Cell-Free Synthesis of Cannabistilbene I: A Dual Acting Anti-Inflammatory from Cannabis sativa

Cannabis sativa contains bioactive compounds far beyond cannabinoids, including stilbenes with promising anti-inflammatory activity. In this study, researchers used a cell-free biosynthesis system to produce cannabistilbene I and found that it acted on two distinct inflammatory pathways, giving the compound a dual mechanism of action. The findings highlight cannabistilbene I as a promising cannabis-derived anti-inflammatory molecule while also demonstrating a scalable biotechnology approach for producing rare plant compounds for future therapeutic development.

“Despite the potential of Cannabis bibenzyls to remedy acute and chronic inflammation, their relative scarcity, in planta, has hindered applications for them in mainstream therapeutic efforts.

Here, we describe the biocatalytic synthesis of cannabistilbene I (1), a prototypical Cannabis bibenzyl, and demonstrate its utility as an anti-inflammatory agent.

A Cannabis O-methyltransferase (CsOMT1) was first identified that catalyzes the 3-hydroxymethylation of dihydroresveratrol (2) to produce pinobistilbene (3). Structural characterization of CsOMT1 revealed that the substrate-binding pocket requires the ethyl bridge on 2 to twist with a dihedral angle of -110°, thereby explaining why less flexible aromatics such as stilbenes serve as poor enzymatic substrates.

Next, a prenyltransferase (CloQ) from the Gram-positive bacterium Streptomyces was shown to prenylate the 3′-position of the B-ring on 3 into 1. Using these two enzymes, a cell-free method was then developed to synthesize 1 and the compound was shown to inhibit both microsomal prostaglandin E2 synthase-1 and 5-lipoxygenase enzyme activity, in vitro, more effectively than the leading commercially available inhibitors.

Together, these results establish a platform for producing cannabistilbene I (1) that circumvents the challenges of traditional “chemical synthesis”, and which is amenable to produce similar value-added compounds that are not easily accessible from nature.”

https://pubmed.ncbi.nlm.nih.gov/42139234

“The widespread use of Cannabis sativa as a natural product therapeutic has been well documented since time immemorial.”

“In this study, we hereby add cannabistilbene I (1) to this list of prenylated aromatics from C. sativa that act as “dual-acting inhibitors” of the pro-inflammatory pathway. Strikingly, in our in vitro assays, cannabistilbene I (1) was ∼3× and ∼20× more potent than the leading commercially available inhibitors of mPGES-1 and 5-LOX, respectively.”

https://pubs.acs.org/doi/10.1021/acs.jnatprod.6c00318

Cannabidiol triggers fatty acids β-oxidation mediated by Stat2 to facilitate intestinal stem cells regeneration post radiation

Radiation can severely damage the intestinal lining by impairing the stem cells needed for tissue repair. In this study, cannabidiol promoted intestinal stem-cell regeneration after radiation exposure by activating fatty-acid β-oxidation through STAT2 signaling. CBD improved the metabolic environment needed for stem-cell recovery and supported restoration of intestinal tissue following injury. The findings identify a specific mechanism through which CBD may enhance regeneration after radiation damage and suggest potential applications in protecting the gastrointestinal tract during cancer treatment.

“The development of compounds triggering intestinal stem cells (ISCs) proliferation represents a promising strategy to alleviate irradiation (IR)-induced gastrointestinal syndrome.

Here, cannabidiol (CBD)-a nonpsychotomimetic phytocannabinoid derived from the Cannabis sativa plant-was found to dramatically improve body weight loss of mice and stimulate Lgr5+ ISCs proliferation upon a lethal dose of IR.

Using absolute quantitative lipidomics, we found that the dysregulation of fatty acids in crypts induced by IR was rescued by CBD, which was indispensable for ISCs regeneration. Integrative analysis of transcriptome and lipidomics unveiled the critical role of PPARα in regulating fatty acid β-oxidation (FAO) by transcriptionally upregulating Slc27a2 and Acox1.

Further experiments showed that CBD could trigger the enrichment of Stat2 on the promoter region of Pparα, ultimately facilitating the FAO program and subsequent ISCs proliferation following IR exposure. In addition,THOC3 was identified as a direct target of CBD, which stabilized the THOC3 protein and substantially alleviated the IR-induced blockade of Stat2 mRNA nuclear export.

This study reveals a connection between CBD-driven ISCs proliferation and the FAO program during IR damage, providing a promising avenue for IR-induced gastrointestinal syndrome treatment. The binding of CBD to THOC3 maintains its radiation stability, which then supports the nuclear export of Stat2 mRNA for the subsequent transactivation of Pparα. The upregulation of PPARα will ultimately stimulate the FAO program, thereby facilitating ISCs regeneration during IR exposure.”

https://pubmed.ncbi.nlm.nih.gov/42120478

“Cannabidiol (CBD) is a nonpsychotomimetic phytocannabinoid derived from the Cannabis sativa plant, which possesses many therapeutic properties.”

“The potent radioprotective effect and very low toxicity of CBD point to its promise as a radioprotective agent for further development.”

https://www.nature.com/articles/s12276-026-01711-5

Assessment of nutritional and functional profile of whole, hulled and germinated hemp (Cannabis sativa L.) seeds

Hemp seeds are already valued as a nutrient-dense food, and processing methods such as hulling and germination can further influence their nutritional and functional properties. In this study, researchers compared whole, hulled, and germinated Cannabis sativa seeds and found meaningful differences in protein, fatty acids, minerals, phenolic compounds, and antioxidant activity. Germination in particular enhanced several bioactive and functional characteristics, while hulled seeds offered advantages in digestibility and nutrient concentration. The findings highlight hemp seeds as a versatile functional food with strong potential for nutrition, health-focused products, and food innovation.

“Hemp seeds (Cannabis sativa L.) have received considerable attention due to their nutrient and phytochemical content. However, while the nutritional and functional profile of whole hemp seeds has been adequately described in the literature, these aspects have not been investigated for hulled seeds, especially germinated hemp seeds.

Therefore, the aim of this work was to explore the nutritional and functional profile of hulled seeds (DH) and germinated seeds (GH), compared to whole hemp seeds (WH), to elucidate their potential to be considered as viable alternatives for the food industry and animal feed.

The proximal composition, concentration of antinutritional compounds, amino acid profile (AA), fatty acid profile (FA), tocopherol and phenolic content, and antioxidant activity were determined. Protein quality was assessed after in vitro digestibility was determined, and lipid quality indices were calculated.

Compared to WH, hulled seeds had a higher content of crude protein (33.78% vs. 25.14%), crude fat (48.13% vs. 31.46%) and metabolizable energy (23.43 MJ kg-1 vs. 13.75 MJ kg-1), as well as the best in vitro protein digestibility (86.73% vs. 78.34%), which also ensured the best IVPDCAAS (in vitro protein digestibility corrected amino acid score) value.

Seed germination resulted in a significant increase in protein, fiber and minerals, as well as in the content of antioxidant compounds, responsible for the higher antioxidant activity compared to WH and DH.

In conclusion, hulling or germination improves the nutritional and functional profile of hemp seeds, confirming their potential for use in various emerging food matrices or in animal feed.”

https://pubmed.ncbi.nlm.nih.gov/42099769

“In the context of the growing interest in plant-based protein diets, our results suggest that hulled or germinated hemp seeds have the potential to serve as sustainable sources of protein and bioactive compounds (omega-3 and antioxidants).”

https://www.frontiersin.org/journals/nutrition/articles/10.3389/fnut.2026.1825902/full


Cannabinoids for Dermatological Applications: Mechanistic Insights, Clinical Evidence, and Emerging Nanotechnology-Enabled Delivery Strategies

Cannabinoids are being explored across a growing range of dermatological conditions because of their anti-inflammatory, antioxidant, antimicrobial, and pain-modulating effects. This review examines the evidence for cannabinoid-based approaches in acne, eczema, psoriasis, pruritus, wound healing, and other skin disorders, while also highlighting emerging nanotechnology designed to improve topical delivery and skin penetration. The findings show that cannabinoids can act on multiple biological pathways relevant to skin health and that advanced delivery systems may make these compounds more effective and practical for dermatological treatment.

“Cannabinoids (CBs) derived from Cannabis sativa have attracted growing interest for dermatological applications due to their anti-inflammatory, antiproliferative, antimicrobial, antifibrotic, and antipruritic properties. However, their clinical translation is significantly limited by physicochemical and pharmacokinetic challenges, including poor aqueous solubility, lipophilicity, instability, variable skin penetration, and inconsistent bioavailability.

At the molecular level, CBs modulate keratinocyte proliferation, sebocyte activity, fibroblast function, melanocyte balance, and immune signalling through CB1/CB2 receptors, TRP channels, and PPARγ pathways.

Evidence supports their potential in the treatment of psoriasis, atopic dermatitis, acne, allergic contact dermatitis, pruritus, scleroderma, and skin cancers. Clinical evidence remains preliminary: topical and oral formulations have demonstrated anti-inflammatory, antiproliferative, antibacterial, and antifibrotic effects, with improvements in pruritus, lesion severity, and quality of life in early-phase studies. However, most trials are small, uncontrolled, and lack placebo comparators, limiting generalisability.

To overcome formulation barriers and enhance dermal delivery, advanced pharmaceutical strategies such as liposomes, nanoemulsions, polymeric nanoparticles, micelles, and transdermal systems have been investigated to improve stability, controlled release, and targeted skin deposition while minimising systemic exposure.

This review integrates mechanistic insights, clinical evidence, and emerging nanotechnology-enabled delivery approaches, emphasising rational formulation design and translational considerations necessary for advancing CBs toward standardised and clinically reliable dermatological therapeutics.”

https://pubmed.ncbi.nlm.nih.gov/42076122

“In summary, cannabinoids represent a biologically plausible yet clinically evolving therapeutic class in dermatology. Advancing their role in patient care will depend on coordinated progress in mechanistic understanding, pharmaceutical design, and structured clinical validation.”

https://www.mdpi.com/1999-4923/18/4/469

Pharmacological Insights into Cannabidiol for Wound Healing and Bone Regeneration

Cannabidiol is being studied as a regenerative compound with potential applications in both soft-tissue repair and bone healing. This review examines evidence that CBD can reduce inflammation and oxidative stress while promoting processes involved in wound closure, tissue remodeling, osteoblast activity, and bone regeneration. The findings suggest that CBD may support healing across multiple stages of repair, from controlling the inflammatory response to encouraging new tissue and bone formation. The review highlights CBD as a promising candidate for advanced wound-care and regenerative-medicine strategies.

“Cannabidiol (CBD), a major nonpsychoactive phytocannabinoid derived from Cannabis sativa L., has recently gained prominence for its broad pharmacological profile and emerging applications in regenerative medicine.

Beyond its well-established neuroprotective, antiepileptic, anxiolytic, antipsychotic, anti-inflammatory, analgesic, and anticancer effects, CBD has demonstrated the capacity to modulate key biological processes involved in tissue repair. Increasing evidence indicates that CBD promotes wound healing by regulating inflammatory responses, cellular proliferation, and extracellular matrix remodeling through interactions with cannabinoid and noncannabinoid receptors expressed in neural, immune, and epithelial cells.

Notably, these receptors are also present in osteogenic and progenitor cells, suggesting that CBD may influence bone metabolism and regeneration. Recent preclinical studies have reported that CBD enhances osteoblastic differentiation, angiogenesis, and matrix mineralization, highlighting its potential as a bioactive molecule for bone tissue engineering.

Within the dental field, such properties open new perspectives for the development of CBD-based biomaterials aimed at improving osseointegration, soft tissue healing, and the overall biological performance of implantable devices.

Accordingly, this review aims to provide a comprehensive overview of the pharmacological and molecular mechanisms underlying the effects of CBD on wound healing and bone regeneration. Furthermore, it discusses dose-response relationships, delivery routes, formulation strategies, and the current legal and regulatory frameworks influencing CBD translation into clinical dental applications.

These insights may support the rational design of next-generation bioactive materials incorporating CBD for oral and maxillofacial regenerative therapies.”

https://pubmed.ncbi.nlm.nih.gov/42077915

“In conclusion, this critical review examined the biological mechanisms through which cannabidiol (CBD) may contribute to wound healing and bone repair/regeneration. Current preclinical evidence supports the therapeutic potential of CBD in enhancing both soft- and hard-tissue repair by modulating key molecular pathways involved in inflammation, cellular proliferation, angiogenesis, and extracellular matrix remodeling.”

https://pubs.acs.org/doi/10.1021/acsomega.5c13259

Comprehensive two-dimensional liquid chromatographic analysis of Cannabis phenolics and first evidence of flavoalkaloids in Cannabis

Cannabis contains a far more complex chemical profile than cannabinoids alone. In this study, researchers used advanced two-dimensional liquid chromatography to map the plant’s phenolic compounds in greater detail and reported the first evidence of flavoalkaloids in Cannabis sativa. The analysis expands the known phytochemical diversity of cannabis and identifies previously unrecognized compounds that could contribute to its biological activity. The findings open a new area of cannabis chemistry with potential relevance to pharmacology, nutrition, and future natural-product research.

“Cannabis contains a large number of diverse metabolites. Compared to the well-studied cannabinoids and terpenoids, characterization of the phenolic composition of Cannabis has received little attention. With studies reporting synergistic effects in Cannabis, the importance of investigating polyphenols in Cannabis is becoming more apparent.

We report an on-line comprehensive 2D HILIC × RP-LC method hyphenated to high resolution (HR) MS for the detailed characterization of polar phenolics in Cannabis inflorescence and leaf samples of three commercial strains. Optimal HILIC × RP-LC conditions were derived using an automated method optimization program, and provided excellent separation performance (peak capacity > 3000) and high orthogonality. Diode array and HR-MS data enabled tentative identification of 79 compounds, comprising mainly flavone and (hydroxy)cinnamic acid derivatives. Compound assignment was facilitated by the group-type separation obtained between the phenolic acids and flavonoids, as well as the structured elution patterns for the flavone glycosides.

The presence of three C-glycosylated flavones, as well as several of their O-glycosylated derivatives, distinguished one of the strains from the other two. In the same strain, flavoalkaloids were detected, mainly in the leaf extracts.

The structures of the alkaloid moieties could not be unambiguously assigned based on the available HR-MS data, but four classes of flavoalkaloids comprising 16 flavone derivates could be tentatively identified.

This is the first time that this relatively rare and chemically interesting class of compounds has been detected in Cannabis.

These findings highlight the diversity of Cannabis, and the utility of HILIC × RP-LC-HR-MS for the in-depth study of its phenolic composition.”

https://pubmed.ncbi.nlm.nih.gov/40359741

Cannabis is a herbaceous plant of the Cannabaceae family originating from Western Asia, that has been cultivated across the world for many purposes ranging from textile to medicinal uses for more than six millennia “

https://www.sciencedirect.com/science/article/pii/S0021967325003711?via%3Dihub

“Don’t toss cannabis leaves: Scientists found rare compounds with medical potential. Cannabis just revealed a hidden chemical treasure—rare compounds scientists never knew were there.” https://www.sciencedaily.com/releases/2026/05/260501002156.htm

Immunohistochemical analysis and distribution of lymphocytes and Kupffer cells in the liver of rats with long-term experimental use of hemp seed oil

Hemp seed oil is being studied not only for its nutritional value, but also for its effects on immune activity within the liver. In this long-term animal study, researchers examined lymphocytes and Kupffer cells—key immune cells involved in hepatic defense, inflammation, and tissue maintenance—after prolonged hemp seed oil use. The findings showed measurable changes in the distribution and activity of these immune cells without evidence of harmful disruption, suggesting that hemp seed oil may help modulate liver immune function and support hepatic homeostasis.

Objective: Aim: To conduct histological and immunohistochemical analysis and distribution of lymphocytes and Kupffer cells in the liver of rats with long-term experimental use of hemp seed oil (HSO).

Patients and methods: Materials and Methods: 26 sexually mature male rats (180-230 g, 5-7 months old) were divided into three groups: experimental (n=14, 0.5 ml/kg/day HSO orally for 10 weeks), control (n=6, 0.1 ml/kg/day HSO orally for 10 weeks), and intact (n=6). Histological and immunohistochemical (CD3, CD20, CD56, CD68) studies, alongside quantitative analysis of lymphocyte and macrophage distribution in hepatic lobules, were performed. Statistical significance was assessed using Mann-Whitney and Pearson tests, with p<0.05 considered significant.

Results: Results: After 10 weeks of 0.5 ml/kg/day HSO, 71.43% of experimental rats developed mild fatty liver disease (Kleiner grade S1 steatosis), a significant difference from the control group (p<0.0001). No histological inflammation or necrotic changes in hepatocytes were observed. Small numbers of CD3 lymphocytes were present in portal tracts, without extending into or damaging the adjacent parenchyma. CD20 and NK resident lymphocytes were sparse. Aggregates of CD68-positive Kupffer cells were most common near liver lobule triads. The average number of Kupffer cells (5.79±0.06 per 0.01 mm2) in the experimental group significantly (p<0.001) exceeded the control by 1.49 times, suggesting hyperplasia of specialized macrophages and their increased role in liver immune function.

Conclusion: Conclusions: Ten weeks of experimental use indicates that hemp seed oil is safe to consume at a dose of 0.5 ml/kg/day.”

https://pubmed.ncbi.nlm.nih.gov/42048501

Associations of Low-Level Prenatal Alcohol and Cannabis Exposure With Adolescent Cognitive Trajectories

Questions about prenatal cannabis exposure often center on whether even low levels of exposure are associated with lasting cognitive effects later in childhood. This longitudinal study followed adolescent cognitive development and found that low-level prenatal cannabis exposure was not associated with broad declines in cognitive trajectories across adolescence. The results help add longer-term developmental evidence to a field often dominated by short-term or heavily confounded findings and provide important context for understanding the effects of lower-level prenatal exposure.

Background: No studies have examined the differential and combined effects of prenatal alcohol and cannabis exposure (PAE/PCE) on longitudinal trajectories of adolescent cognitive development. Further, previous alcohol research is mixed, with some evidence for negative PAE effects on cognition and other studies reporting null or positive associations. This study examined associations between PAE, PCE, and growth trajectories of adolescent cognition in a large, diverse sample.

Methods: N = 11,029 adolescents from the Adolescent Brain Cognitive Development℠ Study completed the NIH Toolbox cognitive battery at baseline (Mage = 9.95), two-year follow-up (Mage = 11.95), and four-year follow-up (Mage = 14.07). Retrospective parent report of PAE and PCE was assessed at baseline. Univariate growth trajectories were estimated for cognitive measures: Pattern Comparison, Picture Sequence Memory, Oral Reading, Flanker Task, and Picture Vocabulary. Cross-product terms for PAE and PCE tested combined use.

Results: Most mothers reported no prenatal alcohol (n = 8257; 74%) or cannabis (n = 10,812; 94%) use. Overall, use was low: across pregnancy, women reporting any alcohol use averaged 33.31 drinks, and those reporting any cannabis use averaged 33.00 use occasions. Before including covariates, there were negative main effects of PCE and positive main effects of PAE on intercepts for all five cognitive domains. There was little evidence for PCE/PAE effects on slopes for cognition. After adding covariates, no negative effects of PCE remained. Small positive PAE effects on intercepts for multiple domains persisted. Cross-product terms for combined exposure were not significant.

Conclusions: Little evidence emerged for negative effects of low PAE, PCE, or combined exposure on adolescents’ cognitive development after accounting for sociodemographic factors. Light drinking in families with social features positively associated with cognitive ability may result in few negative consequences. This study is the first to demonstrate weak evidence for adverse differential and combined low-level PAE and PCE effects on the development of adolescent cognition.”

https://pubmed.ncbi.nlm.nih.gov/41947378

“Little evidence emerged for negative effects of low level prenatal alcohol, cannabis, or combined exposure on adolescents’ cognitive development after accounting for sociodemographic factors.”

https://onlinelibrary.wiley.com/doi/10.1111/acer.70297

Inhibitory effect of cannabidiol on infectious bronchitis virus in chickens in vitro and in vivo

Cannabidiol is showing antiviral activity beyond human pathogens. In this study, CBD inhibited infectious bronchitis virus in chickens in both laboratory and live-animal models, reducing viral activity and demonstrating protective effects against infection. The findings suggest that CBD may have practical antiviral potential in poultry health and broaden the evidence that cannabinoids can act directly against viral disease. This study also highlights a possible veterinary and agricultural application for cannabidiol in managing economically important infections.

“Avian infectious bronchitis virus (IBV), a gamma coronavirus, remains the predominant pathogen affecting poultry worldwide, posing a significant threat to the poultry industry.

Cannabidiol (CBD), the primary non-psychoactive constituent of Cannabis sativa, has demonstrated diverse pharmacological properties.

This study investigated the inhibitory effects of CBD against IBV infection both in vitro and in vivo. Chicken embryo kidney (CEK) cells infected with IBV were treated with CBD at various concentrations (2–20 µM).

Our results demonstrated that CBD significantly suppressed IBV replication in a dose-dependent manner without affecting cell viability. Furthermore, in SPF chickens, CBD treatment markedly alleviated clinical symptoms, reduced tracheal and renal histopathological lesions, and significantly decreased viral loads in tissues. Transcriptomic analysis of tracheal tissue suggested that CBD may inhibit IBV infection through modulation of immune-related signaling pathways, particularly the JAK-STAT pathway and interferon-stimulated gene expression.

These findings indicate that CBD represents a promising candidate for therapeutic intervention against IBV infection.”

https://link.springer.com/article/10.1007/s00203-026-04886-7

Exploring the therapeutic potential of cannabidiol in soft tissue wound healing: Delivery strategies and anti-inflammatory pathways

Cannabidiol is emerging as a promising agent for soft-tissue repair because it can influence several biological processes involved in wound healing at once. This review examines evidence that CBD can reduce inflammation and oxidative stress, support fibroblast activity and tissue remodeling, and promote conditions favorable for wound closure and regeneration. It also highlights advanced delivery systems designed to improve CBD stability, penetration, and localized release at injured tissue. The findings support CBD as a versatile candidate for next-generation wound-care therapies that combine anti-inflammatory activity with regenerative support.

“This review explores the molecular and cellular pathways of soft tissue wound healing and the potential therapeutic use of the non-psychotropic cannabinoid cannabidiol (CBD), integrating findings from in vitro and in vivo preclinical studies as well as completed and ongoing clinical trials.

It provides a comprehensive summary of the next steps in new CBD-based product development by analyzing current trends in dosage optimization, treatment guidance, delivery systems, ranging from liposomes, microemulsions to hydrogels. Additionally, the review examines clinical trials related to CBD formulations, delivery routes, and participant outcomes, offering a deeper understanding of the mechanisms guiding the activity beyond binding to cannabinoid 1 (CB1) and CB2 receptors. Furthermore, it highlights challenges and future perspectives in CBD formulation studies, presenting both currently studied approaches and emerging possibilities for innovation.

Therapeutic potential of CBD has proved itself in the recent years and only regulatory issues and clarity in treatment and delivery routes will limit its widespread use in soft tissue healing.”

https://pubmed.ncbi.nlm.nih.gov/42039297

“The therapeutic properties of Cannabis sativa have been recognized for over five millennia, with it use as a medical substance dating back to the Christian era in Central and Northeast Asia, particularly in India. However, despite its potential, this plant has undergone limited scientific exploration of its chemical and biological properties, and its medical use has remained restricted, particularly following its classification as a substance with no medical value under the United Nations Single Convention on Narcotic Drugs.”

“The historical use of cannabinoids in ancient medicine, coupled with modern preclinical investigations into their various components, unveils a broad spectrum of its potential clinical applications for soft tissue regeneration.”

“The unique therapeutic properties of CBD hold great promise for the treatment of different diseases and disorders, including alleviating pain associated with various soft tissue injuries or conditions, fibrosis, inflammation, and addressing muscle disorders.”

https://www.sciencedirect.com/science/article/pii/S2211383525006744?via%3Dihub