NF-κB signaling pathway, reducing matrix metalloproteinases in osteoarthritis

Posted on October 16, 2024 by David

“Background: The bioactivity and potential medicinal applications of cannabiorcol, a lesser-known derivative of Cannabis sativa, require further investigation. Osteoarthritis (OA) is a chronic joint condition marked by gradual degradation of the cartilage and commonly associated with elevated levels of matrix metalloproteinases (MMPs). However, the influence of cannabiorcol on OA and its underlying mechanisms remains unclear.

Methods: In silico analysis investigated the key transcription factors that regulate MMP expression. A chondrocyte cell model [interleukin (IL)-1β and IL-1⍺-treated C20A4 cell line] was established and treated with cannabiorcol. Associated cytotoxicity was assessed using a WST-8 assay. A monoiodoacetate-induced OA rat model was established and treated with cannabiorcol. Protein translocation and transactivation analyses were conducted using immunofluorescence and dual-luciferase reporter assays, respectively. Western blotting and real-time PCR analyzed relevant markers to examine cannabiorcol’s effects on OA and its fundamental mechanisms.

Results: Cannabiorcol inhibits the expression of IL-1β-induced MMPs compared to other cannabis-related compounds. In silico analysis revealed that the nuclear factor-kappa β (NF-κβ) and mitogen-activated protein kinase (MAPK) pathways are associated with MMP expression as key regulators. In vitro, cannabiorcol inhibits the NF-κB and p38 MAPK pathways independently cannabinoid receptors and transient receptor potential vanilloids. In vivo, cannabiorcol reduces MMP expression and ameliorates monoiodoacetate-induced OA traits in rats.

Conclusion: Cannabiorcol inhibits IL-1β-induced MMP expression in vitro and alleviates OA in an MIA-induced OA rat model by reducing MMP expression and inhibiting the p65/p38 axis.”

https://pubmed.ncbi.nlm.nih.gov/39405610/

“Phytocannabinoids are naturally occurring compounds found in Cannabis sativa that are being investigated as potential therapeutic agents for various diseases. Our findings offer new perspectives on cannabiorcol’s therapeutic potential for OA treatment. Our study demonstrates the potential therapeutic effects of cannabiorcol in OA by inhibiting MMP expression and attenuating inflammatory pathways such as NF-κB and p38 MAPK. Hence, cannabiorcol may represent a promising candidate for further investigation and development of OA treatments.”

https://www.sciencedirect.com/science/article/pii/S0944711324007980?via%3Dihub

Exploring the Potential of Synthetic Cannabinoids: Modulation of Biological Activity of Normal and Cancerous Human Colon Epithelial Cells

Posted on October 16, 2024 by David

“Colorectal cancer (CRC) is a global problem. Oncology currently practices conventional methods of treating this carcinoma, including surgery, chemotherapy, and radiotherapy. Unfortunately, their efficacy is low; hence, the exploration of new therapies is critical.

Recently, many efforts have focused on developing safe and effective anticancer compounds. Some of them include cannabinoids.

In the present study, we obtained cannabinoids, such as cannabidiol (CBD), abnormal cannabigerol (abn-CBG), cannabichromene (CBC), and cannabicitran (CBT), by chemical synthesis and performed the biological evaluation of their activity on colon cancer cells. In this study, we analyzed the effects of selected cannabinoids on the lifespan and metabolic activity of normal colonic epithelial cells and cancer colon cells.

This study demonstrated that cannabinoids can induce apoptosis in cancer cells by modulating mitochondrial dehydrogenase activity and cellular membrane integrity. The tested cannabinoids also influenced cell cycle progression. We also investigated the antioxidant activity of cannabinoids and established a relationship between the type of cannabinoid and nitric oxide (NO) production in normal and cancerous colon cells.

To conclude, it seems that, due to their interesting properties, the cannabinoids studied may constitute an interesting target for further research aimed at their use in alternative or combined therapies for human colon cancer.”

https://pubmed.ncbi.nlm.nih.gov/39404380/

“It seems that, due to their interesting properties, the cannabinoids studied may constitute an interesting target for further research, aimed at their use in alternative or combined therapies for human colon cancer.”

https://www.mdpi.com/2073-4409/13/19/1616

Prenatal Cannabis Use and Offspring Attention Deficit Hyperactivity Disorder and Disruptive Behavior Disorders: A Retrospective Cohort Study

Posted on October 14, 2024 by David

“Objective: To examine whether maternal cannabis use during early pregnancy is associated with offspring attention deficit hyperactivity disorder (ADHD) and disruptive behavior disorders (DBD).

Methods: We conducted a population-based retrospective birth cohort study of children (N = 141,570) born between 2011 and 2018 to pregnant individuals (N = 117,130) in Kaiser Permanente Northern California universally screened for any prenatal cannabis use at the entrance to prenatal care (at ∼8-10 wk gestation). Prenatal cannabis use was defined as (1) self-reported use and/or a positive toxicology test, (2) self-reported use, (3) a positive toxicology test, and (4) self-reported use frequency. Cox proportional hazards regression models adjusting for maternal characteristics (sociodemographics, other substance use and substance use disorders, prenatal care initiation, comorbidities) examined associations between prenatal cannabis use and offspring ADHD and DBD diagnosed by age 11 years.

Results: The sample of pregnant individuals was 27.2% Asian/Pacific Islander, 5.7% Black, 24.5% Hispanic, and 38.8% non-Hispanic White, with a mean (SD) age of 30.9 (5.2) years; 4.6% screened positive for any cannabis use (0.4% daily, 0.5% weekly, 1.1% monthly or less, 2.7% unknown frequency); 3.92% had a positive toxicology test and 1.8% self-reported use; 7.7% of offspring had ADHD and 6.8% had DBD. Maternal prenatal cannabis use was not associated with ADHD (adjusted hazard ratio [aHR]: 0.84, 95% CI, 0.70-1.01), and there was an inverse association with DBD (aHR: 0.83, 95% CI, 0.71-0.97), which remained when cannabis was defined by toxicology testing but not by self-report. Frequency of use was not associated with outcomes.

Conclusion: Maternal prenatal cannabis use was not associated with an increased risk of offspring ADHD or DBD.”

https://pubmed.ncbi.nlm.nih.gov/39400201/

https://journals.lww.com/jrnldbp/abstract/9900/prenatal_cannabis_use_and_offspring_attention.212.aspx

Cannabidiol attenuates arsenic-induced nephrotoxicity via the NOX4 and NF-κB pathways in mice

Posted on October 14, 2024 by David

“Background and purpose: Cannabidiol (CBD) is a phenolic terpene compound with anticancer, antioxidant, anti-inflammatory, antibacterial, neuroprotective, and anticonvulsant properties. Since the effects of CBD on sodium arsenite (As)-induced nephrotoxicity have not been fully determined, this study investigated the effect of CBD on As-induced nephrotoxicity by evaluating the NOX4 and NF-kB pathways in mice.

Experimental approach: 48 male mice were divided into six groups (8 each) including group 1, receiving saline for 14 days; group 2, receiving CBD (10 mg/kg, intraperitoneally) from the 7^th to the 14^th day; group 3, receiving As (10 mg/kg) for 14 days by gavage; and treatment groups 4-6, receiving CBD (2.5, 5, and 10 mg/kg, i.p.) 1.5 h before As (10 mg/kg by gavage, for 14 days) from the 7^th to the 14^th day. Mice were anesthetized after overnight fasting on day 15, and the blood sample was collected from their hearts. The level of antioxidants and pro-inflammatory factors, the expression of ROS and TNF-α, NF-kB, NOX4, iNOS, cleaved PARP, and caspase-3 proteins were measured and histological studies were performed.

Findings/results: Exposure to As significantly increased kidney markers, oxidative stress, apoptosis, and inflammation in mice kidney tissue, and pretreatment with CBD reversed these changes. In addition, CBD significantly decreased the expression of NF-kB and NOX4, and the levels of pro-inflammatory factors and the expression of cleaved PARP and increased the level of antioxidants.

Conclusion and implications: CBD ameliorated As-induced nephrotoxicity related to inhibiting oxidative stress, inflammation, and apoptosis, potentially through the NF-kB/Nox4 pathway.”

https://pubmed.ncbi.nlm.nih.gov/39399730/

“This study confirmed that CBD attenuates As-induced nephrotoxicity in mice. CBD led to the strengthening of antioxidant defense, reduction of lipid peroxidation, inflammation and expression of proteins of NF-kB, NOX4, iNOS, cleaved PARP, and caspase-3. The dose of 10 mg/kg of CBD showed better results than 5, and 2.5 mg/kg. Finally, the findings of the present study provide evidence that CBD may serve as a potential therapeutic agent for the prevention and treatment of arsenic-induced nephrotoxicity. “

https://journals.lww.com/rips/fulltext/2024/19040/cannabidiol_attenuates_arsenic_induced.8.aspx

Cannabidiol ameliorates cognitive decline in 5×FAD mouse model of Alzheimer’s disease through potentiating the function of extrasynaptic glycine receptors

Posted on October 13, 2024 by David

“Emerging evidence supports the therapeutic potential of cannabinoids in Alzheimer’s disease (AD), but the underlying mechanism upon how cannabinoids impact brain cognition and AD pathology remains unclear.

Here we show that chronic cannabidiol (CBD) administration significantly mitigates cognitive deficiency and hippocampal β-amyloid (Aβ) pathology in 5×FAD mouse model of AD. CBD achieves its curative effect mainly through potentiating the function of inhibitory extrasynaptic glycine receptor (GlyR) in hippocampal dentate gyrus (DG).

Based on the in vitro and in vivo electrophysiological recording and calcium imaging, CBD mediated anti-AD effects via GlyR are mainly accomplished by decreasing neuronal hyperactivity of granule cells in the DG of AD mice. Furthermore, the AAV-mediated ablation of DG GlyRα1, or the GlyRα1^S296A mutation that exclusively disrupts CBD binding, significantly intercepts the anti-AD effect of CBD.

These findings suggest a GlyR dependent mechanism underlying the therapeutic potential of CBD in the treatment of AD.”

https://pubmed.ncbi.nlm.nih.gov/39396064/

https://www.nature.com/articles/s41380-024-02789-x

Prevalence and Effect of Cannabinoids in Pain Management for Hand Pathologies

Posted on October 12, 2024 by David

“Background: Cannabinoids are a diverse group of compounds under investigation for various medical purposes, including analgesia. Given the evolving landscape of cannabinoid use, we aimed to analyze their prevalence and effect in pain management among urban orthopedic hand patients.

Methods: An electronic survey was administered to 122 new patients presenting to the orthopedic hand clinic of a major urban academic hospital. Demographic data, numerical rating scale pain scores, cannabinoid usage, and other concomitant pain regimens were recorded.

Results: Approximately half of the new patients were dissatisfied with current pain management for their hand pathology. Prescription (Rx) and over-the-counter (OTC) pain medications were used by 58% (71/122) of patients, while cannabinoids were used by 15% (18/122) of patients. Compared with pre-usage pain scores, both cannabinoids and Rx/OTC medications induced significant reductions in pain associated with patients’ hand pathologies (Cannabinoid: Δ4.4, P = .002; Rx/OTC: Δ3.0, P < .001). Cannabinoids induced a larger analgesic effect, but this difference was not statistically or clinically significant (P = .06). Subjectively, cannabinoid users either preferred their cannabinoid over Rx/OTC medications or liked both equally. Opioid use was higher among cannabinoid users (22.2% vs 12.5%), although this was not statistically significant (P = .28).

Conclusion: Approximately 15% of new urban hand patients use cannabinoids for pain control, and these compounds have similar analgesic efficacy in hand pathologies as Rx/OTC medications. Cannabinoids are equally liked or preferred relative to traditional medications in this cohort, and they may play an important role in pain management for hand patients.”

https://pubmed.ncbi.nlm.nih.gov/39392237/

https://journals.sagepub.com/doi/10.1177/15589447241284275

Cannabidiol Finds Dihydrocannabidiol as Its Twin in Anti-Inflammatory Activities and the Mechanism

Posted on October 12, 2024 by David

“Ethnopharmacological relevance: The hemp (cataloged at the “Medicinal Plant Names Services” as Cannabis sativa L.) extracts, cannabinoids have been used for centuries in Southeast Asia as folk medicines and now authorized by about 50 countries for application in medicine, health care products and cosmetics. As the most consumed cannabinoid, cannabidiol (CBD) has been recognized due to its various bioactivities, including anti-inflammatory and antibacterial properties.

Aims of the study: The utilization of CBD is limited due to its potential conversion to psychoactive Δ9-tetrahydrocannabinol in strong acidic environment, demanding to excavate safer alternatives with clarified bioactivities. Yet the anti-inflammatory and antibacterial properties of CBD still remain unknown, in both of the performances and the corresponding mechanisms. Previously, a synthetic CBD analogue, H2CBD (Dihydrocannabidiol) was found to be effective as CBD does towards some antioxidantive activities and mouse seizure mitigation. Therefore, it is wondering if H2CBD also acted similarly as CBD does in the aspect of anti-inflammatory performance and mechanism, and the safety.

Material and methods: The anti-inflammatory properties of CBD and H2CBD were revealed with enzymatic assays, proteins denaturation and lipopolysaccharide (LPS) stimulated RAW264.7 cells model, with epigallocatechin gallate (EGCG) as the positive control. Their anti-inflammatory mechanism was revealed with ELISA and Western blot assay. The antibacterial properties of CBD and H2CBD were also investigated towards E. faecalis and B. cereus along with their synergistic effect with commercial antibiotics.

Results: CBD and H2CBD exhibited almost same (P> 0.05) performance in all the assayed anti-inflammatory properties, yet their anti-inflammatory efficiencies positively correlated to their antioxidantive activity. Moreover, both of CBD and H2CBD presented anti-inflammation to LPS stimulated RAW264.7 cells through NF-κB and AKT pathway. Furthermore, CBD and H2CBD also supplied strong and very similar (P>0.05) antibacterial activities, comparable to tetracycline in same dose and strength. The erythrocyte hemolytic assay indicates CBD and H2CBD possessing the same safety. All the combinations of H2CBD with other cannabinoids or antibiotics present no antagonism against the bacteria, but nice synergistic or additive effect in some cases.

Conclusion: CBD and H2CBD presented very similarly in all the assayed anti-inflammatory performances, undergoing same inflammatory mechanism with NF-κB and AKT pathway; they also expressed similar antibacterial activity, like twins. These findings will supply CBD a sustainable, safer and economic alternative with same excellent performances.”

https://pubmed.ncbi.nlm.nih.gov/39389390/

“To assess the hypothesis or query that CBD could also find H2CBD performing similar anti-inflammatory properties and mechanism, as well as the safety, this experiment reveals the anti-inflammatory properties of CBD, H2CBD and H2THC using serval enzymatic assays, proteins denaturation assay and LPS-RAW264.7 cells model, with epigallocatechin gallate (EGCG) as the positive control. The results indicate that both of CBD and H2CBD significantly inhibited NO production from the LPS-stimulated RAW.”

https://www.sciencedirect.com/science/article/abs/pii/S0378874124012108?via%3Dihub

Edible cannabis for chronic low back pain: associations with pain, mood, and intoxication

Posted on October 9, 2024 by David

“Introduction: Cannabis, commonly known for both therapeutic and intoxicating effects, is gaining accessibility on legal markets and traction as a potential alternative therapy for pain mediation, particularly in those suffering from chronic low back pain. However, the effectiveness in this population of legal market forms of cannabis, particularly commonly used edibles, is unknown.

Methods: Therefore, this study utilized a naturalistic prospective design where participants with chronic low back pain with intentions to initiate cannabis use for treatment were recruited and self-selected edible cannabis products containing varying amounts of delta- 9 tetrahydrocannabinol (THC) and cannabidiol (CBD). Products were categorized as CBD-dominant, THC-dominant, or combined THC and CBD (THC + CBD).

Results: 249 participants [140 female (56.62%), mean (SD) age of 46.30 (16.02), 90% White] were tracked over 2 weeks of ad libitum use and assessed during a naturalistic acute cannabis administration session on changes in pain, mood, and subjective drug effects. During acute administration, a significant correlation between THC dose and short-term pain relief was found, suggesting that higher THC doses were associated with greater pain reduction (p < .05). In addition, THC was associated with higher levels of subjective cannabis drug effects (p < .001), regardless of whether CBD was also in the edible product. Acute CBD dose was primarily associated with short-term tension relief (p < .05); however, there were no associations between CBD dose and acute pain. Over the 2-week ad libitum administration period results suggested pain reductions across participants using all forms of cannabis. However, trends suggested that more frequent use of CBD-dominant edible cannabis may be associated with greater reductions in perceived pain over the 2-week observation period (p = .07).

Discussion: These findings support the short-term analgesic effects of THC and anxiolytic effects of CBD and further suggest that orally-administered THC and CBD should continue to be evaluated for the potential to provide both acute and extended relief from chronic low back pain.”

https://pubmed.ncbi.nlm.nih.gov/39380911/

“In this naturalistic observational study, it was found that the use of edible cannabinoid products significantly reduced chronic pain in extended and acute use models. More specifically, THC dose was associated with the greatest decrease in pain during the acute use session. Further, there was signal that more frequent use of a CBD-dominant product may provide stronger relief over a 2-week ad libitum use period.

These results indicate that edible cannabis may be a safe and suitable alternative pain therapy for those looking to substitute more traditional pain medications.”

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1464005/full

Preparation of a nanoemulsion containing active ingredients of cannabis extract and its application for glioblastoma: in vitro and in vivo studies

Posted on October 8, 2024 by David

“Recently, the anti-tumor effects of cannabis extract on various cancers have attracted the attention of researchers.

Here, we report a nanoemulsion (NE) composition designed to enhance the delivery of two active components in cannabis extracts (∆9-Tetrahydrocannabinol (THC) and Cannabidiol (CBD)) in an animal model of glioblastoma. The efficacy of the NE containing the two drugs (NED) was compared with the bulk drugs and carrier (NE without the drugs) using the C6 tumor model in rats. Hemocompatibility factors (RBC, MCV, MCH, MCHC, RDW, PPP, PT and PTT) were studied to determine the potential in vivo toxicity of NED. The optimized NED with mean ± SD diameter 29 ± 6 nm was obtained.

It was shown that by administering the drugs in the form of NED, the hemocompatibility increased. Cytotoxicity studies indicated that the NE without the active components (i.e. mixture of surfactants and oil) was the most cytotoxic group, while the bulk group had no toxicity. From the in vivo MRI and survival studies, the NED group had maximum efficacy (with ~4 times smaller tumor volume on day 7 of treatment, compared with the control. Also, survival time of the control, bulk drug, NE and NED were 9, 4, 12.5 and 51 days, respectively) with no important adverse effects.

In conclusion, the NE containing cannabis extract could be introduced as an effective treatment in reducing brain glioblastoma tumor progression.”

https://pubmed.ncbi.nlm.nih.gov/39375818/

“Based on our findings, the nanoemulsion model containing CBD and THC increased the antitumor effect of the drugs. This may be due to the role of nanoemulsions in improving drug delivery across the blood-brain barrier and improving blood compatibility during intravenous drug administration. However, this study is a primary investigation in the rat animal model, and future studies should consider further evaluation of toxicity and efficacy in larger animal populations.”

https://bmcpharmacoltoxicol.biomedcentral.com/articles/10.1186/s40360-024-00788-w

An overview of major depression disorder: The endocannabinoid system as a potential target for therapy

Posted on October 7, 2024 by David

“Major depressive disorder is the psychiatric disease with the highest global prevalence, impacting social functioning and decreasing the quality of life. The partial pathophysiological knowledge of the disease, the economic burden and the low remission rates are sufficient justification to carry out an update on the subject in the search for new therapeutic approaches and targets.

The endocannabinoid system has been linked to the development of depression, and its stimulation or antagonism is a promising approach in the treatment of major depressive disorder.

Cannabidiol (CBD) and its properties have been widely studied recently; its analgesic, anti-inflammatory, antineoplastic and neuroprotective roles have even been reported in animal models and clinical trials, achieving its approved use for certain neurodegenerative pathologies. The use of CBD in depression biomodels and clinical trials has not been the exception, and here we contrast the current evidence of its administration and pharmacology against the pathological mechanisms of major depressive disorder.”

https://pubmed.ncbi.nlm.nih.gov/39370369/

“This focused review discusses the prevalence of major depressive disorder (MDD) globally, its impact on social functioning and quality of life, and the need for new therapeutic approaches. It highlights the role of the endocannabinoid system in MDD and the potential of cannabidiol (CBD) in treating depression due to its various beneficial properties. CBD’s effectiveness is supported by research in animal models and clinical trials, offering promise as a treatment for MDD by targeting its pathological mechanisms.”

https://onlinelibrary.wiley.com/doi/10.1111/bcpt.14089

“Antidepressant-like effect of Δ⁹-tetrahydrocannabinol and other cannabinoids isolated from Cannabis sativa L”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2866040/

“Antidepressant-like effect of Δ9-tetrahydrocannabinol and other cannabinoids isolated from Cannabis sativa L”

“Antidepressant-like effect of Δ⁹-tetrahydrocannabinol and other cannabinoids isolated from Cannabis sativa L”