In vitro anti-malarial interaction and gametocytocidal activity of cryptolepine

Forkuo, Arnold Donkor; Ansah, Charles; Mensah, Kofi Boamah; Annan, Kofi; Gyan, Ben; Theron, Anjo; Mancama, D; Wright, Colin W.

doi:10.1186/s12936-017-2142-z

Cited by 30 publications

(18 citation statements)

References 27 publications

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“…First, the cells (2 × 10 7 cells/ml) were incubated in PBS supplemented or not with 5 mM glucose, and each of these samples was treated or not treated with 16 mM DCA. The functionality of the mitochondrial dehydrogenases (usually considered a reliable indicator of mitochondrial viability) was evaluated by assessing the irreversible reduction of resazurin (7-hydroxy-3H-phenoxazine-3-one 10-oxide; Sigma) to resorufin (7-hydroxy-3H-phenoxazin-3-one), a red-ox fluorimetric indicator, used in viability assays for trypanosomatids and apicomplexans ( 81 – 85 ). Parasite samples (2 × 10 6 cells/ml) from each one of the four groups described above were aliquoted in 96-well plates (100 μl per well) and incubated in the presence of 0.125 μg/μl resazurin for 3 h (in the absence of light) at 37°C.…”

Section: Methodsmentioning

confidence: 99%

Dichloroacetate and Pyruvate Metabolism: Pyruvate Dehydrogenase Kinases as Targets Worth Investigating for Effective Therapy of Toxoplasmosis

Ferrarini

Nisimura

Girard

et al. 2021

mSphere

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Toxoplasmosis, a protozoan infection caused by Toxoplasma gondii, is estimated to affect around 2.5 billion people worldwide. Nevertheless, the side effects of drugs combined with the long period of therapy usually result in discontinuation of the treatment. New therapies should be developed by exploring peculiarities of the parasite’s metabolic pathways, similarly to what has been well described in cancer cell metabolism. An example is the switch in the metabolism of cancer that blocks the conversion of pyruvate into acetyl coenzyme A in mitochondria. In this context, dichloroacetate (DCA) is an anticancer drug that reverts the tumor proliferation by inhibiting the enzymes responsible for this switch: the pyruvate dehydrogenase kinases (PDKs). DCA has also been used in the treatment of certain symptoms of malaria; however, there is no evidence of how this drug affects apicomplexan species. In this paper, we studied the metabolism of T. gondii and demonstrate that DCA also inhibits T. gondii’s in vitro infection with no toxic effects on host cells. DCA caused an increase in the activity of pyruvate dehydrogenase followed by an unbalanced mitochondrial activity. We also observed morphological alterations frequently in mitochondria and in a few apicoplasts, essential organelles for parasite survival. To date, the kinases that potentially regulate the activity of pyruvate metabolism in both organelles have never been described. Here, we confirmed the presence in the genome of two putative kinases (T. gondii PDK [TgPDK] and T. gondii branched-chain α-keto acid dehydrogenase kinase [TgBCKDK]), verified their cellular localization in the mitochondrion, and provided in silico data suggesting that they are potential targets of DCA. IMPORTANCE Currently, the drugs used for toxoplasmosis have severe toxicity to human cells, and the treatment still lacks effective and safer alternatives. The search for novel drug targets is timely. We report here that the treatment of T. gondii with an anticancer drug, dichloroacetate (DCA), was effective in decreasing in vitro infection without toxicity to human cells. It is known that PDK is the main target of DCA in mammals, and this inactivation increases the conversion of pyruvate into acetyl coenzyme A and reverts the proliferation of tumor cells. Moreover, we verified the mitochondrial localization of two kinases that possibly regulate the activity of pyruvate metabolism in T. gondii, which has never been studied. DCA increased pyruvate dehydrogenase (PDH) activity in T. gondii, followed by an unbalanced mitochondrial activity, in a manner similar to what was previously observed in cancer cells. Thus, we propose the conserved kinases as potential regulators of pyruvate metabolism and interesting targets for new therapies.

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Section: Methodsmentioning

confidence: 99%

Dichloroacetate and Pyruvate Metabolism: Pyruvate Dehydrogenase Kinases as Targets Worth Investigating for Effective Therapy of Toxoplasmosis

Ferrarini

Nisimura

Girard

et al. 2021

mSphere

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“…Cryptolepis sanguinolenta is a plant indigenous to Africa where it has been used in traditional medicine to treat malaria, tuberculosis, hepatitis, and septicemia (45). Cryptolepis sanguinolenta has been shown in preclinical studies to have antiinflammatory (46,47) antibacterial (48)(49)(50), anti-fungal (51), anti-amoebic (52), and anti-malarial (53,54) properties. Two preliminary clinical studies have documented significant efficacy in treating uncomplicated malaria without signs of overt toxicity (55).…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Natural and Botanical Medicines for Activity Against Growing and Non-growing Forms of B. burgdorferi

Feng

Leone

Schweig³

et al. 2020

Front. Med.

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Lyme disease is the most common vector-borne disease in the US and Europe. Although the current recommended Lyme antibiotic treatment is effective for the majority of Lyme disease patients, about 10-20% of patients continue to suffer from persisting symptoms. There have been various anecdotal reports on the use of herbal extracts for treating patients with persisting symptoms with varying degree of improvements. However, it is unclear whether the effect of the herb products is due to their direct antimicrobial activity or their effect on host immune system. In the present study, we investigated the antimicrobial effects of 12 commonly used botanical medicines and three other natural antimicrobial agents for potential anti-Borrelia burgdorferi activity in vitro. Among them, 7 natural product extracts at 1% were found to have good activity against the stationary phase B. burgdorferi culture compared to the control antibiotics doxycycline and cefuroxime. These active botanicals include Cryptolepis sanguinolenta, Juglans nigra (Black walnut), Polygonum cuspidatum (Japanese knotweed), Artemisia annua (Sweet wormwood), Uncaria tomentosa (Cat's claw), Cistus incanus, and Scutellaria baicalensis (Chinese skullcap). In contrast, Stevia rebaudiana, Andrographis paniculata, Grapefruit seed extract, colloidal silver, monolaurin, and antimicrobial peptide LL37 had little or no activity against stationary phase B. burgdorferi. The minimum inhibitory concentration (MIC) values of Artemisia annua, Juglans nigra, and Uncaria tomentosa were quite high for growing B. burgdorferi, despite their strong activity against the non-growing stationary phase B. burgdorferi. On the other hand, the top two active herbs, Cryptolepis sanguinolenta and Polygonum cuspidatum, showed strong activity against both growing B. burgdorferi (MIC = 0.03-0.06% and 0.25-0.5%, respectively) and non-growing stationary phase B. burgdorferi. In subculture studies, only 1% Cryptolepis sanguinolenta extract caused complete eradication, while doxycycline and cefuroxime and other active herbs could not eradicate B. burgdorferi stationary phase cells as many spirochetes were visible after 21-day subculture. Further studies are needed to identify the active constituents of the effective botanicals and evaluate their combinations for more effective eradication of B. burgdorferi in vitro and in vivo. The implications of these findings for improving treatment of persistent Lyme disease are discussed.

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“…Cryptolepis sanguinolenta is a plant indigenous to Africa where it has been used in traditional medicine to treat malaria, TB, hepatitis, and septicemia (51). In addition to the various uses documented in ethnomedicine, Cryptolepis sanguinolenta has been shown in preclinical studies to have anti-inflammatory (52, 53) antibacterial (54–59), Anti-fungal (55, 60), anti-amoebic (61) and anti-malarial (62–65) properties. Two preliminary clinical studies have shown Cryptolepis to have significant efficacy in treating uncomplicated malaria without signs of overt toxicity (66, 67).…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Natural and Botanical Medicines for Activity against Growing and Non-growing Forms ofB. burgdorferi

Feng

Leone²,

Schweig³

et al. 2019

Preprint

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Lyme disease is the most common vector-borne disease in the US. Although the current recommended Lyme antibiotic treatment can cure the majority of Lyme disease patients, about 10-20% patients continue to suffer from persisting symptoms. There have been various anecdotal reports on the use of herbal extracts for treating patients with persisting symptoms with varying degree of improvements. However, it is unclear whether the effect of the herb products is due to their direct antimicrobial activity or their effect on host immune system. In the present study, we investigated the antimicrobial effects of 12 commonly used botanical medicines and 3 other natural antimicrobial agents for potential anti-Borrelia burgdorferi activity in vitro. Primary criteria for selecting compounds for the present study included agents that had shown significant anti-borrelial effects in previous studies, have favorable safety profiles, and can be absorbed systemically. Among them, 9 natural product extracts at 1% were found to have good activity against the stationary phase B. burgdorferi culture compared to the control antibiotics doxycycline and cefuroxime. These active herbs include Cryptolepis sanguinolenta, Juglans nigra (Black walnut), Polygonum cuspidatum (Japanese knotweed), Artemesia annua (Sweet wormwood), Uncaria tomentosa (Cat’s claw), Cistus incanus, and Scutellaria baicalensis (Chinese skullcap). In contrast, Stevia rebaudiana, Andrographis paniculata, Grapefruit seed extract, colloidal silver, monolaurin, and antimicrobial peptide LL37 had little or no activity against stationary phase B. burgdorferi. The minimum inhibitory concentration (MIC) values of Artemesia annua, Juglans nigra, and Uncaria tomentosa were quite high for growing B. burgdorferi, despite their strong activity against the non-growing stationary phase B. burgdorferi cells. On the other hand, the top two active herbs, Cryptolepis sanguinolenta and Polygonum cuspidatum, showed strong activity against both growing B. burgdorferi (MIC=0.03%-0.06% and 0.25%-0.5% respectively) and non-growing stationary phase B. burgdorferi. In subculture studies, only 1% Cryptolepis sanguinolenta extract caused complete eradication, while current Lyme antibiotics doxycycline and cefuroxime and other active herbs including Polygonum cuspidatum, Artemesia annua, Juglans nigra and Uncaria tomentosa could not eradicate B. burgdorferi stationary phase cells as many spirochetes were visible after 21-day subculture. Further studies are needed to identify the active ingredients of the effective herbs and evaluate their combinations for more effective eradication of B. burgdorferi in vitro and in vivo. The implications of these findings for more effective treatment of persistent Lyme disease are discussed.

show abstract

In vitro anti-malarial interaction and gametocytocidal activity of cryptolepine

Cited by 30 publications

References 27 publications

Dichloroacetate and Pyruvate Metabolism: Pyruvate Dehydrogenase Kinases as Targets Worth Investigating for Effective Therapy of Toxoplasmosis

Dichloroacetate and Pyruvate Metabolism: Pyruvate Dehydrogenase Kinases as Targets Worth Investigating for Effective Therapy of Toxoplasmosis

Evaluation of Natural and Botanical Medicines for Activity Against Growing and Non-growing Forms of B. burgdorferi

Evaluation of Natural and Botanical Medicines for Activity against Growing and Non-growing Forms ofB. burgdorferi

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