humulene and Necrosis

Cannabis arteritis (CA) is a major and underdiagnosed cause of peripheral arterial disease in young patients. A 34-year-old man, daily smoker of 20 cigarettes and two cannabis cigarettes for 14 years, presented with a necrotic plaque of left hallux for 3 weeks. The Doppler ultrasound and angiography were compatible with severe Buerger's disease. Submitted to a revascularisation procedure and hypocoagulation with rivaroxaban. He had ceased smoking but maintained consumption of cannabis. Owing to the persistence of distal necrosis, amputation of the hallux was performed with good evolution. CA is a subtype of Buerger's disease. It is poorly known but increasingly prevalent and manifests in cannabis users regardless of tobacco use. The drug is considered at least a cofactor of the arteriopathy. The most effective treatment is cessation of consumption. Being cannabis one of the most consumed drugs, its mandatory to ask about its use in all young patients with arteriopathy.

Topics: Adult; Amputation, Surgical; Angiography; Arteritis; Cannabis; Diagnosis, Differential; Diagnostic Imaging; Hallux; Humans; Leg; Male; Marijuana Abuse; Necrosis; Smoking

Topics: Antifungal Agents; Aspergillosis, Allergic Bronchopulmonary; Bronchoscopy; Cannabis; Comorbidity; Female; Humans; Itraconazole; Lung; Marijuana Smoking; Middle Aged; Necrosis; Pulmonary Disease, Chronic Obstructive; Radiography

Cannabinoids are secondary metabolites stored in capitate-sessile glands on leaves of Cannabis sativa. We discovered that cell death is induced in the leaf tissues exposed to cannabinoid resin secreted from the glands, and identified cannabichromenic acid (CBCA) and Delta(1)-tetrahydrocannabinolic acid (THCA) as unique cell death mediators from the resin. These cannabinoids effectively induced cell death in the leaf cells or suspension-cultured cells of C. sativa, whereas pretreatment with the mitochondrial permeability transition (MPT) inhibitor cyclosporin A suppressed this cell death response. Examinations using isolated mitochondria demonstrated that CBCA and THCA mediate opening of MPT pores without requiring Ca(2+) and other cytosolic factors, resulting in high amplitude mitochondrial swelling, release of mitochondrial proteins (cytochrome c and nuclease), and irreversible loss of mitochondrial membrane potential. Therefore, CBCA and THCA are considered to cause serious damage to mitochondria through MPT. The mitochondrial damage was also confirmed by a marked decrease of ATP level in cannabinoid-treated suspension cells. These features are in good accord with those of necrotic cell death, whereas DNA degradation was also observed in cannabinoid-mediated cell death. However, the DNA degradation was catalyzed by nuclease(s) released from mitochondria during MPT, indicating that this reaction was not induced via a caspase-dependent apoptotic pathway. Furthermore, the inhibition of the DNA degradation only slightly blocked the cell death induced by cannabinoids. Based on these results, we conclude that CBCA and THCA have the ability to induce necrotic cell death via mitochondrial dysfunction in the leaf cells of C. sativa.

Topics: Calcium; Cannabis; Caspases; Cell Membrane Permeability; Cyclosporine; DNA Fragmentation; Dronabinol; Mitochondria; Mitochondrial Proteins; Necrosis; Plant Leaves; Plant Proteins

Marijuana smoke shares many components in common with tobacco smoke except for the presence of Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the psychotropic compound found only in Cannibis sativa. Delta(9)-THC has been shown to potentiate smoke-induced oxidative stress and necrotic cell death. In the present study, our objective was to determine the effects of Delta(9)-THC on the balance between Fas-induced apoptosis and necrosis in A549 lung tumor cells. We found that Fas-induced activation of caspase-3 was inhibited by whole smoke from both tobacco and marijuana cigarettes. Gas-phase smoke, which generates high levels of intracellular reactive oxygen species, had no effect on caspase-3 activity. However, particulate-phase smoke (tar) was a potent inhibitor of Fas-induced caspase-3 activity, with marijuana tar being more potent than either tobacco or placebo marijuana tar (lacking Delta(9)-THC). Delta(9)-THC also inhibited Fas-induced caspase-3 activity in A549 cells. In contrast, no inhibition was observed when Delta(9)-THC was incubated with activated caspase-3 enzyme, suggesting that Delta(9)-THC acts on the cell pathway(s) leading to caspase-3 activation and not directly on enzyme function. Flow cytometry was used to measure the percentage of cells undergoing apoptosis (staining for annexin V) versus necrosis (staining for propidium iodide) and confirmed that both marijuana tar extract and synthetic Delta(9)-THC inhibit Fas-induced apoptosis while promoting necrosis. These observations suggest that the Delta(9)-THC contained in marijuana smoke disrupts elements of the apoptotic pathway, thereby shifting the balance between apoptotic and necrotic cell death. This shift may affect both the carcinogenic and immunologic consequences of marijuana smoke exposure.

Topics: Annexin A5; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Apoptosis; Cannabis; Caspase 3; Caspase Inhibitors; Cell Survival; Dose-Response Relationship, Drug; Dronabinol; Flow Cytometry; Fluorescein-5-isothiocyanate; Humans; Necrosis; Phosphatidylserines; Propidium; Smoke; Tumor Cells, Cultured

1. Daily administration of cannabis extract (12.5 mg/kg body wt. for 30 days) produced a complete arrest of spermatogenesis in dogs. Distinct degenerative effects were produced in the form of extensive fibrosis and exfoliation of the seminiferous elements. 2. RNA, protein and sialic acid contents of the testis and epididymides were reduced after cannabis extract administration, whereas, testicular cholesterol and enzyme phosphatase were elevated. 3. Serum transaminases were slightly elevated, whereas the alkaline phosphatase and haemoglobin/haematocrit values were in normal range. 4. Histophysiological examination of the liver did not show any damage. 5. Reduced androgen production was reflected in low levels of sialic acid in the testis and epididymides, and shrunken Leydig cell nuclei and luminal epididymal epithelium. 6.. Cannabis extract at 12.5 mg/kg body wt. dose level did not cause severe damage to the vital organs but it produced an effective inhibition of spermatogenesis in male dogs in 30 days and thus induces an antifertility state. The possibility of an adverse effect of frequent marihuana use on male reproductive organ functioning in man is alarming.

Topics: Animals; Cannabis; Cholesterol; Dronabinol; Epididymis; Male; Necrosis; Organ Size; Plant Extracts; Proteins; RNA; Sialic Acids; Testis