (especially polyunsaturated fatty acids). In addition, there are hemp varieties that are popular for their pharmacological and medical uses thanks to their high levels of secondary metabolites, including terpenoids, flavonoids, and phytocannabinoids. These latter are mainly represented by cannabidiol (CBD). CBD extracted from hemp flowers can help to reduce inflammation, and has shown promise as a treatment for stress, anxiety, depression, insomnia, and diseases of the central nervous system such as schizophrenia, multiple sclerosis and epilepsy. Hemp cultivation also holds many environmental benefits. This crop has a good resistance to drought and pests. For its ability to tolerate elevated concentrations of heavy metals in the soil, hemp has promising phytoremediation potential; its roots extend deeply into the soil, and this increases the capability of removing widespread contamination. Its well-developed root system also contributes to the prevention of soil erosion.

In this context, the present Special Issue aims to bring together contributions from scholars of different fields of expertise, including but not limited to agronomy, plant physiology and biochemistry, food technology, pharmaceutics and medicine, to promote outstanding research concerning all aspects of hemp cultivation and use.

Dr. Daniela Trono
Dr. Beleggia Romina
Guest Editors

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Keywords

Cannabis sativa
hemp
fiber
biofuel
cannabinoids
nutritional quality
health benefits
phytoremediation

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Published Papers (8 papers)

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29 pages, 10628 KiB

Open AccessArticle

Fetal Cannabinoid Syndrome: Behavioral and Brain Alterations of the Offspring Exposed to Dronabinol during Gestation and Lactation

by Daniela Navarro, Ani Gasparyan, Francisco Navarrete and Jorge Manzanares

Int. J. Mol. Sci. 2024, 25(13), 7453; https://doi.org/10.3390/ijms25137453 - 7 Jul 2024

Cited by 1 | Viewed by 1207

Abstract

This study establishes a fetal cannabinoid syndrome model to evaluate the effects of high doses of dronabinol (synthetic THC) during pregnancy and lactation on behavioral and brain changes in male and female progeny and their susceptibility to alcohol consumption. Female C57BL/6J mice received dronabinol (10 mg/kg/12 h, p.o.) from gestational day 5 to postnatal day 21. On the weaning day, the offspring were separated by sex, and on postnatal day 60, behavioral and neurobiological changes were analyzed. Mice exposed to dronabinol exhibited increased anxiogenic and depressive-like behaviors and cognitive impairment. These behaviors were associated with neurodevelopment-related gene and protein expression changes, establishing, for the first time, an association among behavioral changes, cognitive impairment, and neurobiological alterations. Exposure to dronabinol during pregnancy and lactation disrupted the reward system, leading to increased motivation to consume alcohol in the offspring. All these modifications exhibited sex-dependent patterns. These findings reveal the pronounced adverse effects on fetal neurodevelopment resulting from cannabis use during pregnancy and lactation and strongly suggest the need to prevent mothers who use cannabis in this period from the severe and permanent side effects on behavior and brain development that may occur in their children. Full article

(This article belongs to the Special Issue Cannabis sativa: From Plants to Humans)

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12 pages, 3601 KiB

Open AccessArticle

Cannabigerol Induces Autophagic Cell Death by Inhibiting EGFR-RAS Pathways in Human Pancreatic Ductal Adenocarcinoma Cell Lines

by Laura Zeppa, Cristina Aguzzi, Maria Beatrice Morelli, Oliviero Marinelli, Martina Giangrossi, Margherita Luongo, Consuelo Amantini, Giorgio Santoni and Massimo Nabissi

Int. J. Mol. Sci. 2024, 25(4), 2001; https://doi.org/10.3390/ijms25042001 - 7 Feb 2024

Cited by 1 | Viewed by 3366

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the most frequent infiltrating type of pancreatic cancer. The poor prognosis associated with this cancer is due to the absence of specific biomarkers, aggressiveness, and treatment resistance. PDAC is a deadly malignancy bearing distinct genetic alterations, the most common being those that result in cancer-causing versions of the KRAS gene. Cannabigerol (CBG) is a non-psychomimetic cannabinoid with anti-inflammatory properties. Regarding the anticancer effect of CBG, up to now, there is only limited evidence in human cancers. To fill this gap, we investigated the effects of CBG on the PDAC cell lines, PANC-1 and MIAPaCa-2. The effect of CBG activity on cell viability, cell death, and EGFR-RAS-associated signaling was investigated. Moreover, the potential synergistic effect of CBG in combination with gemcitabine (GEM) and paclitaxel (PTX) was investigated. MTT was applied to investigate the effect of CBG on PDAC cell line viabilities. Annexin-V and Acridine orange staining, followed by cytofluorimetric analysis and Western blotting, were used to evaluate CBG’s effect on cell death. The modulation of EGFR-RAS-associated pathways was determined by Western blot analysis and a Milliplex multiplex assay. Moreover, by employing the MTT data and SynergyFinder Plus software analysis, the effect of the combination of CBG and chemotherapeutic drugs was determined. Full article

(This article belongs to the Special Issue Cannabis sativa: From Plants to Humans)

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43 pages, 33319 KiB

Open AccessArticle

Challenges to Cannabis sativa Production from Pathogens and Microbes—The Role of Molecular Diagnostics and Bioinformatics

by Zamir K. Punja, Dieter Kahl, Ron Reade, Yu Xiang, Jack Munz and Punya Nachappa

Int. J. Mol. Sci. 2024, 25(1), 14; https://doi.org/10.3390/ijms25010014 - 19 Dec 2023

Viewed by 3272

Abstract

The increased cultivation of Cannabis sativa L. in North America, represented by high Δ⁹-tetrahydrocannabinol-containing (high-THC) cannabis genotypes and low-THC-containing hemp genotypes, has been impacted by an increasing number of plant pathogens. These include fungi which destroy roots, stems, and leaves, in some cases causing a build-up of populations and mycotoxins in the inflorescences that can negatively impact quality. Viroids and viruses have also increased in prevalence and severity and can reduce plant growth and product quality. Rapid diagnosis of the occurrence and spread of these pathogens is critical. Techniques in the area of molecular diagnostics have been applied to study these pathogens in both cannabis and hemp. These include polymerase chain reaction (PCR)-based technologies, including RT-PCR, multiplex RT-PCR, RT-qPCR, and ddPCR, as well as whole-genome sequencing (NGS) and bioinformatics. In this study, examples of how these technologies have enhanced the rapidity and sensitivity of pathogen diagnosis on cannabis and hemp will be illustrated. These molecular tools have also enabled studies on the diversity and origins of specific pathogens, specifically viruses and viroids, and these will be illustrated. Comparative studies on the genomics and metabolomics of healthy and diseased plants are urgently needed to provide insight into their impact on the quality and composition of cannabis and hemp-derived products. Management of these pathogens will require monitoring of their spread and survival using the appropriate technologies to allow accurate detection, followed by appropriate implementation of disease control measures. Full article

(This article belongs to the Special Issue Cannabis sativa: From Plants to Humans)

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16 pages, 5673 KiB

Open AccessArticle

Epicutaneous Sensitization to the Phytocannabinoid β-Caryophyllene Induces Pruritic Inflammation

by Saadet Inan, Sara J. Ward, Citlalli T. Baltazar, Gabrielle A. Peruggia, Elham Javed and Ajay P. Nayak

Int. J. Mol. Sci. 2023, 24(18), 14328; https://doi.org/10.3390/ijms241814328 - 20 Sep 2023

Cited by 2 | Viewed by 1629

Abstract

In recent years, there has been increased accessibility to cannabis for recreational and medicinal use. Incidentally, there has been an increase in reports describing allergic reactions to cannabis including exacerbation of underlying asthma. Recently, multiple protein allergens were discovered in cannabis, yet these fail to explain allergic sensitization in many patients, particularly urticaria and angioedema. Cannabis has a rich chemical profile including cannabinoids and terpenes that possess immunomodulatory potential. We examined whether major cannabinoids of cannabis such as cannabidiol (CBD) and the bicyclic sesquiterpene beta-caryophyllene (β-CP) act as contact sensitizers. The repeated topical application of mice skin with β-CP at 10 mg/mL (50 µL) induced an itch response and dermatitis at 2 weeks in mice, which were sustained for the period of study. Histopathological analysis of skin tissues revealed significant edema and desquamation for β-CP at 10 mg/mL. For CBD and β-CP, we observed a dose-dependent increase in epidermal thickening with profound thickening observed for β-CP at 10 mg/mL. Significant trafficking of CD11b cells was observed in various compartments of the skin in response to treatment with β-CP in a concentration-dependent manner. Mast cell trafficking was restricted to β-CP (10 mg/mL). Mouse proteome profiler cytokine/chemokine array revealed upregulation of complement C5/5a (anaphylatoxin), soluble intracellular adhesion molecule-1 (sICAM-1) and IL-1 receptor antagonist (IL-1RA) in animals dosed with β-CP (10 mg/mL). Moreover, we observed a dose-dependent increase in serum IgE in animals dosed with β-CP. Treatment with β-CP (10 mg/mL) significantly reduced filaggrin expression, an indicator of barrier disruption. In contrast, treatment with CBD at all concentrations failed to evoke scratching and dermatitis in mice and did not result in increased serum IgE. Further, skin tissues were devoid of any remarkable features, although at 10 mg/mL CBD we did observe the accumulation of dermal CD11b cells in skin tissue sections. We also observed increased filaggrin staining in mice repeatedly dosed with CBD (10 mg/mL). Collectively, our studies indicate that repeated exposure to high concentrations of β-CP can induce dermatitis-like pathological outcomes in mice. Full article

(This article belongs to the Special Issue Cannabis sativa: From Plants to Humans)

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13 pages, 4650 KiB

Open AccessArticle

Proteomics-Based Approach for Detailing the Allergenic Profile of Cannabis Chemotypes

by Cali Loblundo, Jenna Severa, Gabrielle A. Peruggia, Kristina Reid Black, Suman Chandra, Hemant Lata, Mahmoud ElSohly, Martin D. Chapman, Deepak A. Deshpande and Ajay P. Nayak

Int. J. Mol. Sci. 2023, 24(18), 13964; https://doi.org/10.3390/ijms241813964 - 11 Sep 2023

Cited by 3 | Viewed by 1576

Abstract

Allergic sensitization to cannabis is an emerging public health concern and is difficult to clinically establish owing to lack of standardized diagnostic approaches. Attempts to develop diagnostic tools were largely hampered by the Schedule I restrictions on cannabis, which limited accessibility for research. Recently, however, hemp was removed from the classified list, and increased accessibility to hemp allows for the evaluation of its practical clinical value for allergy diagnosis. We hypothesized that the proteomic profile is preserved across different cannabis chemotypes and that hemp would be an ideal source of plant material for clinical testing. Using a proteomics-based approach, we examined whether distinct varieties of cannabis plant contain relevant allergens of cannabis. Cannabis extracts were generated from high tetrahydrocannabinol variety (Mx), high cannabidiol variety (V1-19) and mixed profile variety (B5) using a Plant Total Protein Extraction Kit. Hemp extracts were generated using other standardized methods. Protein samples were subjected to nanoscale tandem mass spectrometry. Acquired peptides sequences were examined against the Cannabis sativa database to establish protein identity. Non-specific lipid transfer protein (Can s 3) level was measured using a recently developed ELISA 2.0 assay. Proteomic analysis identified 49 distinct potential allergens in protein extracts from all chemotypes. Most importantly, clinically relevant and validated allergens, such as profilin (Can s 2), Can s 3 and Bet v 1-domain-containing protein 10 (Can s 5), were identified in all chemotypes at label-free quantification (LFP) intensities > 106. However, the oxygen evolving enhancer protein 2 (Can s 4) was not detected in any of the protein samples. Similarly, Can s 2, Can s 3 and Can s 5 peptides were also detected in hemp protein extracts. The validation of these findings using the ELISA 2.0 assay indicated that hemp extract contains 30–37 ng of Can s 3 allergen per µg of total protein. Our proteomic studies indicate that relevant cannabis allergens are consistently expressed across distinct cannabis chemotypes. Further, hemp may serve as an ideal practical substitute for clinical testing, since it expresses most allergens relevant to cannabis sensitization, including the validated major allergen Can s 3. Full article

(This article belongs to the Special Issue Cannabis sativa: From Plants to Humans)

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23 pages, 2724 KiB

Open AccessArticle

Effect of Genotype, Year, and Their Interaction on the Accumulation of Bioactive Compounds and the Antioxidant Activity in Industrial Hemp (Cannabis sativa L.) Inflorescences

by Romina Beleggia, Valeria Menga, Flavia Fulvio, Clara Fares and Daniela Trono

Int. J. Mol. Sci. 2023, 24(10), 8969; https://doi.org/10.3390/ijms24108969 - 18 May 2023

Cited by 10 | Viewed by 1811

Abstract

The phytochemical content and the antioxidant activity in the inflorescences of six industrial hemp (Cannabis sativa L.) genotypes, four monoecious (Codimono, Carmaleonte, Futura 75, and Santhica 27), and two dioecious (Fibrante and Carmagnola Selezionata), were assessed for three consecutive years from 2018 to 2020. The total phenolic content, total flavonoid content, and antioxidant activity were determined by spectrophotometric measurements, whereas HPLC and GC/MS were used to identify and quantify the phenolic compounds, terpenes, cannabinoids, tocopherols, and phytosterols. All the measured traits were significantly affected by genotype (G), cropping year (Y), and their interaction (G × Y), although the Y effect prevailed as a source of variation, ranging from 50.1% to 88.5% for all the metabolites except cannabinoids, which were equally affected by G, Y, and G × Y interaction (33.9%, 36.5%, and 21.4%, respectively). The dioecious genotypes presented a more constant performance over the three years compared to the monoecious genotypes, with the highest and most stable phytochemical content observed in the inflorescences of Fibrante, which was characterized by the highest levels of cannabidiol, α-humulene and β-caryophyllene, which may confer on the inflorescences of this genotype a great economic value due to the important pharmacological properties of these metabolites. Conversely, the inflorescences of Santhica 27 were characterized by the lowest accumulation of phytochemicals over the cropping years, with the notable exception of cannabigerol, a cannabinoid that exhibits a wide range of biological activities, which was found at its highest level in this genotype. Overall, these findings can be used by breeders in future programs aimed at the selection of new hemp genotypes with improved levels of phytochemicals in their inflorescences, which can provide better health and industrial benefits. Full article

(This article belongs to the Special Issue Cannabis sativa: From Plants to Humans)

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16 pages, 2570 KiB

Open AccessArticle

Rare Phytocannabinoids Exert Anti-Inflammatory Effects on Human Keratinocytes via the Endocannabinoid System and MAPK Signaling Pathway

by Daniel Tortolani, Camilla Di Meo, Sara Standoli, Francesca Ciaramellano, Salam Kadhim, Eric Hsu, Cinzia Rapino and Mauro Maccarrone

Int. J. Mol. Sci. 2023, 24(3), 2721; https://doi.org/10.3390/ijms24032721 - 1 Feb 2023

Cited by 12 | Viewed by 5571

Abstract

Increasing evidence supports the therapeutic potential of rare cannabis-derived phytocannabinoids (pCBs) in skin disorders such as atopic dermatitis, psoriasis, pruritus, and acne. However, the molecular mechanisms of the biological action of these pCBs remain poorly investigated. In this study, an experimental model of inflamed human keratinocytes (HaCaT cells) was set up by using lipopolysaccharide (LPS) in order to investigate the anti-inflammatory effects of the rare pCBs cannabigerol (CBG), cannabichromene (CBC), Δ⁹-tetrahydrocannabivarin (THCV) and cannabigerolic acid (CBGA). To this aim, pro-inflammatory interleukins (IL)-1β, IL-8, IL-12, IL-31, tumor necrosis factor (TNF-β) and anti-inflammatory IL-10 levels were measured through ELISA quantification. In addition, IL-12 and IL-31 levels were measured after treatment of HaCaT cells with THCV and CBGA in the presence of selected modulators of endocannabinoid (eCB) signaling. In the latter cells, the activation of 17 distinct proteins along the mitogen-activated protein kinase (MAPK) pathway was also investigated via Human Phosphorylation Array. Our results demonstrate that rare pCBs significantly blocked inflammation by reducing the release of all pro-inflammatory ILs tested, except for TNF-β. Moreover, the reduction of IL-31 expression by THCV and CBGA was significantly reverted by blocking the eCB-binding TRPV1 receptor and by inhibiting the eCB-hydrolase MAGL. Remarkably, THCV and CBGA modulated the expression of the phosphorylated forms (and hence of the activity) of the MAPK-related proteins GSK3β, MEK1, MKK6 and CREB also by engaging eCB hydrolases MAGL and FAAH. Taken together, the ability of rare pCBs to exert an anti-inflammatory effect in human keratinocytes through modifications of eCB and MAPK signaling opens new perspectives for the treatment of inflammation-related skin pathologies. Full article

(This article belongs to the Special Issue Cannabis sativa: From Plants to Humans)

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Review

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19 pages, 577 KiB

Open AccessReview

Dysmenorrhoea: Can Medicinal Cannabis Bring New Hope for a Collective Group of Women Suffering in Pain, Globally?

by Amelia Seifalian, Julian Kenyon and Vik Khullar

Int. J. Mol. Sci. 2022, 23(24), 16201; https://doi.org/10.3390/ijms232416201 - 19 Dec 2022

Cited by 3 | Viewed by 5132

Abstract

Dysmenorrhoea effects up to 90% of women of reproductive age, with medical management options including over-the-counter analgesia or hormonal contraception. There has been a recent surge in medicinal cannabis research and its analgesic properties. This paper aims to critically investigate the current research of medicinal cannabis for pain relief and to discuss its potential application to treat dysmenorrhoea. Relevant keywords, including medicinal cannabis, pain, cannabinoids, tetrahydrocannabinol, dysmenorrhoea, and clinical trial, have been searched in the PubMed, EMBASE, MEDLINE, Google Scholar, Cochrane Library (Wiley) databases and a clinical trial website (clinicaltrials.gov). To identify the relevant studies for this paper, 84 papers were reviewed and 20 were discarded as irrelevant. This review critically evaluated cannabis-based medicines and their mechanism and properties in relation to pain relief. It also tabulated all clinical trials carried out investigating medicinal cannabis for pain relief and highlighted the side effects. In addition, the safety and toxicology of medicinal cannabis and barriers to use are highlighted. Two-thirds of the clinical trials summarised confirmed positive analgesic outcomes, with major side effects reported as nausea, drowsiness, and dry mouth. In conclusion, medicinal cannabis has promising applications in the management of dysmenorrhoea. The global medical cannabis market size was valued at USD 11.0 billion in 2021 and is expected to expand at a compound annual growth rate (CAGR) of 21.06% from 2022 to 2030. This will encourage academic as well as the pharmaceutical and medical device industries to study the application of medical cannabis in unmet clinical disorders. Full article

(This article belongs to the Special Issue Cannabis sativa: From Plants to Humans)

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