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Prenylated apigenin derivatives from Cannabis sativa L.: isolation, biosynthesis, and anti-inflammatory properties

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“Background: Cannabis sativa L. accumulates a wide array of specialized compounds, many of which are non-psychotropic and show significant promise in medical and therapeutic applications. One such group of C. sativa compounds is prenylated flavonoids, which have emerged as potential treatments for chronic pain and inflammation. Accordingly, the aim of this study was to isolate, identify, and synthesize prenylated flavonoids from C. sativa and test their efficacy as anti-inflammatory agents.

Methods: An enriched polyphenol extract from C. sativa was fractionated using flash chromatography and high-performance liquid chromatography to isolate prenylated flavonoids. Liquid chromatography-mass spectrometry (LC-MS) and nuclear magnetic resonance (NMR) spectroscopy were employed to determine their structures. Phylogenomic and classical biochemical approaches were combined to identify the enzyme involved in the biosynthesis of the isolated compounds. Finally, these prenylated flavonoids were tested to determine their inhibitory properties against microsomal prostaglandin E synthase-1 (mPGES-1) activity.

Results: Two prenylated flavonoids were isolated from the aerial parts of the C. sativa plant using classical chromatographic procedures and identified as 6-prenylapigenin (6-PA) and 6-geranylapigenin (6-GA). A C. sativa prenyltransferase (CsPT3) from the UbiA superfamily was identified to complete the final prenylation step in 6-PA and 6-GA biosynthesis from the widespread plant flavonoid known as apigenin. The inhibitory potentials of 6-PA and 6-GA against mPGES-1 activity were approximately as effective as, or better than, that of a leading commercially available inhibitor, MK-886. Molecular docking simulations confirmed strong binding affinities of 6-PA and 6-GA to mPGES-1 compared to its natural substrate.

Conclusions: 6-PA and 6-GA are prenylated derivatives of the widespread plant flavonoid known as apigenin. These non-psychotropic flavonoids accumulate in C. sativa and exhibit potent inhibition of mPGES-1, a chief mediator in the pro-inflammatory pathway. Identification of the final step in 6-PA and 6-GA biosynthesis, together with their now-established anti-inflammatory activity, presents propitious biotechnological avenues for these therapeutically relevant C. sativa compounds.”

https://pubmed.ncbi.nlm.nih.gov/41987337

https://link.springer.com/article/10.1186/s42238-026-00438-4

“Apigenin: A Promising Molecule for Cancer Prevention”

https://pmc.ncbi.nlm.nih.gov/articles/PMC2874462

“Apigenin: A Bioflavonoid with a Promising Role in Disease Prevention and Treatment”

https://pmc.ncbi.nlm.nih.gov/articles/PMC11202028

Phenolic Constituents Drive Antimicrobial and Antibiotic-Enhancing Activities of Cannabis sativa Seed Extracts Obtained by Two Extraction Methods

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“Hemp seeds (Cannabis sativa L.) are a rich source of phenolic compounds with antioxidant and antimicrobial potential.

Still, their genotype-dependent variability and ability to enhance antibiotic efficacy remain insufficiently explored. This study compared three Romanian hemp seed cultivars (Lovrin 110, Silvana, and LV 585) extracted by conventional hydroalcoholic extraction (CE) and ultrasound-assisted extraction (UAE) to evaluate their phenolic composition, antimicrobial effects, and synergistic interactions with amoxicillin and miconazole.

HPLC identified genotype- and method-dependent differences, with UAE extracts showing substantially higher levels of epicatechin, quercetin, rosmarinic acid, resveratrol, and ferulic acid. These patterns showed stronger antimicrobial inhibition against Gram-positive and Gram-negative bacteria and yeasts, confirmed by MIC, fold-reduction, and percent enhancement assays. The most pronounced synergy occurred in Streptococcus pyogenes, Staphylococcus aureus, Bacillus cereus, and Candida albicans. PCA revealed two dominant phenolic-activity axes: a rosmarinic/resveratrol/ferulic axis associated with potent inhibition in Escherichia coli and C. albicans, and a quercetin-driven axis linked to Gram-positive bacteria.

Overall, UAE extracts displayed superior phenolic enrichment and bioactivity, demonstrating that specific phenolic structures-not total phenolic content-govern antimicrobial performance and antibiotic-enhancing potential in hemp seed extracts.”

https://pubmed.ncbi.nlm.nih.gov/41514973

“Cannabis sativa L. (hemp) is an herbaceous, anemophilous species in the Cannabaceae family. It is considered one of the oldest domesticated crops. Due to its long history of use, it is now seen as a versatile, sustainable crop with a relatively low environmental impact and significance across sectors such as agriculture, phytoremediation, food and feed production, cosmetics, construction materials, and pharmaceuticals.”

“Hemp seed has historically served as a medicinal resource, used to address a range of conditions such as arthritis, asthma, menstrual discomfort, atopic dermatitis, cancer, hypertension, and other inflammatory diseases.”

“These findings identify hemp seeds—particularly when extracted by UAE—as promising natural antimicrobial agents and effective adjuvants for conventional antibiotics and antifungals.”

https://www.mdpi.com/2223-7747/15/1/27

Broad-spectrum bactericidal synergy of silver-cannabichromene-cannabigerol triple combinations against healthcare-associated pathogens

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“Aims: Healthcare-associated infections (HAI) place substantial burden on healthcare systems globally, with growing antimicrobial resistance (AMR) restricting treatment options, increasing patient mortality and raising the cost of care. Silver is a broad-spectrum antimicrobial used widely to help control HAI. However, its utility is limited by AMR and concentration-dependent cytotoxicity. To address these challenges, we systematically evaluated the antimicrobial amplification properties of non-intoxicating cannabinoids, naturally occurring molecules having a narrow spectrum of antimicrobial activity, aiming to increase the antimicrobial effect of silver against gram-positive and gram-negative HAI pathogens.

Methods and results: Administered individually, silver and cannabinoid compounds CBD, CBC, CBG, CBDA, CBCA and CBGA produced modest bacteriostatic effects on time-kill analysis. Pairwise silver-cannabinoid combinations were neither synergistic nor bactericidal consistently against both Escherichia coli and Pseudomonas aeruginosa. Whereas triple combinations comprising silver (as silver sulfate or nanoparticles), CBC and CBG were consistently synergistic and bactericidal against Staphylococcus aureus (MRSA), E. coli and P. aeruginosa on time-kill analysis, and achieved up to 64-fold lowering of silver MIC on checkerboard assay. Silver-CBC-CBG triple combinations further precluded emergence of MRSA resistance on 20-day serial passaging, ameliorated the potential for cytotoxicity in fibroblasts and keratinocytes, and demonstrated significant clearing of biofilms formed by MRSA (p < 0.001) and P. aeruginosa (p < 0.001).

Conclusions: The increased potency, broad-spectrum bactericidal action and anti-biofilm properties of these novel synergistic silver-CBC-CBG triple combinations may provide a useful solution for bacterial silver resistance and the control of HAI.”

https://pubmed.ncbi.nlm.nih.gov/41983582

https://academic.oup.com/jambio/advance-article/doi/10.1093/jambio/lxag092/8654259

Impact of Preoperative Marijuana Use on Functional Recovery and Complications After Spinopelvic Fusion in Adult Spinal Deformity

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“Background and objectives: With the rising prevalence of marijuana use and increasing rates of complex spinal deformity surgeries, understanding the impact of cannabis on perioperative outcomes is crucial. Previous studies yield mixed results on fusion success, complications, and opioid use in spine surgery, but none have focused on long-segment spinopelvic fusions.

Methods: This retrospective cohort study analyzed 155 adult patients undergoing posterior spinal fusion from the pelvis to L2 or higher between 2015 and 2023. Patients were stratified by preoperative marijuana use (n = 34 users vs n = 121 nonusers). Baseline demographics, surgical parameters, clinical outcomes [Oswestry Disability Index (ODI), visual analog scale], radiographic measures (pelvic tilt, lumbar lordosis, and sagittal vertical axis), and complications were compared using t-tests, χ2 tests, and logistic regression, with P < .05 considered significant.

Results: Marijuana users had higher preoperative opioid dependence (64.7% vs 42.9%, P = .025), more previous spine surgeries (52.9% vs 19.0%, P < .001), and elevated preoperative ODI scores (56.9 vs 52.8, P = .038), but demonstrated greater ODI improvement (43.7 vs 37.1, P = .003). No significant differences were observed in visual analog scale changes, radiographic corrections, hospital stay (8.8 vs 8.9 days, P = .920), transfusions (2.2 vs 1.5 units, P = .240), medical complications (eg, deep vein thrombosis/pulmonary embolism: 4 vs 21, P = .599), or mechanical complications (eg, pseudarthrosis: 10 vs 36, P > .999, and hardware failure: 12 vs 53, P = .434).

Conclusion: In this cohort, preoperative marijuana use was not associated with statistically significant differences in complication rates or inferior outcomes after long-segment spinopelvic fusion. Users experienced enhanced functional recovery, although this finding must be interpreted in the context of their higher baseline disability. Given the modest sample size, these findings should be viewed as preliminary; prospective studies with standardized cannabis exposure metrics are needed to confirm these results.”

https://pubmed.ncbi.nlm.nih.gov/41982324

https://journals.lww.com/neurosurgpraconline/fulltext/2026/06000/impact_of_preoperative_marijuana_use_on_functional.8.aspx

Hemp seed oil mediates injury mitigation and anti-inflammation in radiated splenic T cells

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“Background: Exposure to acute radiation results in hematopoietic damage, immune defects, and organ injury, ultimately leading to severe lethality. However, few drugs or compounds have been reported to effectively mitigate the injuries induced by high-dose ionizing radiation.

Methods: To elucidate the radioprotective mechanisms of hemp seed oil against acute radiation, lethal radiation was applied to evaluate the radio-protective function. The survival rates of mice were recorded, and the immune populations, particularly T cells, in the spleen were analyzed using flow cytometry. The expression of inflammation-related cytokines was detected for proving the anti-inflammatory function of hemp seed oil. Single-cell RNA sequencing was employed to explore the mechanisms underlying the radio-protective effects of hemp seed oil. In addition, we integrated HPLC-based phytochemical profiling with network pharmacology to identify bioactive constituents and characterize their molecular targets and signaling pathways.

Results: Hemp seed oil exhibited outstanding radio-protecting function, raising the survival ratio to above 50 % in mice exposed to lethal irradiation. Additionally, hemp seed oil preserved the immune populations, especially T cells, in the spleen. Single-cell RNA sequencing demonstrated that hemp seed oil alleviated oxidative stress, apoptosis, and inflammation-related features in T cells. Treatment with hemp seed oil enhanced the expression of inflammation-suppressing genes and promoted the differentiation of naïve CD4 T cells towards Treg cells. Further analyses indicated that the enhanced differentiation of Treg cells induced by hemp seed oil might be contributed by signals from fibroblasts through upregulated Itgb8. Meanwhile, HPLC analysis characterized 10 bioactive compounds in hemp seed oil. Integrating network pharmacology with in silico molecular docking revealed statistically significant correlations between these phytochemicals and key pathways regulating immune response and inflammatory processes, suggesting multitargeted immunomodulatory effects.

Conclusions: This research demonstrated a strong role of hemp seed oil in increasing survival rates and protecting splenic lymphocytes in mice facing acute irradiation. These findings offer a promising alternative for radioprotective medications and provide insights into the mechanisms underlying the radio-protective effects of hemp seed oil.”

https://pubmed.ncbi.nlm.nih.gov/41797188

“Hemp seed oil (HSO) is the extraction of hemp seed, a traditional Chinese medicine that can be applied as medicine as well as food.”

“In the present study, we evaluated the radioprotective function of HSO in vivo and demonstrated the improvement of spleen immune cell survival rate induced by HSO treatment.”

“Overall, our data support the use of HSO as a radioprotective and anti-inflammatory drug under conditions including acute radiation exposure.”

https://www.sciencedirect.com/science/article/abs/pii/S0944711326002412?via%3Dihub

Hemp seed protein: a promising meat protein substitute with high nutritional value, high safety, and high meat like aroma characteristics

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“Despite advances in alternative proteins, it remains unclear whether novel plant proteins can achieve high nutritional digestibility, safety, and meat-like flavor. Therefore, this study evaluates hemp seed protein as a meat substitute through comparison with other alternative proteins and beef.

Nutritional analyses (amino/fatty acid composition, in vivo/in vitro digestibility) showed that Hemp seed protein meat patties (HSMP) are abundant in essential amino acids and unsaturated fatty acids, with higher protein digestibility-corrected amino acid score (PDCAAS), metabolic amino acid digestibility (MAAD) and true ileal digestibility (TID) than plant-based protein meet patties (PPMPs). Safety evaluations (sensitization, storage stability) indicated low IgG/IgE reactivity and robust pH/carbonylation stability for HSMP. Sensory evaluation combined with GC-IMS showed that the flavor of HSMP is most similar to beef depending on 1,8-eucalyptol, octanal, and 2-ethyl-3,5-dimethylpyrazine.

In summary, this study confirms that HSMP is a valid alternative food protein source and provides methodological insights to improve product applicability.”

https://pubmed.ncbi.nlm.nih.gov/41916225

https://www.sciencedirect.com/science/article/abs/pii/S0308814626011787?via%3Dihub

Hemp Essential Oils as Novel Antioxidant and Bacteriostatic Agents in PLA-Based Packaging

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“Poly(lactic acid) (PLA) films containing two different hemp-derived essential oils (EOs), Carmagnola CS (Carm) and Futura 75 (Fut), at 1, 5, and 10% wt were successfully produced via solvent casting for packaging applications. The influence of EO presence, type, and concentration on the chemical, morphological, and thermal properties of the PLA-based films was investigated. In addition, radical-scavenging activity, water transport properties, and antimicrobial performance were evaluated to assess the effect of EOs on the structural and functional characteristics of the resulting packaging materials.

FTIR spectroscopy confirmed the successful incorporation of the hemp essential oils Carm and Fut into the polymer matrix, with a concentration-dependent effect that is more pronounced for Fut than for Carm. In the second heating run, evaluated by DSC measurements, both EOs lowered Tg from 60.3 °C (PLA) to 52.0 °C for PLA_10 Carm and 55.1 °C for PLA_10 Fut.

The EOs act as plasticizers in the PLA matrix, improving the deformation at break. Gas barrier measurements showed that permeability decreased from 3027 ± 300 Barrer (PLA) to (2499 ± 44) Barrer in PLA_10 Carm and 2623 ± 130 Barrer in PLA_10 Fut, with a corresponding reduction in diffusivity. The barrier improvement factor reached 17% for Carm and 15% for Fut, confirming the enhanced barrier performance of PLA_EOs films. DPPH assays showed that PLA_EOs films retained most of the antioxidant activity of the free oils, with only a 10-15% reduction for PLA_Fut and no significant loss for PLA_Carm after one week. After one month, the activity of Carm in PLA film decreased by 18%, whereas the performance of its free form remained unchanged, confirming the superior and more stable radical scavenging capacity of Carm compared to Fut.

Overall, the study demonstrates that hemp essential oils can be effectively integrated into PLA without compromising structural integrity, while preserving antioxidant performance and enhancing water barrier properties, supporting their potential as sustainable active packaging components.”

https://pubmed.ncbi.nlm.nih.gov/41977572

https://www.mdpi.com/2073-4360/18/7/824

Natural Hydrophobic Deep Eutectic Solvent-Based Enhanced Extraction of Bioactive Compounds from Cannabis sativa L. Leaf for Pharmaceutical Applications

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“Cannabis sativa L. leaves (CSL) are a rich in bioactive compounds and known for their medicinal and recreational uses. In this study, a natural hydrophobic deep eutectic solvent (HDES) system composed of menthol and thymol (1:1) was employed for the efficient extraction of bioactive compounds from CSL.

Extraction of bioactives was optimized at various conditions involving DES/ethanol ratio, temperature, and extraction time, as well as shaking speed through statistical models including response surface methodology (RSM) and artificial neural network (ANN). The maximum bioactive yield, equal to 70% (w/w) of powdered CSL, was achieved at optimized values of 5.5 mL DES, 4.5 mL ethanol, and 225 rpm shaking speed at 55 °C for 107.5 min. It was observed that slightly adjusting the shaking speed and temperatures customized the nature of bioactives with more antioxidant, antidiabetic, and antimicrobial properties. The extracts of CSL produced while applying natural HDES were found to be non-toxic during hemolytic assay.

Overall, HDES when mixed with ethanol in 55:45 ratio produced CSL extracts with an ample level of phenolics (133.75 mg GAE/g) and flavonoids (120.05 mg QE/g). GC-MS analysis of CSL extracts produced by HDES revealed the presence of multiple bioactives like tetrahydrocannabivarin, cannabidiol, cannabinol, cannabidivarol, dl-menthol, levomenthol, and 4-hydroxy-3-methylacetophenone.

Based on these findings, it can be concluded that HDES in combination with ethanol may work as an efficient extraction solvent to recover CSL bioactives without compromising their antioxidant features and safety for use in food and pharmaceutical applications.”

https://pubmed.ncbi.nlm.nih.gov/41977123

 “In conclusion, HDES–ethanol extraction offers a green, efficient, and biocompatible approach for isolating bioactive compounds from C. sativa, with promising applications in pharmaceuticals targeting oxidative stress, metabolic disorders, and microbial infections.”

https://www.mdpi.com/1422-0067/27/7/2933

A pharmacological roadmap for the Cannabaceae family: Prioritizing the therapeutic potential of neglected genera beyond Cannabis and Humulus

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“The Cannabaceae family presents a significant paradox in modern pharmacology; it is simultaneously one of the most intensely researched and most profoundly neglected plant families. The immense scientific, cultural, and economic significance of Cannabis and Humulus has cast a long shadow, obscuring the potential of the family’s other nine genera.

This paper provides the first comprehensive synthesis of the available ethnobotanical, phytochemical, and pharmacological data across all 11 genera to systematically expose this research disparity. It argues that genera such as Trema, Celtis, and Aphananthe, which possess a rich history of use in traditional medicine, represent an underexplored frontier for discovering novel, safer, and non-psychoactive therapeutics.

These genera are rich in flavonoids, polyphenols, triterpenoids, and alkaloids, offering alternatives to THC-based medicines and their associated adverse effects. By juxtaposing the well-characterized pharmacology of Cannabis and Humulus with the nascent data and vast potential of their relatives, this analysis reveals critical knowledge gaps and opportunity costs.

Ultimately, this report presents a strategic roadmap for future research, outlining a multidisciplinary approach and a prioritization model to guide the scientific community.

The aim is to rebalance research priorities and unlock the full medicinal promise of the entire Cannabaceae family, bridging the gap between traditional wisdom and modern drug discovery.”

https://pubmed.ncbi.nlm.nih.gov/41946416

https://www.sciencedirect.com/science/article/abs/pii/S0367326X26001486?via%3Dihub

Dynamic Mechanism for Subtype Selectivity of Endocannabinoids

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“Endocannabinoids are naturally occurring lipid-like molecules that bind to cannabinoid receptors (CB1 and CB2) and regulate many of human bodily functions via the endocannabinoid system.

There is a tremendous interest in developing selective drugs that target the CB receptors.

However, the biophysical mechanisms responsible for the subtype selectivity for endocannabinoids have not been established. Recent experimental structures of CB receptors show that endocannabinoids potentially bind via membrane using the lipid access channel in the transmembrane region of the receptors. Furthermore, the N-terminus of the receptor could move in and out of the binding pocket thereby modulating both the pocket volume and its residue composition.

On the basis of these observations, we propose two hypotheses to explain the selectivity of the endocannabinoid, anandamide for CB1 receptor. First, the selectivity arises from distinct enthalpic ligand-protein interactions along the ligand binding pathway formed due to the movement of N-terminus and subsequent shifts in the binding pocket composition. Second, selectivity arises from the volumetric differences in the binding pocket allowing for differences in ligand conformational entropy.

To quantitatively test these hypotheses, we perform extensive molecular dynamics simulations (∼0.9 milliseconds) along with Markov state modeling and deep learning-based VAMPnets to provide an interpretable characterization of the anandamide binding process to cannabinoid receptors and explain its selectivity for CB1.

Our findings reveal that the distinct N-terminus positions along lipid access channels between TM1 and TM7 lead to different binding mechanisms and interactions between anandamide and the binding pocket residues. To validate the critical stabilizing interactions along the binding pathway, relative free energy calculations of anandamide analogs are used. Moreover, the larger CB2 pocket volume increases the entropic effects of ligand binding by allowing higher ligand fluctuations but reduced stable interactions. Therefore, the opposing enthalpy and entropy effects between the receptors shape the endocannabinoid selectivity.

Overall, the CB1 selectivity of anandamide is explained by the dominant enthalpy contributions due to ligand-protein interactions in stable binding poses. This study shed lights on potential selectivity mechanisms for endocannabinoids that would aid in the discovery of CB selective drugs.”

https://pubmed.ncbi.nlm.nih.gov/41962866

“By situating these results within the broader landscape of pharmacological and structural evidence, we provide a cohesive mechanistic framework for endocannabinoid selectivity that can inform the rational design of CB1-selective therapeutics.”

https://www.jbc.org/article/S0021-9258(26)00304-2/fulltext