Malarial hemozoin: From target to tool

Malaria is an extremely devastating disease that continues to affect millions of people each year. A distinctive attribute of malaria infected red blood cells is the presence of malarial pigment or so-called hemozoin. Hemozoin is a biocrystal synthesized by Plasmodium and other blood-feeding parasites to avoid the toxicity of free heme derived from the digestion of hemoglobin during invasion of the erythrocytes.Malaria is an extremely devastating disease that continues to affect millions of people each year. A distinctive attribute of malaria infected red blood cells is the presence of malarial pigment or so-called hemozoin. Hemozoin is a biocrystal synthesized by Plasmodium and other blood-feeding parasites to avoid the toxicity of free heme derived from the digestion of hemoglobin during invasion of the erythrocytes.Centro de Biología Celulary Molecularde Enfermedades, Instituto de Investigaciones Científicas y Servicios de AltaTecnología, Ciudad del Saber, Panama b Department ofBiotechnology, Acharya Nagarjuna University, Guntur 522510, A.P., India c Electricaland Computer Engineering, Clarkson University, Postdam, NY 13699-5720, US

Evaluation of phytotoxic, cytotoxic and antiparasitic in vitro activities of Borreria verticillata, a weed of Panamanian coffee crops.

In recent years, there have been significant changes in weed populations in different agricultural production systems. Coffee production is economically important in the Republic of Panama, and the specie Borreria verticillata affects a significant portion of this crop. Weeds may directly affect the yields of economically important plants through two main ways: by producing allelochemicals which inhibit plant growth or by competition for nutrients and water availability in the soil. Borreria verticillata was selected to evaluate its phytotoxic activity by which this weed affects the coffee crops. In addition, we carried out antiparasitic evaluations for determining the activity of Borreria verticillata extract against three human parasites: Leishmania donovani, Trypanosoma cruzi and Plasmodium falciparum. The experimental results revealed that the extract prepared using the aerial parts of Borreria verticillata did not show significant phytotoxic and cytotoxic effects. On the other hand, the antiparasitic evaluations showed that the extract possessed only moderate activities against Plasmodium falciparum. Finally, we proceeded to identify the major chemical components of this extract and we obtained three known compounds: scualene (1), epoxyscualene (2) and borrecapine (3).In recent years, there have been significant changes in weed populations in different agricultural production systems. Coffee production is economically important in the Republic of Panama, and the specie Borreria verticillata affects a significant portion of this crop. Weeds may directly affect the yields of economically important plants through two main ways: by producing allelochemicals which inhibit plant growth or by competition for nutrients and water availability in the soil. Borreria verticillata was selected to evaluate its phytotoxic activity by which this weed affects the coffee crops. In addition, we carried out antiparasitic evaluations for determining the activity of Borreria verticillata extract against three human parasites: Leishmania donovani, Trypanosoma cruzi and Plasmodium falciparum. The experimental results revealed that the extract prepared using the aerial parts of Borreria verticillata did not show significant phytotoxic and cytotoxic effects. On the other hand, the antiparasitic evaluations showed that the extract possessed only moderate activities against Plasmodium falciparum. Finally, we proceeded to identify the major chemical components of this extract and we obtained three known compounds: scualene (1), epoxyscualene (2) and borrecapine (3)

Evaluation of antiparasitic, anticancer, antimicrobial and hypoglycemic properties of organic extracts from Panamanian mangrove plants

To investigate 33 organic extracts of mangrove plants for: antiparasitic, anticancer, and antibacterial activities, as well as their ability to inhibit the activity of the 毩-glucosidase enzyme. Methods: Leaves from all different plant mangrove species located in five mangrove zones of the Pacific coast of Panama were collected according to standard procedures. Qualitative phytochemical analysis of the organic extracts was performed by thin layer chromatography. The antiparasitic activity against Plasmodium falciparum, Trypanosoma cruzi and Leishmania donovani, toxicity against Artemia salina, anticancer activity in MCF-7 cell line, and antibacterial activity against Staphylococcus aureus, Bacillus subtilis, Escherichia coli and Pseudomonas aeruginosa of all organic extract were investigated according protocols stablished in our institution. Finally, the ability to inhibit the enzymatic activity of 毩-glucosidase was evaluated by monitoring the hydrolysis of p-nitrophenyl 毩-Dglucopyranoside. Results: Thirty-three different samples belonging to nine different species of vascular plants with seeds of true mangroves were collected. Triterpenoids, phenolics, and tannins were the main groups of compounds found in the sampled mangroves. Saponins, quinones, and coumarins were found in less than 50% of the samples. Laguncularia racemosa showed moderate activity against Plasmodium falciparum. None of the extracts presented anticancer activity. Rhizophora mangle exhibited potent activity against Staphylococcus aureus and Bacillus subtilis [(90.41±7.33)% and (96.02±6.14)% of inhibition]; Avicennia germinans and Conocarpus erectus had activity against Escherichia coli [(71.17±6.15)% and (60.60±5.13)% of inhibition, respectively]. About 60% of the mangroves showed 毩-glucosidase inhibitory activity. In particular, extracts from Laguncularia racemosa, Pelliciera rhizophorae, Conocarpus erectus, Mora oleifera, and Tabebuia palustris species showed 毩-glucosidase inhibitory potential, with IC50 values of (29.45±0.29), (20.60±0.70), (730.06±3.74), (25.59±0.37), and (853.39±5.30) µg/mL, respectively. Conclusions: Panamanian mangroves are mainly a promising potential source of hypoglycemic compounds, specifically 毩-glucosidase inhibitors. These results highlight the therapeutic virtues of extracts from American mangrove plants.To investigate 33 organic extracts of mangrove plants for: antiparasitic, anticancer, and antibacterial activities, as well as their ability to inhibit the activity of the 毩-glucosidase enzyme. Methods: Leaves from all different plant mangrove species located in five mangrove zones of the Pacific coast of Panama were collected according to standard procedures. Qualitative phytochemical analysis of the organic extracts was performed by thin layer chromatography. The antiparasitic activity against Plasmodium falciparum, Trypanosoma cruzi and Leishmania donovani, toxicity against Artemia salina, anticancer activity in MCF-7 cell line, and antibacterial activity against Staphylococcus aureus, Bacillus subtilis, Escherichia coli and Pseudomonas aeruginosa of all organic extract were investigated according protocols stablished in our institution. Finally, the ability to inhibit the enzymatic activity of 毩-glucosidase was evaluated by monitoring the hydrolysis of p-nitrophenyl 毩-Dglucopyranoside. Results: Thirty-three different samples belonging to nine different species of vascular plants with seeds of true mangroves were collected. Triterpenoids, phenolics, and tannins were the main groups of compounds found in the sampled mangroves. Saponins, quinones, and coumarins were found in less than 50% of the samples. Laguncularia racemosa showed moderate activity against Plasmodium falciparum. None of the extracts presented anticancer activity. Rhizophora mangle exhibited potent activity against Staphylococcus aureus and Bacillus subtilis [(90.41±7.33)% and (96.02±6.14)% of inhibition]; Avicennia germinans and Conocarpus erectus had activity against Escherichia coli [(71.17±6.15)% and (60.60±5.13)% of inhibition, respectively]. About 60% of the mangroves showed 毩-glucosidase inhibitory activity. In particular, extracts from Laguncularia racemosa, Pelliciera rhizophorae, Conocarpus erectus, Mora oleifera, and Tabebuia palustris species showed 毩-glucosidase inhibitory potential, with IC50 values of (29.45±0.29), (20.60±0.70), (730.06±3.74), (25.59±0.37), and (853.39±5.30) µg/mL, respectively. Conclusions: Panamanian mangroves are mainly a promising potential source of hypoglycemic compounds, specifically 毩-glucosidase inhibitors. These results highlight the therapeutic virtues of extracts from American mangrove plants

Antiplasmodial activity of Cocos nucifera leaves in Plasmodium berghei-infected mice

Plasmodium falciparum (P. falciparum) malaria presents serious public health problems worldwide. The parasite s resistance to antimalarial drugs has proven to be a significant hurdle in the search for effective treatments against the disease. For this reason, the study of natural products to find new antimalarials remains a crucial step in the fight against malaria. In this study, we aimed to study the in vivo performance of the decoction of C. nucifera leaves in P. berghei-infected mice. We analyzed the effectiveness of different routes of administration and the acute toxicity of the extract. Additionally, we determined the suppressive, curative and prophylactic activity of the extract. The results showed that the decoction of leaves of C. nucifera is most effective when administered intramuscularly to mice in comparison to intraperitoneal, subcutaneous and intragastric methods. We also found that organ signs of acute toxicity appear at 2000 mg/kg/day as evidenced by necropsy examination. Additionally, we found that the prophylactic effect of the extract is of 48% inhibition, however, there is no curative effect. Finally, in a 4-day suppressive assay, we found that the extract can inhibit the growth of the parasite by up to 54% at sub-toxic doses when administered intramuscularly.Plasmodium falciparum (P. falciparum) malaria presents serious public health problems worldwide. The parasite s resistance to antimalarial drugs has proven to be a significant hurdle in the search for effective treatments against the disease. For this reason, the study of natural products to find new antimalarials remains a crucial step in the fight against malaria. In this study, we aimed to study the in vivo performance of the decoction of C. nucifera leaves in P. berghei-infected mice. We analyzed the effectiveness of different routes of administration and the acute toxicity of the extract. Additionally, we determined the suppressive, curative and prophylactic activity of the extract. The results showed that the decoction of leaves of C. nucifera is most effective when administered intramuscularly to mice in comparison to intraperitoneal, subcutaneous and intragastric methods. We also found that organ signs of acute toxicity appear at 2000 mg/kg/day as evidenced by necropsy examination. Additionally, we found that the prophylactic effect of the extract is of 48% inhibition, however, there is no curative effect. Finally, in a 4-day suppressive assay, we found that the extract can inhibit the growth of the parasite by up to 54% at sub-toxic doses when administered intramuscularly

Revisión de Modelos Hiperelásticos utilizados en Tejidos

This work is related to the hyperelastic models most used in soft tissue. The importance of obtaining accurate mechanical properties of tissues are of great interest for various medical applications, for example: in treatment of diseases and surgical simulations in real time. The aim of this literature review is to evaluate the models used for proposing a mathematical formulation and modelling the mechanical behaviour of a sequence of layers of soft tissues and your reply to undergo external actions of mechanical nature, in order to improve the techniques of characterization of soft tissuesThis work is related to the hyperelastic models most used in soft tissue. The importance of obtaining accurate mechanical properties of tissues are of great interest for various medical applications, for example: in treatment of diseases and surgical simulations in real time. The aim of this literature review is to evaluate the models used for proposing a mathematical formulation and modelling the mechanical behaviour of a sequence of layers of soft tissues and your reply to undergo external actions of mechanical nature, in order to improve the techniques of characterization of soft tissue

Malarial hemozoin: From target to tool

Malaria is an extremely devastating disease that continues to affect millions of people each year. A distinctive attribute of malaria infected red blood cells is the presence of malarial pigment or the so-called hemozoin. Hemozoin is a biocrystal synthesized by Plasmodium and other blood-feeding parasites to avoid the toxicity of free heme derived from the digestion of hemoglobin during invasion of the erythrocytes. Scope of review: Hemozoin is involved in several aspects of the pathology of the disease as well as in important processes such as the immunogenicity elicited. It is known that the once best antimalarial drug, chloroquine, exerted its effect through interference with the process of hemozoin formation. In the present review we explore what is known about hemozoin, from hemoglobin digestion, to its final structural analysis, to its physicochemical properties, its role in the disease and notions of the possible mechanisms that could kill the parasite by disrupting the synthesis or integrity of this remarkable crystal. Major conclusions: The importance and peculiarities of this biocrystal have given researchers a cause to consider it as a target for new antimalarials and to use it through unconventional approaches for diagnostics and therapeutics against the disease. General significance: Hemozoin plays an essential role in the biology of malarial disease. Innovative ideas could use all the existing data on the unique chemical and biophysical properties of this macromolecule to come up with new ways of combating malaria.Malaria is an extremely devastating disease that continues to affect millions of people each year. A distinctive attribute of malaria infected red blood cells is the presence of malarial pigment or the so-called hemozoin. Hemozoin is a biocrystal synthesized by Plasmodium and other blood-feeding parasites to avoid the toxicity of free heme derived from the digestion of hemoglobin during invasion of the erythrocytes. Scope of review: Hemozoin is involved in several aspects of the pathology of the disease as well as in important processes such as the immunogenicity elicited. It is known that the once best antimalarial drug, chloroquine, exerted its effect through interference with the process of hemozoin formation. In the present review we explore what is known about hemozoin, from hemoglobin digestion, to its final structural analysis, to its physicochemical properties, its role in the disease and notions of the possible mechanisms that could kill the parasite by disrupting the synthesis or integrity of this remarkable crystal. Major conclusions: The importance and peculiarities of this biocrystal have given researchers a cause to consider it as a target for new antimalarials and to use it through unconventional approaches for diagnostics and therapeutics against the disease. General significance: Hemozoin plays an essential role in the biology of malarial disease. Innovative ideas could use all the existing data on the unique chemical and biophysical properties of this macromolecule to come up with new ways of combating malaria

Separation of Plasmodium falciparum Late Stage-infected Erythrocytes by Magnetic Means

Unlike other Plasmodium species, P. falciparum can be cultured in the lab, which facilitates its study 1. While the parasitemia achieved can reach the ≈40% limit, the investigator usually keeps the percentage at around 10%. In many cases it is necessary to isolate the parasite-containing red blood cells (RBCs) from the uninfected ones, to enrich the culture and proceed with a given experiment. When P. falciparum infects the erythrocyte, the parasite degrades and feeds from haemoglobin 2, 3. However, the parasite must deal with a very toxic iron-containing haem moiety 4, 5. The parasite eludes its toxicity by transforming the haem into an inert crystal polymer called haemozoin 6, 7. This iron-containing molecule is stored in its food vacuole and the metal in it has an oxidative state which differs from the one in haem 8. The ferric state of iron in the haemozoin confers on it a paramagnetic property absent in uninfected erythrocytes. As the invading parasite reaches maturity, the content of haemozoin also increases 9, which bestows even more paramagnetism on the latest stages of P. falciparum inside the erythrocyte. Based on this paramagnetic property, the latest stages of P. falciparum infected-red blood cells can be separated by passing the culture through a column containing magnetic beads. These beads become magnetic when the columns containing them are placed on a magnet holder. Infected RBCs, due to their paramagnetism, will then be trapped inside the column, while the flow-through will contain, for the most part, uninfected erythrocytes and those containing early stages of the parasite. Here, we describe the methodology to enrich the population of late stage parasites with magnetic columns, which maintains good parasite viability 10. After performing this procedure, the unattached culture can be returned to an incubator to allow the remaining parasites to continue growing.Unlike other Plasmodium species, P. falciparum can be cultured in the lab, which facilitates its study 1. While the parasitemia achieved can reach the ≈40% limit, the investigator usually keeps the percentage at around 10%. In many cases it is necessary to isolate the parasite-containing red blood cells (RBCs) from the uninfected ones, to enrich the culture and proceed with a given experiment. When P. falciparum infects the erythrocyte, the parasite degrades and feeds from haemoglobin 2, 3. However, the parasite must deal with a very toxic iron-containing haem moiety 4, 5. The parasite eludes its toxicity by transforming the haem into an inert crystal polymer called haemozoin 6, 7. This iron-containing molecule is stored in its food vacuole and the metal in it has an oxidative state which differs from the one in haem 8. The ferric state of iron in the haemozoin confers on it a paramagnetic property absent in uninfected erythrocytes. As the invading parasite reaches maturity, the content of haemozoin also increases 9, which bestows even more paramagnetism on the latest stages of P. falciparum inside the erythrocyte. Based on this paramagnetic property, the latest stages of P. falciparum infected-red blood cells can be separated by passing the culture through a column containing magnetic beads. These beads become magnetic when the columns containing them are placed on a magnet holder. Infected RBCs, due to their paramagnetism, will then be trapped inside the column, while the flow-through will contain, for the most part, uninfected erythrocytes and those containing early stages of the parasite. Here, we describe the methodology to enrich the population of late stage parasites with magnetic columns, which maintains good parasite viability 10. After performing this procedure, the unattached culture can be returned to an incubator to allow the remaining parasites to continue growing

Dudawalamides A−D, Antiparasitic Cyclic Depsipeptides from the Marine Cyanobacterium Moorea producens

HPLC. DudA family of 2,2-dimethyl-3-hydroxy-7-octynoic acid (Dhoya)-containing cyclic depsipeptides, named dudawalamides A−D (1−4), was isolated from a Papua New Guinean field collection of the cyanobacterium Moorea producens using bioassay-guided and spectroscopic approaches. The planar structures of dudawalamides A−D were determined by a combination of 1D and 2D NMR experiments and MS analysis, whereas the absolute configurations were determined by X-ray crystallography, modified Marfey’s analysis, chiral-phase GCMS, and chiral-phase awalamides A−D possess a broad spectrum of antiparasitic activity with minimal mammalian cell cytotoxicity. Comparative analysis of the Dhoya-containing class of lipopeptides reveals intriguing structure−activity relationship features of these NRPS−PKS-derived metabolites and their derivatives.HPLC. DudA family of 2,2-dimethyl-3-hydroxy-7-octynoic acid (Dhoya)-containing cyclic depsipeptides, named dudawalamides A−D (1−4), was isolated from a Papua New Guinean field collection of the cyanobacterium Moorea producens using bioassay-guided and spectroscopic approaches. The planar structures of dudawalamides A−D were determined by a combination of 1D and 2D NMR experiments and MS analysis, whereas the absolute configurations were determined by X-ray crystallography, modified Marfey’s analysis, chiral-phase GCMS, and chiral-phase awalamides A−D possess a broad spectrum of antiparasitic activity with minimal mammalian cell cytotoxicity. Comparative analysis of the Dhoya-containing class of lipopeptides reveals intriguing structure−activity relationship features of these NRPS−PKS-derived metabolites and their derivatives

19-Hydroxy-bufalin, a major bufadienolide isolated from the parotoid gland secretions of the Panamanian endemic toad Rhinella centralis (Bufonidae), inhibits the growth of Trypanosoma cruzi

American trypanosomiasis is a parasitic neglected disease, responsible for the death of approximately 10,000 people every year. Amphibians are recognized for producing in their cutaneous glands substances with pharmacological potential against a variety of pathologies. Here we investigated the antiprotozoal activity against Trypanosoma cruzi of bufadienolides isolated from the parotoid glands secretions of the toad Rhinella centralis from Panama. NMR and mass spectrometry analysis led to the identification of the active compound 19-hydroxybufalin, for which its antitrypanosomal activity and occurrence in the genus Rhinella are reported for the first time. This compound showed low cytotoxicity and significant selectivity which confers to it a potential role for the treatment of Chagas diseaseAmerican trypanosomiasis is a parasitic neglected disease, responsible for the death of approximately 10,000 people every year. Amphibians are recognized for producing in their cutaneous glands substances with pharmacological potential against a variety of pathologies. Here we investigated the antiprotozoal activity against Trypanosoma cruzi of bufadienolides isolated from the parotoid glands secretions of the toad Rhinella centralis from Panama. NMR and mass spectrometry analysis led to the identification of the active compound 19-hydroxybufalin, for which its antitrypanosomal activity and occurrence in the genus Rhinella are reported for the first time. This compound showed low cytotoxicity and significant selectivity which confers to it a potential role for the treatment of Chagas diseas

Antiparasitic Compounds from the Panamanian Marine Bacterium Pseudomonas aeruginosa

Fractionation of the ethyl acetate extract of the bacterium Pseudomonas aeruginosa led to the isolation of five compounds, cyclo –(L-Phe-L-Pro) (1), 3-heptyl-3-hydroxy-1,2,3,4-tetrahydroquinoline-2.4-dione (2), 2-heptyl-4-hydroxyquinoline (3), 2-nonyl-4-hydroxyquinoline (4), and 1-phenazinecarboxylic acid (5). The structures of compounds 1-5 were established by spectroscopic analyses. Compounds 2 4 produced inhibition on the growth of Plasmodium falciparum, with IC50 values of 3.47, 2.57 and 2.79 μg/mL, respectively. Compounds 3-4 had activity against Trypanosoma cruzi, with IC50 values of 3.66 and 3.99 μg/mL. Finally, all compounds were found inactive when tested against Leishmania donovani at 10 μg/mL.Fractionation of the ethyl acetate extract of the bacterium Pseudomonas aeruginosa led to the isolation of five compounds, cyclo –(L-Phe-L-Pro) (1), 3-heptyl-3-hydroxy-1,2,3,4-tetrahydroquinoline-2.4-dione (2), 2-heptyl-4-hydroxyquinoline (3), 2-nonyl-4-hydroxyquinoline (4), and 1-phenazinecarboxylic acid (5). The structures of compounds 1-5 were established by spectroscopic analyses. Compounds 2 4 produced inhibition on the growth of Plasmodium falciparum, with IC50 values of 3.47, 2.57 and 2.79 μg/mL, respectively. Compounds 3-4 had activity against Trypanosoma cruzi, with IC50 values of 3.66 and 3.99 μg/mL. Finally, all compounds were found inactive when tested against Leishmania donovani at 10 μg/mL