Category Archives: Liver Disease

The protective role of cannabidiol in stress-induced liver injury: modulating oxidative stress and mitochondrial damage

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“Background: Stress-induced liver injury, resulting from acute or chronic stress, is associated with oxidative stress and inflammation. The endocannabinoid system, particularly cannabinoid receptor 2 (CB2R), plays a crucial role in liver damage. However, there are currently no clinical drugs targeting CB2R for liver diseases. Cannabidiol (CBD), a CB2R agonist, possesses anti-inflammatory and antioxidant properties. This study aims to investigate the pharmacological effects of CBD in a mouse model of stress-induced liver injury.

Methods: We employed a mouse model of stress-induced liver injury to evaluate the protective effects of CBD. Assessments included histopathological analysis, cytokine detection via ELISA, protein expression analysis using immunohistochemistry and Western blot, and gene transcription differential analysis. Transmission electron microscopy was utilized to observe mitochondrial morphology. Additionally, we examined the expression levels of CB2R, SLC7A11, α-SMA, and ACSL4 proteins to elucidate the mechanisms underlying CBD’s effects.

Results: CBD exhibited significant protective effects against stress-induced liver injury in mice. Decreases in liver function indicators (including Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT)) and inflammatory cytokines (such as IL-1β and Tumor Necrosis Factor-alpha (TNF-α)) were observed. CBD enhanced CB2R expression and reduced α-SMA levels, mitigating liver fibrosis. It also decreased ACSL4 levels, increased SOD and GSH-Px activities, and upregulated SLC7A11 protein expression. Furthermore, CBD improved mitochondrial morphology, indicating a reduction in oxidative cell death.

Conclusion: CBD activates the CB2R/α-SMA pathway to modulate liver inflammation and fibrosis. Through the SLC7A11/ACSL4 signaling pathway, CBD alleviates oxidative stress in stress-induced liver injury, enhances mitochondrial morphology, and reduces liver damage. These findings provide a theoretical basis for the potential application of CBD in the prevention and treatment of stress-induced liver injury.”

https://pubmed.ncbi.nlm.nih.gov/40160456/

“The cold-water immersion restraint method effectively simulates a stress-induced liver injury model caused by conditions such as hunger, cold exposure, and the fear of death. CBD demonstrates protective effects against stress-induced liver injury, and its protective mechanism may be associated with the activation of CB2R and mitochondrial metabolism. Specifically, CBD appears to exert its anti-liver fibrosis and antioxidative effects by activating CB2R, inhibiting the expression of α-SMA and ACSL4 proteins, and enhancing the expression of SLC7A11 protein, thereby alleviating liver damage.”

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2025.1567210/full

Cannabidiol and sphingolipid metabolism – an unexplored link offering a novel therapeutic approach against high-fat diet-induced hepatic insulin resistance

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“Despite extensive research on insulin resistance, which is associated with type 2 diabetes and obesity, there remains a lack of effective and safe methods to treat it. Thus, we hypothesized that cannabidiol (CBD), which influences lipid accumulation and inflammatory response, may interact with sphingolipid metabolism and insulin signaling.

To investigate the effects of CBD, male Wistar rats were fed a standard rodent chow or high-fat diet for 7 weeks to induce IR and were treated with CBD or its vehicle administered intraperitoneally for the last two weeks of the experiment. High-Performance Liquid Chromatography (HPLC) was used to assess sphingolipid concentration in the liver, while multiplex assay and western blotting were used to investigate the level or expression of proteins in the insulin signaling pathway and sphingolipid metabolism.

Our results revealed that CBD prevented ceramide deposition in the liver of high-fat-fed rats through inhibition of the ceramide de novo synthesis pathway. Moreover, the accumulation of sphingosine-1-phosphate was notably increased with impaired catabolic pathway. Observed changes in the sphingolipid pathway coincided with improved insulin signaling after CBD treatment in animals fed a high-fat diet.

Considering the presented evidence, CBD exerted a beneficial effect on insulin sensitivity in a state of lipid overload through the modification of sphingolipid deposition.

Our study reveals the importance of broadening IR treatment methods, especially with natural substances that lack serious side effects such as CBD.”

https://pubmed.ncbi.nlm.nih.gov/39986634/

“Cannabidiol – a novel therapeutic for the treatment of liver diseases.”

https://www.sciencedirect.com/science/article/abs/pii/S0955286325000282?via%3Dihub

Cannabidiol mitigates methotrexate-induced hepatic injury via SIRT-1/p53 signaling and mitochondrial pathways: reduces oxidative stress and inflammation

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“Methotrexate (MTX), a widely used chemotherapeutic agent, often induces hepatotoxicity, limiting its clinical utility.

Cannabidiol (CBD), derived from hemp, possesses antioxidant, anti-inflammatory, and antiapoptotic properties.

This study aims to investigate CBD’s protective effects against MTX-induced liver injury and elucidate the underlying mechanisms.

Thirty-two female Wistar Albino rats were divided into four groups: control, MTX (20 mg/kg intraperitoneally [i.p.] once), MTX+CBD (20 mg/kg i.p. once + 5 mg/kg i.p. for seven days), and CBD (5 mg/kg, i.p. for seven days). Biochemical analyses of serum and liver tissues were performed to assess oxidative stress markers (total oxidant status, total antioxidant status, oxidative stress index), liver function tests (AST, ALT), and antioxidant enzyme activities (glutathione peroxidase, superoxide dismutase). Histopathological and immunohistochemical examinations were conducted to evaluate liver tissue damage and TNF-α expression. Genetic analyses were performed to measure the expression levels of SIRT-1, p53, Bcl-2, and Bax genes using RT-qPCR. MTX administration increased oxidative stress markers, liver enzymes, TNF-α, p53, and Bax levels while decreasing antioxidant defenses and SIRT-1 expression.

CBD administration reversed these alterations effectively.

CBD mitigated MTX-induced hepatotoxicity by reducing oxidative stress, inflammation, and apoptosis. It activates antioxidant defenses via SIRT-1 upregulation, suppresses inflammation by reducing TNF-α, and prevents apoptosis by modulating p53, Bcl-2, and Bax gene expressions.

These findings suggest CBD could be a promising therapeutic agent for chemotherapy-induced liver damage. Further research is warranted to explore additional pathways and broader molecular mechanisms.”

https://pubmed.ncbi.nlm.nih.gov/39603835/

https://www.tandfonline.com/doi/full/10.1080/01480545.2024.2425994


Hepatoprotective Effect of Cannabidiol on the Progression of Experimental Hepatic Cirrhosis in Rats

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“Introduction: Liver cirrhosis is a condition characterized by the gradual replacement of normal liver tissue with scar tissue, ultimately leading to liver failure. This slow and progressive disease begins with a chronic inflammatory process induced by a noxious agent. In its advanced stages, the disease lacks effective therapies. Research has demonstrated the significant involvement of the endocannabinoid system in the pathogenesis of this disease. This study evaluated the hepatoprotective effect of cannabidiol (CBD) in the progression of experimental hepatic cirrhosis induced by thioacetamide (TAA) in rats. 

Methods: A randomized experimental design was employed using Holtzman rats. Hepatic cirrhosis was induced by intraperitoneal administration of TAA at a dose of 150 mg/kg for 6 weeks, with treatment initiated additionally. The groups were as follows: Group 1: TAA + vehicle; Group 2: TAA + CBD 2 mg/kg; Group 3: TAA + CBD 9 mg/kg; Group 4: TAA + CBD 18 mg/kg; Group 5: TAA + silymarin 50 mg/kg; and Group 6: Healthy control. Serum biochemical analysis (total bilirubin, direct bilirubin, ALT, AST, alkaline phosphatase, and albumin) and hepatic histopathological study were performed. The Knodell histological activity index (HAI) was determined, considering periportal necrosis, intralobular degeneration, portal inflammation, fibrosis, and focal necrosis. 

Results: All groups receiving TAA exhibited an elevation in AST levels; however, only those treated with CBD at doses of 2 mg/kg and 18 mg/kg did not experience significant changes compared to their baseline values (152.8 and 135.7 IU/L, respectively). Moreover, ALT levels in animals treated with CBD showed no significant variation compared to baseline. The HAI of hepatic tissue was notably lower in animals treated with CBD at doses of 9 and 18 mg/kg, scoring 3.0 and 3.25, respectively, in contrast to the TAA + vehicle group, which recorded a score of 7.00. Animals treated with CBD at 18 mg/kg showed a reduced degree of fibrosis and necrosis compared to those receiving TAA alone (p ≤ 0.05). 

Conclusion: Our findings demonstrate that cannabidiol exerts a hepatoprotective effect in the development of experimental hepatic cirrhosis induced in rats.”

https://pubmed.ncbi.nlm.nih.gov/38885158/

https://www.liebertpub.com/doi/10.1089/can.2023.0285


Cannabidiol alleviates carbon tetrachloride-induced liver fibrosis in mice by regulating NF-κB and PPAR-α pathways

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“Liver fibrosis has become a serious public health problem that can develop into liver cirrhosis and hepatocellular carcinoma and even lead to death.

Cannabidiol (CBD), which is an abundant nonpsychoactive component in the cannabis plant, exerts cytoprotective effects in many diseases and under pathological conditions.

In our previous studies, CBD significantly attenuated liver injury induced by chronic and binge alcohol in a mouse model and oxidative bursts in human neutrophils. However, the effects of CBD on liver fibrosis and the underlying mechanisms still need to be further explored. A mouse liver fibrosis model was induced by carbon tetrachloride (CCl4) for 10 weeks and used to explore the protective properties of CBD and related molecular mechanisms. After the injection protocol, serum samples and livers were used for molecular biology, biochemical and pathological analyses.

The results showed that CBD could effectively improve liver function and reduce liver damage and liver fibrosis progression in mice; the expression levels of transaminase and fibrotic markers were reduced, and histopathological characteristics were improved. Moreover, CBD inhibited the levels of inflammatory cytokines and reduced the protein expression levels of p-NF-κB, NF-κB, p-IκBα, p-p38 MAPK, and COX-2 but increased the expression level of PPAR-α. We found that CBD-mediated protection involves inhibiting NF-κB and activating PPAR-α.

In conclusion, these results suggest that the hepatoprotective effects of CBD may be due to suppressing the inflammatory response in CCl4-induced mice and that the NF-κB and PPAR-α signaling pathways might be involved in this process.”

https://pubmed.ncbi.nlm.nih.gov/38711461/

“In summary, we have shown that intraperitoneal injection of CBD exerts potent anti-inflammatory and antifibrotic activities in vivo. Moreover, we found that the first time CBD efficacy in reducing CCl4-induced hepatic fibrosis by multiple mechanisms. These mechanisms may involve inhibition of NF-κB, activation of the PPAR-α pathway, and inhibition of oxidative stress. Based on these findings, CBD has the potential to be further developed as a treatment for hepatic fibrosis, especially as a combination therapy with the currently available therapies.”

https://www.ebm-journal.org/journals/experimental-biology-and-medicine/articles/10.3389/ebm.2024.10141/full

Cannabidiol may prevent the development of congestive hepatopathy secondary to right ventricular hypertrophy associated with pulmonary hypertension in rats

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“Background: Pulmonary hypertension (PH) can cause right ventricular (RV) failure and subsequent cardiohepatic syndrome referred to as congestive hepatopathy (CH). Passive blood stasis in the liver can affect inflammation, fibrosis, and ultimately cirrhosis. Cannabidiol (CBD) has many beneficial properties including anti-inflammatory and reduces RV systolic pressure and RV hypertrophy in monocrotaline (MCT)-induced PH in rats. Thus, it suggests that CBD may have the potential to limit CH development secondary to RV failure. The present study aimed to determine whether chronic administration of CBD can inhibit the CH secondary to RV hypertrophy associated with MCT-induced PH.

Methods: The experiments involved rats with and without MCT-induced PH. CBD (10 mg/kg) or its vehicle was administered once daily for 3 weeks after MCT injection (60 mg/kg).

Results: Monocrotaline administration increased the liver/body weight ratio. In histology examinations, we observed necrosis and vacuolar degeneration of hepatocytes as well as sinusoidal congestion. In biochemical studies, we observed increased levels of nuclear factor-κappa B (NF-κB), tumour necrosis factor-alpha (TNA-α), interleukin 1 beta (IL-1β), and interleukin 6 (IL-6). CBD administration to PH rats reduced the liver/body weight ratio, improved the architecture of the liver, and inhibited the formation of necrosis. Cannabidiol also decreased the level of NF-κB, TNF-α, IL-1β and IL-6.

Conclusions: The studies show that CBD can protect the liver from CH probably through attenuating PH, protective effects on the RV, and possibly direct anti-inflammatory effects on liver tissue through regulation of the NF-κB pathway.”

https://pubmed.ncbi.nlm.nih.gov/38519732/

“In conclusion, we confirmed that the NF-κB pathway may be involved in the development of CH, especially at an early stage. Furthermore, the studies presented show that CBD can protect the liver from CH probably through attenuating PH, protective effects on the RV, and possibly direct anti-inflammatory effects on liver tissue through regulation of the NF-κB pathway. In addition, like other authors, we confirm that CBD did not cause any adverse changes in the liver of healthy rats, demonstrating its high safety potential.”

https://link.springer.com/article/10.1007/s43440-024-00579-4

The Role of Cannabidiol in Liver Disease: A Systemic Review

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“Cannabidiol (CBD), a non-psychoactive phytocannabinoid abundant in Cannabis sativa, has gained considerable attention for its anti-inflammatory, antioxidant, analgesic, and neuroprotective properties. It exhibits the potential to prevent or slow the progression of various diseases, ranging from malignant tumors and viral infections to neurodegenerative disorders and ischemic diseases.

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease, and viral hepatitis stand as prominent causes of morbidity and mortality in chronic liver diseases globally. The literature has substantiated CBD’s potential therapeutic effects across diverse liver diseases in in vivo and in vitro models. However, the precise mechanism of action remains elusive, and an absence of evidence hinders its translation into clinical practice.

This comprehensive review emphasizes the wealth of data linking CBD to liver diseases. Importantly, we delve into a detailed discussion of the receptors through which CBD might exert its effects, including cannabinoid receptors, CB1 and CB2, peroxisome proliferator-activated receptors (PPARs), G protein-coupled receptor 55 (GPR55), transient receptor potential channels (TRPs), and their intricate connections with liver diseases. In conclusion, we address new questions that warrant further investigation in this evolving field.”

https://pubmed.ncbi.nlm.nih.gov/38397045/

https://www.mdpi.com/1422-0067/25/4/2370

Effectiveness of cannabidiol (CBD) on histopathological changes and gene expression in hepatocellular carcinoma (HCC) model in male rats: the role of Hedgehog (Hh) signaling pathway

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“The third most prevalent malignancy to cause mortality is hepatocellular carcinoma (HCC). The Hedgehog (Hh) signaling pathway is activated by binding to the transmembrane receptor Patched-1 (PTCH-1), which depresses the transmembrane G protein-coupled receptor Smoothened (SMO).

This study was performed to examine the preventative and therapeutic effects of cannabidiol in adult rats exposed to diethyl nitrosamine (DENA)-induced HCC.

A total of 50 male rats were divided into five groups of 10 rats each. Group I was the control group. Group II received intraperitoneal (IP) injections of DENA for 14 weeks. Group III included rats that received cannabidiol (CBD) orally (3-30 mg/kg) for 2 weeks and DENA injections for 14 weeks. Group IV rats received oral CBD for 2 weeks before 14 weeks of DENA injections. Group V included rats that received CBD orally for 2 weeks after their last injection of DENA. Measurements were made for alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transferase (GGT), superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), and alpha fetoprotein (AFP). Following total RNA extraction, Smo, Hhip, Ptch-1, and Gli-1 expressions were measured using quantitative real-time polymerase chain reaction (qRT-PCR). A histopathological analysis of liver tissues was performed.

The liver enzymes, oxidant-antioxidant state, morphological, and molecular parameters of the adult male rat model of DENA-induced HCC showed a beneficial improvement after CBD administration.

In conclusion, by focusing on the Hh signaling system, administration of CBD showed a beneficial improvement in the liver enzymes, oxidant-antioxidant status, morphological, and molecular parameters in the DENA-induced HCC in adult male rats.”

https://pubmed.ncbi.nlm.nih.gov/38296878/

https://link.springer.com/article/10.1007/s00418-023-02262-w

How Does CBG Administration Affect Sphingolipid Deposition in the Liver of Insulin-Resistant Rats?

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“Background: Cannabigerol (CBG), a non-psychotropic phytocannabinoid found in Cannabis sativa plants, has been the focus of recent studies due to its potential therapeutic properties. We proposed that by focusing on sphingolipid metabolism, which plays a critical role in insulin signaling and the development of insulin resistance, CBG may provide a novel therapeutic approach for metabolic disorders, particularly insulin resistance.

Methods: In a rat model of insulin resistance induced by a high-fat, high-sucrose diet (HFHS), we aimed to elucidate the effect of intragastrically administered CBG on hepatic sphingolipid deposition and metabolism. Moreover, we also elucidated the expression of sphingolipid transporters and changes in the sphingolipid concentration in the plasma.

Results: The results, surprisingly, showed a lack of changes in de novo ceramide synthesis pathway enzymes and significant enhancement in the expression of enzymes involved in ceramide catabolism, which was confirmed by changes in hepatic sphingomyelin, sphinganine, sphingosine-1-phosphate, and sphinganine-1-phosphate concentrations.

Conclusions: The results suggest that CBG treatment may modulate sphingolipid metabolism in the liver and plasma, potentially protecting the liver against the development of metabolic disorders such as insulin resistance.”

https://pubmed.ncbi.nlm.nih.gov/37892425/

https://www.mdpi.com/2072-6643/15/20/4350

Effects of Full-Spectrum Cannabis Oil with a Cannabidiol:Tetrahydrocannabinol 2:1 Ratio on the Mechanisms Involved in Hepatic Steatosis and Oxidative Stress in Rats Fed a Sucrose-Rich Diet

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“Introduction: This study aimed to analyze the effects of cannabis oil (cannabidiol:tetrahydrocannabinol [CBD:THC], 2:1 ratio) on the mechanisms involved in hepatic steatosis and oxidative stress in an experimental model of metabolic syndrome (MS) induced by a sucrose-rich diet (SRD). We hypothesized that noninvasive oral cannabis oil administration improves hepatic steatosis through a lower activity of lipogenic enzymes and an increase in carnitine palmitoyltransferase-1 (CPT-1) enzyme activity involved in the mitochondrial oxidation of fatty acids. Furthermore, cannabis oil ameliorates liver oxidative stress through the regulation of the main regulatory factors involved, nuclear factor erythroid 2 (NrF2) and nuclear factor-kB (NF-κB) p65. For testing this hypothesize, a relevant experimental model of MS was induced by feeding rats with a SRD for 3 weeks.

Methods: Male Wistar rats were fed the following diets for 3 weeks: reference diet: standard commercial laboratory diet, SRD, and SRD + cannabis oil: noninvasive oral administration of 1 mg/kg body weight cannabis oil daily. The full-spectrum cannabis oil presents a total cannabinoid CBD:THC 2:1 ratio. Serum glucose, triglyceride, total cholesterol, HDL-cholesterol, LDL-cholesterol, uric acid, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase (AP), N-arachidonoylethanolamine or anandamide and 2-arachidonoylglycerol endocannabinoids levels, thiobarbituric acid reactive substance (TBARS) levels, and non-enzymatic antioxidant capacity (ferric ion-reducing antioxidant power [FRAP]) were evaluated. In the liver tissue: histology, nonalcoholic fatty liver disease activity score (NAS), triglycerides and cholesterol content, lipogenic enzyme activities (fatty acid synthase, acetyl-CoA carboxylase, malic enzyme, and glucose-6-phosphate dehydrogenase), enzyme related to mitochondrial fatty acid oxidation (CPT-1), reactive oxygen species, TBARS, FRAP, glutathione, catalase, glutathione peroxidase, and glutathione reductase enzyme activities. 4-hydroxynonenal, NrF2, and NF-κB p65 levels were analyzed by immunohistochemistry.

Results: The results showed that SRD-fed rats developed dyslipidemia, liver damage, hepatic steatosis (increase of key enzymes related to the novo fatty acid synthesis and decrease of key enzyme related to mitochondrial fatty acid oxidation), lipid peroxidation, and oxidative stress. Hepatic NrF2 expression was significantly decreased and NF-κB p65 expression was increased. Cannabis oil administration improved dyslipidemia, liver damage, hepatic steatosis, lipid peroxidation (improving enzymes involved in lipid metabolism), and oxidative stress. In the liver tissue, NrF2 expression increased, and NF-κB p65 expression was reduced.

Conclusion: The present study revealed new aspects of liver damage and steatosis, lipid peroxidation, and oxidative stress in dyslipidemic insulin-resistant SRD-fed rats. We demonstrated new properties and molecular mechanisms of cannabis oil (CBD:THC, 2:1 ratio) on lipotoxicity and hepatic oxidative stress in an experimental model of MS.”

https://pubmed.ncbi.nlm.nih.gov/38023489/

“our results suggest that full-spectrum cannabis oil with a CBD:THC 2:1 ratio may serve as a natural nutraceutical agent to prevent metabolic disorders related to hepatic steatosis, oxidative stress, and NASH. We cannot rule out the possibility that other components of cannabis oil, such as terpenes, flavonoids, and alkaloids, may also contribute to the beneficial effects found in the present study.”

https://karger.com/mca/article/6/1/170/869880/Effects-of-Full-Spectrum-Cannabis-Oil-with-a