Khat (Catha edulis) alters the phenotype and anti-microbial activity of peripheral blood mononuclear cells

Murdoch, Craig; Aziz, Hesham Abdul; Fang, Hsin-Yu; Jezan, Hussun Saeed; Musaid, Raga Ahmed Ali; Muthana, Munitta

doi:10.1016/j.jep.2011.10.030

Cited by 13 publications

(22 citation statements)

References 46 publications

(63 reference statements)

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“…In agreement with our observations, khat was recently reported to induce p38 MAPK phosphorylation in PBMCs in vitro , and khat-treatment was seen to induce cell death by apoptosis [32]. p38 is probably acting upstream of p53, and may be pivotal in khat-induced abnormal differentiation of in vitro -reconstructed human normal buccal mucosa [37].…”

Section: Discussionsupporting

confidence: 90%

“…The different impact on signal transduction proteins in the leukocytes was reflected in the functional assays, demonstrating khat-induced cell death and reduced T-lymphocyte proliferation, whereas no cytotoxic effects were detected for cathinone, cathine and norephedrine (Figure 6). Toxic effects by khat have been reported in in vivo and in vitro studies [3,30-32]. We have previously shown that khat induce caspase-dependent apoptosis in myeloid cells and keratinocytes [30,31,33].…”

Section: Discussionmentioning

confidence: 99%

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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: Discussionsupporting

confidence: 90%

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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“…[ 46 ], in Swiss albino mice infected with PbA , parasitemia started progress on the 2 nd day of p.i and reached significant levels from day 4 th - 6 th and all untreated animals died by the 6 th day of infection. Thus, lack of significant effect of khat on some clinical and parasitological state of khat treated mice on early stage of infection cannot be due to absolute suppressive effect of khat, but due to anti-inflammatory activity of the khat [ 47 , 48 ] that can suppress the effect of inflammatory reactions or due to cytotoxicity effect of the plant on the parasite [ 31 ]. However, as the parasite load increased and kidney function affected by the parasite and the khat, the inflammation reaction mediated by the uric acid and some parasite’s components [glycosylphosphatidylinositol (GPI)] and toxin released from infected RBC (hemozine) during malaria infection [ 39 ] incidence of some pathologies such as cerebral malaria and other could be exacerbated.…”

Section: Discussionmentioning

confidence: 99%

Effect of chronic khat (Catha edulis, Forsk) use on outcome of Plasmodium berghei ANKA infection in Swiss albino mice

et al. 2015

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BackgroundThe objective of this study was to explore effects of khat (Catha edulis) on outcome of rodent malaria infection and its anti-plasmodial activities on Plasmodium berghei ANKA (PbA).MethodsFemale Swiss albino mice were orally treated with crude khat (Catha edulis) extracts (100, 200 and 300 mg/kg) on a daily basis for 4 weeks prior to PbA infection. Physical, clinical, hematological, biochemical and histo-pathological features of the mice were assessed. In addition, in vivo anti-plasmodial activities of khat were evaluated.ResultsThe finding of this study showed that khat use was strongly associated with increment of levels of liver and kidney biomarkers, leucopenia, severe anemia, rise in level of inflammation biomarkers: C-reactive protein (CRP), uric acid (UA), increased monocyte-lymphocyte count ratio (MLCR), manifestation of cerebral malaria symptoms such as ataxia, paralysis and deviation of the head but with no pulmonary edema. Significantly lower level of parasitemia (P < 0.05), rectal temperature, but, high level of hemoglobin were observed at the early stage of the PbA infection in khat treated mice than the control. With extension of the treatment period, however, drastic increments were observed in parasite load and rectal temperature although there was reduction in hemoglobin (Hb) level. Moreover, khat showed poor anti-plasmodial activity with <10% parasite suppression activity and lack protection against major malaria symptoms. The significant reduction (P < 0.01) of hematological parameters during PbA infection strengthen the notion that hematological parameters could be good predictors of severe malaria complications in human.ConclusionsIn mice model treated with khat prior to infection with the rodent malaria parasite, khat was found to worsen manifestation of most malaria complications. Furthermore, the same plant showed poor in vivo anti-plasmodial activity and protection against major malaria symptoms.

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“…Moreover, khat has some positive characteristics, which encourage its further studies. These effects include lowering of plasma cholesterol and reduction in glucose and triglycerides concentration ( 13 ) in addition to its potent cytotoxicity and antibacterial activity ( 14 ). These effects are predominantly due to cathinone, the main psychoactive component in khat.…”

Section: Introductionmentioning

confidence: 99%

Characterization of the Antinociceptive Mechanisms of Khat Extract (Catha edulis) in Mice

et al. 2017

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This study investigated the antinociceptive mechanisms of khat extract (100, 200, and 400 mg/kg, i.p.) in four pain models: two thermic (hot plate, tail-flick) and two chemical (acetic acid, formalin) models. Male mice were pretreated intraperitoneally (i.p.) with the opioid receptor blocker naloxone (5 mg/kg), the cholinergic antagonist atropine (2 mg/kg), the selective α1 blocker prazosin (1 mg/kg), the dopamine D2 antagonist haloperidol (1.5 mg/kg), or the GABAA receptor antagonist, bicuculline (1 mg/kg) 15 minutes prior to i.p. injection of khat extract (400 mg/kg). Khat extract reduced the nociceptive response of mice in the four pain tests. Naloxone significantly inhibited the antinociceptive effect of khat extract in the hot plate, tail-flick, and the first phase of formalin tests. Bicuculline significantly antagonized the antinociceptive effect of khat extract on the hot plate and tail-flick tests. Haloperidol significantly reversed the antinociceptive effect of khat extract on the tail-flick test and the first phase of formalin test. These results provide strong evidence that the antinociceptive activity of khat extract is mediated via opioidergic, GABAergic, and dopaminergic pathways. The mechanism of the antinociceptive action of khat may be linked to the different types of pain generated in animal models.

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Khat (Catha edulis) alters the phenotype and anti-microbial activity of peripheral blood mononuclear cells

Cited by 13 publications

References 46 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 chronic khat (Catha edulis, Forsk) use on outcome of Plasmodium berghei ANKA infection in Swiss albino mice

Characterization of the Antinociceptive Mechanisms of Khat Extract (Catha edulis) in Mice

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