Khat a drug of abuse: roles of free radicals and antioxidants

Aleryani, Samir; Aleryani, Rowaida A.; Al-Akwa, Ahmed A.

doi:10.1002/dta.224

Cited by 21 publications

(15 citation statements)

References 28 publications

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“…We have previously shown that khat induce caspase-dependent apoptosis in myeloid cells and keratinocytes [30,31,33]. Khat-induced apoptosis may involve induction of reactive oxygen species [31] (see also Aleruyani et al for review [34]), which is described to function upstream of p53 and p38 in some model systems, while in others ROS production could be a downstream effect of p53 activation [35,36]. We therefore anticipated that single cell signalling analysis of total and modified p53 and phosphorylated p38 MAPK should reveal the mechanisms involved in khat toxicity when compared with cathinone and its natural derivatives.…”

Section: Discussionmentioning

confidence: 99%

Distinct single cell signal transduction signatures in leukocyte subsets stimulated with khat extract, amphetamine-like cathinone, cathine or norephedrine

Bredholt

Ersvær

Erikstein

et al. 2013

BMC Pharmacol Toxicol

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BackgroundAmphetamine and amphetamine derivatives are suggested to induce an immunosuppressive effect. However, knowledge of how amphetamines modulate intracellular signaling pathways in cells of the immune system is limited. We have studied phosphorylation of signal transduction proteins (Akt, CREB, ERK1/2, NF-κB, c-Cbl, STAT1/3/5/6) and stress sensors (p38 MAPK, p53) in human leukocyte subsets following in vitro treatment with the natural amphetamine cathinone, the cathinone derivatives cathine and norephedrine, in comparison with a defined extract of the psychostimulating herb khat (Catha edulis Forsk.). Intracellular protein modifications in single cells were studied using immunostaining and flow cytometry, cell viability was determined by Annexin V-FITC/Propidium Iodide staining, and T-lymphocyte proliferation was measured by 3H-thymidine incorporation.ResultsCathinone, cathine and norephedrine generally reduced post-translational modifications of intracellular signal transducers in T-lymphocytes, B-lymphocytes, natural killer cells and monocytes, most prominently affecting c-Cbl (pTyr700), ERK1/2 (p-Thr202/p-Tyr204), p38 MAPK (p-Thr180/p-Tyr182) and p53 (both total p53 protein and p-Ser15). In contrast, the botanical khat-extract induced protein phosphorylation of STAT1 (p-Tyr701), STAT6 (p-Tyr641), c-Cbl (pTyr700), ERK1/2 (p-Thr202/p-Tyr204), NF-κB (p-Ser529), Akt (p-Ser473), p38 MAPK (p-Thr180/p-Tyr182), p53 (Ser15) as well as total p53 protein. Cathinone, cathine and norephedrine resulted in unique signaling profiles, with B-lymphocytes and natural killer cells more responsive compared to T-lymphocytes and monocytes. Treatment with norephedrine resulted in significantly increased T-lymphocyte proliferation, whereas khat-extract reduced proliferation and induced cell death.ConclusionsSingle-cell signal transduction analyses of leukocytes distinctively discriminated between stimulation with cathinone and the structurally similar derivatives cathine and norephedrine. Cathinone, cathine and norephedrine reduced phosphorylation of c-Cbl, ERK1/2, p38 MAPK and p53(Ser15), and norephedrine induced T-lymphocyte proliferation. Khat-extract induced protein phosphorylation of signal transducers, p38 MAPK and p53, followed by reduced cell proliferation and cell death. This study suggests that protein modification-specific single-cell analysis of immune cells could unravel pharmacologic effects of amphetamines and amphetamine-like agents, and further could represent a valuable tool in elucidation of mechanism(s) of action of complex botanical extracts.

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Section: Discussionmentioning

confidence: 99%

Distinct single cell signal transduction signatures in leukocyte subsets stimulated with khat extract, amphetamine-like cathinone, cathine or norephedrine

Bredholt

Ersvær

Erikstein

et al. 2013

BMC Pharmacol Toxicol

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“…Khat induces an increase in ROS and a depletion of intracellular glutathione in the cell cultures of human keratinocytes and fibroblasts, the reactions that could be opposed by addition of exogenous antioxidants [17]. Recently, it is reported that chewing Khat inhibits ROS scavenging enzymes in the human blood serum, resulting in significant elevations in free radical loads, which cause the increase in oxidative stress [18,19].…”

Section: Ros Molecules Include Hydrogen Peroxide (H 2 O 2 ) Superoximentioning

confidence: 99%

Effect of Daily Chewing Soft Buds and Leaves of Catha edulis (Khat) on the Antioxidant Defense System and Oxidative Stress Markers in Blood

et al. 2014

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Catha edulis (Khat) is one of the major economic, social and health problems in Yemen. This paper aimed to study the effect of Khat on the oxidative status of Khat chewers by measuring the levels of enzymatic and non-enzymatic antioxidant as well as lipid peroxidation. The results exhibited significant reduction in erythrocytes superoxide dismutase (SOD, EC: 1.15.1.1), and catalase (CAT, EC: 1.11.1.6) in Khat chewers, in addition to elevation of serum glutathione-S-transferase (GST, EC: 2.5.1.18). Furthermore, non-enzymatic antioxidants glutathione (GSH) and vitamin C were significantly reduced ( p < 0.001; p < 0.015), whereas malondialdehyde (MDA) was significantly elevated ( p < 0.001). The depletion of GSH and vitamin C along with MDA elevation in Khat chewers compared with control reflects the obvious oxidative status, a result of enormous reactive oxygen species (ROS) formation, leading to membrane damage. ROS possibly induced by active components of Khat or by pesticides added to the Khat tree. In addition, the reduction of SOD and CAT is indicative to cellular proteins damage which occurred by ROS. As well, the elevation of GST may due to a leakage of cellular GST to blood stream; this implies that GST active site was not affected. This study concludes that daily chewing Khat for long period certainly induce ROS production, leading to oxidative toxicity. Both enzymatic and non-enzymatic antioxidants are involved in the protection against this toxicity. People who habitually chew Khat for long term will be susceptible to the oxidative toxicity; therefore, they recommended giving up of Khat chewing.

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“…For instance, neutrophilia has been observed in heroin and opium addicts (43,55) while neutropenia, eosinopenia and lymphopenia have been associated with the abuse of Marijuana ( Cannabis sativa ) (56) and chronic alcoholism (57). Monocytosis has been observed in individuals who use Khat ( Catha edulis ) (58) while monocytopenia associated with Cannabis use and alcoholism hence decreased proliferation and impaired monocyte and macrophage function (56,57). It is, therefore, possible that these derangements in the haematologic and immune profiles are exacerbated in HIV-positive substance users.…”

Section: Introductionmentioning

confidence: 99%

Erythrocyte indices, anaemia levels and types in Kenyan injection and non-injection substance users

Were

Khazalwa

Mulama

et al. 2018

Preprint

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The impact of injection and non-injection substance use in HIV infections is an area of great public importance especially with respect to hematologic and immune profiles. Evaluations of hematologic and immune status are critical for better disease classification and clinical management especially of HIV positive substance users. However, not much information is known about the hematologic and immune derangements in HIV infected injection and non-injection substance users. This study, therefore, aimed at determining the laboratory markers of hematologic and immune derangements in HIV infected substance users. Hematologic and immune profiles were evaluated on venous blood specimens obtained from injection substance users, ISU (HIV-infected, n=62 and -uninfected, n=213) and non-injection substance users (HIV-infected, n=33 and -uninfected, n=186); and non-substance using controls (n=56) from Mombasa, coastal town of Kenya. The prevalence of anemia was higher in HIV infected ISU (48.4%) and non-ISU (63.6%) (p<0.0001); and HIV uninfected ISUs (56.3%) compared to HIV-uninfected non-ISUs (39.2%) and non-substance using controls (28.6%; p=0.0028). Hypochromic anaemia was more prevalent in the HIV-infected ISU (50.0%) and non-ISU (61.9%), and HIV-negative ISU (63.3%) relative to the HIV-negative non-ISU (39.7%) and non-substance using controls (56.3%; p=0.0007). Mild immunodeficiency dominated in the HIV infected individuals (HIV-infected ISU, 32.3% and non-ISU, 21.2%) versus HIV-uninfected ISU (16.9%); non-ISU (12.9%); and non-substance users (14.3%) while severe immunosuppression prevailed in HIV infected substance users (ISU, 14.5% and non-ISU, 15.2%) against HIV uninfected substance users (ISU, 5.2% and non-ISU, 3.8%); thus immunosuppression in substance users is aggravated with HIV infection. Moreover, drug-induced immunosuppression is associated with a higher likelihood of anaemia in HIV-uninfected substance users; ISU (OR=3.95, CI=1.934-8.077, p<0.0001) and non-ISU (OR=3.63, CI=1.571-8.39, p=0.003). Altogether, hypochromic anaemia, normochromic anaemia and CD4+ T-helper cytopenia are the most prevalent hemocytopenias in HIV infected and uninfected injection and non-injection substance users.

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Khat a drug of abuse: roles of free radicals and antioxidants

Cited by 21 publications

References 28 publications

Distinct single cell signal transduction signatures in leukocyte subsets stimulated with khat extract, amphetamine-like cathinone, cathine or norephedrine

Distinct single cell signal transduction signatures in leukocyte subsets stimulated with khat extract, amphetamine-like cathinone, cathine or norephedrine

Effect of Daily Chewing Soft Buds and Leaves of Catha edulis (Khat) on the Antioxidant Defense System and Oxidative Stress Markers in Blood

Erythrocyte indices, anaemia levels and types in Kenyan injection and non-injection substance users

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