“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.”
“Background: Protein-tyrosine phosphatase 1B (PTP1B) is a master negative regulator of insulin and leptin receptor tyrosine kinase (RTK) signaling, and its chronic overactivation is strongly implicated in metabolic dysfunction. However, natural compounds capable of simultaneously inhibiting PTP1B and stimulating AMPK-the two major metabolic control nodes-remain scarce.
Methods: Two phenylpropionamide lignanamides, Cannabisin A (CA) and Cannabisin B (CB), were isolated from hemp seed hulls and their functions were evaluated using a multimodal workflow integrating molecular docking (AutoDock 4.2), mixed-type Lineweaver-Burk kinetic modeling, and 100 ns molecular dynamics simulations (CHARMM36/TIP3P). Functional assays included in vitro models such as enzyme inhibition, insulin- and leptin-stimulated glucose uptake assays in C2C12 myotubes and hepatocytes (Hepa1C1C7 and primary hepatocytes from high-fat diet mice), and in vivo models such as a multiple low-dose streptozotocin (MLD-STZ)-induced diabetic mouse model (C57BL/6J). In silico analyses of human transcriptomic and GWAS data (GEO, HuGeAMP) were conducted to assess translational relevance. BioTransformer-based metabolic predictions were used to explore absorption feasibility.
Results: CA and CB inhibited PTP1B with IC₅₀ values of 0.37 and 0.84 μM, respectively. Kinetic analysis demonstrated competitive-dominant (CA) and mixed-type (CB) inhibition, while MD simulations confirmed stable binding via catalytic-site residues (Asp48, Asp181, Arg221, Phe182). In PA-challenged C2C12 cells, both compounds restored glucose uptake and reactivated p-IRS-1, p-AKT, p-AMPK, and p-JAK2/STAT3. Similar recovery was observed in hepatocyte models, including suppression of SREBP-1c and enhancement of GLUT2 in primary HFD hepatocytes. In vivo, oral administration of CA/CB (1.5 and 3 mg/kg) in MLD-STZ diabetic mice improved fasting glucose in a dose-dependent manner, restored OGTT and ITT responses, and reactivated IRS-1/AKT/JAK2 signaling in skeletal muscle and AMPK/AKT/GLUT2 signaling in liver. Human transcriptome data and BioTransformer PK modeling showed that orally administered CA and CB can acquire sufficient polarity through O-demethylation and hydroxylation to exert PTP1B inhibitory effects in obesity and type 2 diabetes.
Conclusion: CA and CB are natural dual-target antidiabetic agents that inhibit PTP1B while activating AMPK, enabling coordinated re-engagement of insulin, leptin, and metabolic signaling. Their multi-tissue efficacy in vitro, ex vivo, and in vivo, combined with human-dataset alignment, highlights their translational potential as first-in-class insulin/leptin sensitizers derived from hemp seed hulls.”
“Cannabis sativa L. (Cannabaceae) has long been cultivated for fiber, seed oil, and medicinal uses.”
“In this study, we identified two phenylpropionamides—Cannabisin A (CA) and Cannabisin B (CB)—from hemp seed hulls as first-in-class dual-node metabolic regulators.”
“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.”
“Neuroinflammation is a hallmark of multiple sclerosis (MS). MS is marked by glial cell activation, autoreactive T cells, and the release of pro-inflammatory cytokines and free radicals. Current therapeutic strategies aim to modulate the immune response using disease-modifying therapies, to slow disease progression.
The specific aims of this study were: (a) to investigate the effect of cannabinoid acids on the release of glial neuroinflammatory mediators, (b) to examine the effect of intraperitoneally administered cannabinoid acids on symptoms of MS, and (c) to evaluate their effects on microglial and astrocyte activation and CD4+ T cell infiltration into the spinal cords of MS mice.
Exposure of BV2 microglia to cannabinoid acids attenuated lipopolysaccharide (LPS)-induced expression of inducible nitric oxide synthase by 40-90% it also reduced the release of nitric oxide and interleukin-17A. Among the cannabinoid acids tested, cannabidiolic acid (CBDA) significantly increased tumor necrosis factor alpha (TNFα) secretion by up to 40% in LPS-stimulated BV2 cells. Intraperitoneal administration of CBDA also resulted in a twofold increase in TNFα secretion in splenocytes isolated from MS mice, compared to untreated MS controls.
This study provides evidence that CBDA significantly reduces neurological scores, while both cannabinoid acids attenuate microgliosis, astrogliosis, and CD4+ T cell migration in lumbar spinal cord sections of MS mice. These compounds cross the blood-brain barrier (BBB) and act directly within the central nervous system. The consistent elevation of TNFα in the presence of CBDA across three experimental models suggests a distinctive immunomodulatory role for CBDA, with potential therapeutic implications in MS.”
“Cannabinoid acids, including tetrahydrocannabinolic acid (THCA) and cannabidiolic acid (CBDA), are precursors of the main active cannabinoids tetrahydrocannabinol (THC) and cannabidiol (CBD), respectively. CBDA and THCA are the main cannabinoids found in cannabis and have attracted attention for their potential immunomodulatory properties.”
“Our findings provide direct evidence supporting immunomodulatory effects of CBDA and THCA in both in vitro and in vivo models, highlighting their potential therapeutic relevance in MS.”
“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.”
“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.”
“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.”
“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.”
“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.”
“Cannabidiol (CBD), a bioactive phytochemical derived from Cannabis sativa, exhibits anti-inflammatory, antioxidant, and emerging antitumor properties.
Oral squamous cell carcinoma (OSCC), the most common oral cancer, remains challenging to treat due to its aggressive nature and limited therapeutic options. Extracellular vesicles (EVs) have been increasingly recognized as key mediators of tumor progression, facilitating intercellular communication, remodeling the tumor microenvironment (TME), and promoting metastasis, angiogenesis, and chemoresistance in OSCC.
This review discusses the pharmacological properties of CBD, including its bioavailability limitations, multi-target mechanisms, and potential for combination therapy. Notably, we explore the hypothesis that CBD may exert antitumor effects through modulation of EV secretion-a novel and underexplored mechanism in OSCC. Although direct evidence in OSCC models remains limited, studies in non-OSCC systems suggest that CBD influences EV biogenesis and release via pathways involving Wnt/β-catenin, STAT3 signaling, and mitochondrial calcium homeostasis.
Based on these findings, we propose a hypothetical framework linking CBD-mediated EV modulation to OSCC therapy. Despite its therapeutic promise, the clinical translation of CBD faces key hurdles, including poorly characterized mechanisms of EV regulation in OSCC, a lack of targeted delivery systems that compromises specificity and bioavailability, and a general scarcity of OSCC-specific evidence.
This review underscores the urgent need for future research to prioritize long-term evaluations, explore synergistic CBD-drug combinations, develop advanced CBD delivery systems, and assess its dual role in tumor suppression and pain management to enable clinical use.”
“Cannabidiol (CBD) is a non-psychoactive phytocannabinoid derived from Cannabis sativa L., characterized by low toxicity and a broad spectrum of pharmacological activities.These include antiepileptic, anti-inflammatory, neuroprotective, antiemetic, anticonvulsant, anxiolytic, antispasmodic, and anticancer effects.”
“Diabetic heart disease (DHD) is a major contributor to global cardiovascular morbidity, driven by a complex interplay of metabolic, inflammatory, oxidative, and fibrotic mechanisms. These interconnected pathways are not fully addressed by current cardiometabolic therapies, highlighting the need for novel multi-target interventions.
Cannabidiol (CBD), a non-psychoactive phytocannabinoid, has emerged as a potential modulator of several key processes implicated in DHD pathogenesis.
Preclinical evidence demonstrates that CBD attenuates oxidative stress by reducing reactive oxygen species (ROS) production, suppresses nuclear factor-κB (NF-κB)-mediated inflammatory signaling, preserves endothelial function by improving nitric oxide (NO) bioavailability, and inhibits transforming growth factor-β (TGF-β)-driven fibrotic remodeling.
These effects have been observed across in vitro and in vivo models of diabetic cardiomyopathy, where CBD improves both myocardial and vascular function. Mechanistically, CBD exerts its actions through negative allosteric modulation of CB₁ receptors and interaction with non-cannabinoid targets, including transient receptor potential vanilloid 1 (TRPV1), peroxisome proliferator-activated receptor gamma (PPARγ), and G protein-coupled receptor 55 (GPR55).
Despite this robust preclinical foundation, clinical evidence supporting the efficacy of CBD in DHD remains limited. Existing human studies are largely restricted to non-diabetic populations or short-term metabolic and hemodynamic outcomes, and do not address disease-specific cardiac endpoints. Furthermore, translational challenges, including variability in dosing, product standardization, and potential drug-drug interactions, remain significant barriers to clinical implementation.
Collectively, CBD represents a promising investigational candidate with multi-target potential to modulate the core pathophysiology of DHD. However, well-designed, disease-specific clinical trials are required to establish its therapeutic relevance and safety in diabetic populations.”
“Diabetic heart disease involves oxidative, inflammatory, and fibrotic pathways.”
“Cannabidiol (CBD) targets multiple pathological processes implicated in diabetic heart disease, including oxidative stress, inflammation, endothelial dysfunction, and fibrotic remodeling.”
“Cannabidiol (CBD), a non-psychoactive phytocannabinoid derived from Cannabis sativa, has attracted increasing interest due to its pleiotropic pharmacological actions across multiple molecular targets.”
“Background: Methotrexate (MTX) is the anchor drug for rheumatoid arthritis (RA) treatment, but its clinical application is limited by dose-dependent adverse events, such as hepatotoxicity and gastrointestinal intolerance, and incomplete efficacy in some patients. Cannabidiol (CBD) is a nonpsychotropic cannabinoid that has powerful therapeutic efficacy in alleviating pain and inflammation, as well as favourable safety and tolerability profiles. However, whether CBD can synergize with MTX to enhance therapeutic outcomes and mitigate toxicity remains unclear. This study aimed to investigate the synergistic efficacy, safety profile, and underlying molecular mechanism of the CBD-MTX combination in the treatment of RA.
Methods: Mice were randomly divided into 8 groups (n = 5 per group): a normal control group (NC), a model control group (MC), 3 MTX monotherapy groups (low/medium/high dose), and 3 CBD + MTX combination groups (low/medium/high dose). Arthritis severity was assessed by clinical scoring and micro-CT. Systemic safety was evaluated via histopathological examination of the liver, kidney, and testis. Flow cytometry, ELISA and Western blotting were used to validate the mechanisms involved. Network pharmacology and molecular docking were used to predict potential targets.
Results: Compared with MTX monotherapy, the CBD-MTX combination had dose-dependent synergistic effects, significantly attenuating joint swelling, inflammation, and bone erosion. The medium-dose combination approached the efficacy of high-dose MTX (dose-sparing effect). CBD mitigated MTX-induced testicular toxicity and spermatogenic failure. Mechanistically, the combination suppressed M1 macrophage polarization and proinflammatory cytokine (TNF-α, IL-6, and IL-1β) secretion by inhibiting STAT3 and NF-κB signalling (downregulation of p-STAT3 and p-NF-κB p65).
Conclusion: The CBD-MTX combination exerts superior antiarthritic effects by inhibiting STAT3/NF-κB-mediated M1 macrophage polarization and protecting against MTX-induced reproductive toxicity. This study provides a preclinical rationale for this novel combination strategy in RA management.”
“In summary, our findings identify the combination of CBD and MTX as a robust therapeutic strategy for RA management. We demonstrate that this regimen exerts synergistic antiarthritic effects by inhibiting the STAT3/NF-κB axis and suppressing M1 macrophage polarization. Importantly, CBD not only enhances MTX efficacy but also mitigates MTX-induced reproductive toxicity.”
