Cannabidiol alleviates suture-induced corneal pathological angiogenesis and inflammation by inducing myeloid-derived suppressor cells

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“Background: Currently, no perfect treatment for neovascularization and lymphangiogenesis exist, and each treatment method has its complications and side effects. This study aimed to investigate the anti-angiogenic and anti-inflammatory effects of cannabidiol and its mechanism of action.

Method: An in vivo corneal neovascularization (CNV) model was established using the suture method to investigate the inhibitory effects of CBD on suture-induced corneal inflammation, pathological blood vessel formation, and lymphangiogenesis. Additionally, the impact of CBD on immune cells was studied. In vitro methodologies, including cell sorting and co-culture, were employed to elucidate its mechanism of action.

Results: Compared with the CNV group, CBD can inhibit CNV, lymphangiogenesis, and inflammation induced via the suture method. In addition, CBD specifically induced CD45+CD11b+Gr-1+ cell upregulation, which significantly inhibited the proliferation of CD4+ T lymphocytes in vitro and exhibited a CD31+ phenotype, proving that they were myeloid-derived suppressor cells (MDSCs). We administered anti-Gr-1 to mice to eliminate MDSCs in vivo and found that anti-Gr-1 partially reversed the anti-inflammatory and angiogenic effects of CBD. Furthermore, we found that compared with MDSCs in the normal group, CBD-induced MDSCs overexpress peroxisome proliferator-activated receptor-gamma (PPAR-γ). Administering PPAR-γ inhibitor in mice almost reversed the induction of MDSCs by CBD, demonstrating the role of PPAR-γ in the function of CBD.

Conclusion: This study indicates that CBD may induce MDSCs upregulation by activating the nuclear receptor PPAR-γ, exerting anti-inflammatory, antiangiogenic, and lymphangiogenic effects, and revealing potential therapeutic targets for corneal neovascularization and lymphangiogenesis.”

https://pubmed.ncbi.nlm.nih.gov/38851157/

https://www.sciencedirect.com/science/article/pii/S1567576924009500?via%3Dihub

Neuroprotective Effects of Cannabispirenone A against NMDA-Induced Excitotoxicity in Differentiated N2a Cells

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“The endocannabinoid system is found throughout the central nervous system, and its cannabinoids receptor 1 is critical in preventing neurotoxicity caused by N-methyl-D-aspartate receptor activation (NMDARs). The activity of NMDARs places demands on endogenous cannabinoids to regulate their calcium currents.

Endocannabinoids keep NMDAR activity within safe limits, protecting neural cells from excitotoxicity. Cannabinoids are remembered to deliver this outcome by repressing presynaptic glutamate discharge or obstructing postsynaptic NMDAR-managed flagging pathways.

The endocannabinoid system must exert a negative influence proportional to the strength of NMDAR signaling for such control to be effective. The goal of this paper is to draw the attention towards the neuroprotective mechanism of constituents of Cannabis sativa against NMDA-induced excitotoxic result.

Phytochemical investigation of the cannabis flowers led to the isolation of nine secondary metabolites. A spiro-compound, Cannabispirenone A, which on treatment of the cells prior to NMDA exposure significantly increases cell survival while decreasing ROS production, lipid peroxidation, and intracellular calcium.

Our findings showed that this compound showed neuroprotection against NMDA-induced excitotoxic insult, has antioxidative properties, and increased cannabinoid receptor 1 expression, which may be involved in the signaling pathway for this neuroprotection.”

https://pubmed.ncbi.nlm.nih.gov/38855429/

“In the current study, we assessed the flowers of the cannabis plant that showed ability to protect cells from NMDA-induced insult and discovered that it could prevent cell death. To our knowledge, we here reporting the first-time neuroprotective properties of the molecule isolated from the flowers of the cannabis plant.”

https://onlinelibrary.wiley.com/doi/10.1155/2024/3530499

The development of cannabinoids as therapeutic agents in the United States

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“Cannabis is one of the oldest and widely used substances in the world. Cannabinoids within the cannabis plant, known as phytocannabinoids, mediate cannabis’ effects through interactions with the body’s endogenous cannabinoid system.

This endogenous system, the endocannabinoid system, has important roles in physical and mental health. These roles point to the potential to develop cannabinoids as therapeutic agents, while underscoring the risks related to interfering with the endogenous system during non-medical use.

This scoping narrative review synthesizes the current evidence for both the therapeutic and adverse effects of the major (i.e., Δ9-tetrahydrocannabinol and cannabidiol) and lesser studied minor phytocannabinoids, from nonclinical to clinical research. We pay particular attention to the areas where evidence is well-established, including analgesic effects after acute exposures and neurocognitive risks after acute and chronic use.

In addition, drug development considerations for cannabinoids as therapeutic agents within the United States are reviewed. The proposed clinical study design considerations encourage methodological standards for greater scientific rigor and reproducibility, ultimately, to extend our knowledge of the risks and benefits of cannabinoids for patients and providers.

Significance Statement This work provides a review of prior research related to phytocannabinoids, including therapeutic potential and known risks in the context of drug development within the United States. We also provide study design considerations for future cannabinoid drug development.”

https://pubmed.ncbi.nlm.nih.gov/38849155/

https://pharmrev.aspetjournals.org/content/early/2024/06/07/pharmrev.123.001121

Select Minor Cannabinoids from Cannabis sativa are Cannabimimetic and Antinociceptive in a Mouse Model of Chronic Neuropathic Pain

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“Chronic pain conditions affect nearly 20% of the population in the United States. Current medical interventions, such as opioid drugs, are effective at relieving pain but are accompanied by many undesirable side effects. This is one reason increased numbers of chronic pain patients have been turning to Cannabis for pain management. 

Cannabis contains many bioactive chemical compounds; however, current research looking into lesser-studied minor cannabinoids in Cannabis lacks uniformity between experimental groups and/or excludes female mice from investigation. This makes it challenging to draw conclusions between experiments done with different minor cannabinoid compounds between labs or parse out potential sex differences that could be present.

We chose five minor cannabinoids found in lower quantities within Cannabis: cannabinol (CBN), cannabidivarin (CBDV), cannabigerol (CBG), Δ8-tetrahydrocannabinol (Δ8-THC), and Δ9-tetrahydrocannabivarin (THCV). These compounds were then tested for their cannabimimetic and pain-relieving behaviors in a cannabinoid tetrad assay and a chemotherapy-induced peripheral neuropathy (CIPN) pain model in male and female CD-1 mice.

We found that the minor cannabinoids we tested differed in the cannabimimetic behaviors evoked, as well as the extent. We found that CBN, CBG, and high dose Δ8-THC evoked some tetrad behaviors in both sexes, while THCV and low dose Δ8-THC exhibited cannabimimetic tetrad behaviors only in females. Only CBN efficaciously relieved CIPN pain, which contrasts with reports from other researchers. Together these findings provide further clarity to the pharmacology of minor cannabinoids and suggest further investigation into their mechanism and therapeutic potential. 

Significance Statement Minor cannabinoids are poorly studied ligands present in lower levels in Cannabis than cannabinoids like THC. In this study we evaluated 5 minor cannabinoids (CBN, CBDV, CBG, THCV, and Δ8-THC) for their cannabimimetic and analgesic effects in mice. We found that 4 of the 5 minor cannabinoids showed cannabimimetic activity, while one was efficacious in relieving chronic neuropathic pain. This work is important in further evaluating the activity of these drugs, which are seeing wider public use with marijuana legalization.”

https://pubmed.ncbi.nlm.nih.gov/38834356/

https://jpet.aspetjournals.org/content/early/2024/06/04/jpet.124.002212

The minor phytocannabinoid delta-8-tetrahydrocannabinol attenuates collagen-induced arthritic inflammation and pain-depressed behaviors

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“Patients with arthritis report using cannabis for pain management, and the major cannabinoid Δ9-THC has anti-inflammatory properties, yet the effects of minor cannabinoids on arthritis are largely unknown.

The goal of the present study was to determine the antiarthritic potential of the minor cannabinoid Δ8-THC using the collagen-induced arthritis (CIA) mouse model.

Adult male DBA/1J mice were immunized and boosted 21 days later with an emulsion of collagen and complete Freund’s adjuvant. Beginning on the day of the booster, mice were administered twice-daily injections of Δ8-THC (3 or 30 mg/kg), the steroid dexamethasone (2 mg/kg), or vehicle for two weeks. Dorsal-ventral paw thickness and qualitative measures of arthritis were recorded daily, and latency to fall from an inverted grid was measured on alternating days, to determine arthritis severity and functional impairment. On the final day of testing, spontaneous wire-climbing behavior and temperature preference in a thermal gradient ring were measured to assess CIA-depressed and -conditioned behavior, respectively.

The Δ8-THC treatment (30 mg/kg) reduced paw swelling and qualitative signs of arthritis. Δ8-THC also blocked CIA-depressed climbing and CIA-induced preference for a heated floor without producing locomotor effects but did not affect latency to fall from a wire grid. In alignment with the morphological and behavioral assessments in vivo, histology revealed that Δ8-THC reduced synovial inflammation, proteoglycan loss and cartilage and bone erosion in the foot joints in a dose-dependent manner.

Together, these findings suggest that Δ8-THC not only blocked morphological changes but also prevented functional loss caused by collagen-induced arthritis. 

Significance Statement Despite increasing use of cannabis products, the potential effects of minor cannabinoids are largely unknown. Here, the minor cannabinoid Δ8-THC blocked the development of experimentally induced arthritis by preventing both pathophysiological as well as functional effects of the disease model.

These data support the development of novel cannabinoid treatments for inflammatory arthritis.”

https://pubmed.ncbi.nlm.nih.gov/38834355/

https://jpet.aspetjournals.org/content/early/2024/06/04/jpet.124.002189

The Inhibitory Effects of the Herbals Secondary Metabolites (7α-acetoxyroyleanone, Curzerene, Incensole, Harmaline, and Cannabidiol) on COVID-19: A Molecular Docking Study

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“Background: Since the COVID-19 outbreak in early 2020, researchers and studies are continuing to find drugs and/or vaccines against the disease. As shown before, medicinal plants can be very good sources against viruses because of their secondary compounds which may cure diseases and help in survival of patients. There is a growing trend in the filed patents in this field.

Aims: In the present study, we test and suggest the inhibitory potential of five herbal based extracts including 7α-acetoxyroyleanone, Curzerene, Incensole, Harmaline, and Cannabidiol with antivirus activity on the models of the significant antiviral targets for COVID-19 like spike glycoprotein, Papain-like protease (PLpro), non-structural protein 15 (NSP15), RNA-dependent RNA polymerase and core protease by molecular docking study.

Methods: The Salvia rythida root was extracted, dried, and pulverized by a milling machine. The aqueous phase and the dichloromethane phase of the root extractive were separated by two-phase extraction using a separatory funnel. The separation was performed using the column chromatography method. The model of the important antivirus drug target of COVID-19 was obtained from the Protein Data Bank (PDB) and modified. TO study the binding difference between the studied molecules, the docking study was performed.

Results: These herbal compounds are extracted from Salvia rhytidea, Curcuma zeodaria, Frankincense, Peganum harmala, and Cannabis herbs, respectively. The binding energies of all compounds on COVID-19 main targets are located in the limited area of 2.22-5.30 kcal/mol. This range of binding energies can support our hypothesis for the presence of the inhibitory effects of the secondary metabolites of mentioned structures on COVID-19. Generally, among the investigated herbal structures, Cannabidiol and 7α- acetoxyroyleanone compounds with the highest binding energy have the most inhibitory potential. The least inhibitory effects are related to the Curzerene and Incensole structures by the lowest binding affinity.

Conclusion: The general arrangement of the basis of the potential barrier of binding energies is in the order below: Cannabidiol > 7α-acetoxyroyleanone > Harmaline> Incensole > Curzerene. Finally, the range of docking scores for investigated herbal compounds on the mentioned targets indicates that the probably inhibitory effects on these targets obey the following order: main protease> RNA-dependent RNA polymerase> PLpro> NSP15> spike glycoprotein.”

https://pubmed.ncbi.nlm.nih.gov/38817009/

https://www.eurekaselect.com/article/136307

Cannabidiol mitigates radiation-induced intestine ferroptosis via facilitating the heterodimerization of RUNX3 with CBFβ thereby promoting transactivation of GPX4

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“Radiation enteritis remains a major challenge for radiotherapy against abdominal and pelvic malignancies. Nevertheless, there is no approved effective therapy to alleviate irradiation (IR)-induced gastrointestinal (GI) toxicity.

In the current study, Cannabidiol (CBD) was found to mitigate intestinal injury by GPX4-mediated ferroptosis resistance upon IR exposure.

RNA-sequencing was employed to investigate the underlying mechanism involved in the radio-protective effect of CBD, wherein runt-related transcription factor 3 (RUNX3) and its target genes were changed significantly. Further experiment showed that the transactivation of GPX4 triggered by the direct binding of RUNX3 to its promoter region, or by stimulating the transcriptional activity of NF-κB via RUNX3-mediated LILRB3 upregulation was critical for the anti-ferroptotic effect of CBD upon IR injury.

Specially, CBD was demonstrated to be a molecular glue skeleton facilitating the heterodimerization of RUNX3 with its transcriptional chaperone core-biding factor β (CBFβ) thereby promoting their nuclear localization and the subsequent transactivation of GPX4 and LILRB3.

In short, our study provides an alternative strategy to counteract IR-induced enteritis during the radiotherapy on abdominal/pelvic neoplasms.”

https://pubmed.ncbi.nlm.nih.gov/38830513/

https://www.sciencedirect.com/science/article/abs/pii/S0891584924005069?via%3Dihub

Cannabidiol reverts the malignant phenotype of hepatocellular carcinoma cells via the GPR55/TP53/MAPK axis

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“Cannabidiol (CBD) has antioxidant and anti-inflammatory activities. However, the anti-tumor effect of CBD on hepatocellular carcinoma (HCC) remains unclear. Here, we investigated whether CBD displays anti-tumorigenic effects in HCC cells and whether it could reduce tumorigenesis and metastases in vivo.

First, this study treated HCC cells with different concentrations of CBD, followed by analyzing the changes in the proliferative, apoptotic, migratory and invasive abilities. The effects of CBD on the growth and metastasis of HCC cells in vivo were verified by tumorigenesis and metastasis assays. Subsequently, the target genes of CBD were predicted through the SwissTarget website and the genes differentially expressed in cells after CBD treatment were analyzed by microarray for intersection. The enrichment of the pathways after CBD treatment was analyzed by KEGG enrichment analysis, followed by western blot validation. Finally, rescue assays were used to validate the functions of genes as well as pathways in the growth and metastasis of HCC cells.

A significant weakening of the ability of HCC cells to grow and metastasize in vitro and in vivo was observed upon CBD treatment. Mechanistically, CBD reduced GRP55 expression in HCC cells, along with increased TP53 expression and blocked MAPK signaling activation. In CBD-treated cells, the anti-tumor of HCC cells was restored after overexpression of GRP55 or deletion of TP53. CBD inhibits the MAPK signaling activation and increases the TP53 expression by downregulating GRP55 in HCC cells, thereby suppressing the growth and metastasis of HCC cells.”

https://pubmed.ncbi.nlm.nih.gov/38825256/

“CBD treatment inhibits the growth and metastasis of HCC cells in vitro and in vivo. CBD can be used as a clinical treatment for HCC.”

https://www.sciencedirect.com/science/article/abs/pii/S0304416524000941?via%3Dihub


Inflammation and cancer: friend or foe?

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“Chronic inflammation plays a crucial role in the onset and progression of pathologies like neurodegenerative and cardiovascular diseases, diabetes, and cancer, since tumor development and chronic inflammation are linked, sharing common signaling pathways. At least 20% of breast and colorectal cancers are associated with chronic inflammation triggered by infections, irritants, or autoimmune diseases.

Obesity, chronic inflammation, and cancer interconnection underscore the importance of population-based interventions in maintaining healthy body weight, to disrupt this axis. Given that the dietary inflammatory index is correlated with an increased risk of cancer, adopting an anti-inflammatory diet supplemented with nutraceuticals may be useful for cancer prevention.

Natural products and their derivatives offer promising antitumor activity with favorable adverse effect profiles; however, the development of natural bioactive drugs is challenging due to their variability and complexity, requiring rigorous research processes.

It has been shown that combining anti-inflammatory products, such as non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and statins, with plant-derived products demonstrate clinical utility as accessible adjuvants to traditional therapeutic approaches, with known safety profiles.

Pharmacological approaches targeting multiple proteins involved in inflammation and cancer pathogenesis emerge as a particularly promising option. Given the systemic and multifactorial nature of inflammation, comprehensive strategies are essential for long term success in cancer therapy. To gain insights into carcinogenic phenomena and discover diagnostic or clinically relevant biomarkers, is pivotal to understand genetic variability, environmental exposure, dietary habits, and TME composition, to establish therapeutic approaches based on molecular and genetic analysis. Furthermore, the use of endocannabinoid, cannabinoid, and prostamide-type compounds as potential therapeutic targets or biomarkers requires further investigation.

This review aims to elucidate the role of specific etiological agents and mediators contributing to persistent inflammatory reactions in tumor development. It explores potential therapeutic strategies for cancer treatment, emphasizing the urgent need for cost-effective approaches to address cancer-associated inflammation.”

https://pubmed.ncbi.nlm.nih.gov/38799159/

“Cannabis-derived substances in cancer therapy–an emerging anti-inflammatory role for the cannabinoids”

https://pubmed.ncbi.nlm.nih.gov/20925645/

“Analysis of Anti-Cancer and Anti-Inflammatory Properties of 25 High-THC Cannabis Extracts”

https://pubmed.ncbi.nlm.nih.gov/36144796/

Cannabidiol in the dorsal hippocampus attenuates emotional and cognitive impairments related to neuropathic pain: Role of prelimbic neocortex-hippocampal connections

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“Background and purpose: Chronic neuropathic pain (NP) is commonly associated with cognitive and emotional impairments. Cannabidiol (CBD) presents a broad spectrum of action with a potential analgesic effect. This work investigates the CBD effect on comorbidity between chronic NP, depression, and memory impairment.

Experimental approach: The connection between the neocortex and the hippocampus was investigated with biotinylated dextran amine (BDA) deposits in the prelimbic cortex (PrL). Wistar rats were submitted to chronic constriction injury (CCI) of the sciatic nerve and CA1 treatment with CBD (15, 30, 60 nmol).

Key results: BDA-labeled were found in CA1 and dentate gyrus. CCI-induced mechanical and cold allodynia increased c-Fos protein expression in the PrL and CA1. The number of astrocytes in PrL and CA1 increased, and the number of neuroblasts decreased in CA1. The CCI animals showed increasing depressive-like behaviors, such as memory impairment. CBD (60 nmol) treatment decreased mechanical and cold allodynia, attenuated depressive-associated behaviors, and improved memory performance. Cobalt chloride (CoCl2: 1 nM), WAY-100635 (0.37 nmol), and AM251 (100 nmol) intra-PrL reversed the CBD (60 nmol) effect intra-CA1, both in nociceptive, cognitive, and depressive behaviors.

Conclusion: CBD represents a promising therapeutic perspective in the pharmacological treatment of chronic NP and associated comorbidities such as depression and memory impairments. The CBD effects possibly recruit the CA1-PrL pathway, inducing neuroplasticity. CBD acute treatment into the CA1 produces functional and molecular morphological improvements.”

https://pubmed.ncbi.nlm.nih.gov/38797491/

“Cannabidiol (CBD), in turn, is an essential tool for treating symptoms associated with pain and comorbidities with emotional and cognitive changes.”

https://www.sciencedirect.com/science/article/abs/pii/S0278584624001076?via%3Dihub