Alzheimer&amp... more Alzheimer's disease (AD) is the most common senile dementia in the world. Although important progress has been made in understanding the pathogenesis of AD, current therapeutic approaches provide only modest symptomatic relief. In this study, we evaluated the neuroprotective effect of quercetin (25 mg/kg) administration via i.p. injection every 48 h for 3 months on aged (21-24 months old) triple transgenic AD model (3xTg-AD) mice. Our data show that quercetin decreases extracellular β-amyloidosis, tauopathy, astrogliosis and microgliosis in the hippocampus and the amygdala. These results were supported by a significant reduction in the paired helical filament (PHF), β-amyloid (βA) 1-40 and βA 1-42 levels and a decrease in BACE1-mediated cleavage of APP (into CTFβ). Additionally, quercetin induced improved performance on learning and spatial memory tasks and greater risk assessment behavior based on the elevated plus maze test. Together, these findings suggest that quercetin reverses histological hallmarks of AD and protects cognitive and emotional function in aged 3xTg-AD mice.
Biomédica : revista del Instituto Nacional de Salud
Dihydrofolate reductase (DHFR) has been used successfully as a drug target in the area of anti-ba... more Dihydrofolate reductase (DHFR) has been used successfully as a drug target in the area of anti-bacterial, anti-cancer and anti-malarial therapy. Although this bifunctional enzyme is also a potential drug target for treatment of leishmaniasis, there have been no reports on its efficacy against Leishmania (Viannia) species. The gene encoding the bifunctional DHFR and thymidylate synthase (TS) of Le. (V.) braziliensis was isolated and expressed in E. coli. The enzyme was purified and characterized. The inhibitory effects of antifolates and four aporphine alkaloids on its activity were evaluated. The full-length gene consists of a 1560-bp open reading frame encoding a 58 kDa translated peptide containing DHFR and TS domains linked together in a single polypeptide chain. The recombinant DHFR-TS enzyme revealed Km and Vmax values of 55.35 ± 4.02 µ M (mean ± SE) and 0.02 ± 5.34 x 10 -4 µ M/min respectively for dihydrofolic acid (H₂F). The Le. braziliensis rDHFR-TS have Ki values for antimi...
Biomédica : revista del Instituto Nacional de Salud, 2005
Protozoan parasites are important causative agents of morbidity and mortality throughout the worl... more Protozoan parasites are important causative agents of morbidity and mortality throughout the world--a problem further complicated by the emergence of drug resistance in these parasites. Mechanisms of drug resistance include the following: decreased uptake of the drug into the cell, loss of drug activation, alterations in the drug target, and over-expression of a well-known multiple drug transporter proteins. In this review, two critical components of resistance are stressed: (1) the role of ATP binding cassette proteins, such as P-glycoproteins, in mediating drug resistance in Leishmania and other protozoans, followed by development of cross-resistance to many structurally and functionally unrelated drugs, and (2) some concepts concerning the reversal mechanism of multidrug resistance by drugs and natural products. Several modulators or chemosensitizers alter the capacity of P-glycoproteins to maintain subtoxic intracellular drug concentrations. Calcium channel blockers such as vera...
In the course of from ethnobotanical or chemotaxonomical studies on biologically active substance... more In the course of from ethnobotanical or chemotaxonomical studies on biologically active substances with antiparasitic effects from Anonaceae colombian plants, substantial antiplasmodial activity was observed from the ethyl acetate extract of the stem of Rollinia pittieri and Pseudomalmea boyacana (Annonaceae), the alkaloids isolated from these were studied. Of the alkaloids, liriodenine exhibited the highest activity against chloroquine sensitive and chloroquine resistant strains of Plasmodium falciparum (CI50 = 8.0-10.0 µg/ml). In addition, inhibition of β-hematin formation (Ifb-h) by isolated compounds was evaluated (Ifß-h). O-methylmoschatoline and melosmine showed inhibition percentage >96% at 2 mg/ml. Some degree of cytotoxic to U-937 cells activity was observed by oxoporphine alkaloids.
The bulbs of Phaedranassa dubia (Amaryllidaceae) were found to contain the novel compound phaedra... more The bulbs of Phaedranassa dubia (Amaryllidaceae) were found to contain the novel compound phaedranamine, together with seven known alkaloids. The structure and stereochemistry of the alkaloids were determined by physical and spectroscopic methods. An in vitro screening against four different parasitic protozoa was carried out using the isolated compounds. The alkaloids ungeremine, pseudolycorine and haemanthamine showed good activity in in vitro assays against Trypanosoma brucei rhodesiense, T. cruzi and Plasmodium falciparum with IC50 values in the range of 3.66μM or lower.
Journal of pharmaceutical and biomedical analysis, 2015
Acetylcholinesterase (AChE) enzymatic inhibition is an important target for the management of Alz... more Acetylcholinesterase (AChE) enzymatic inhibition is an important target for the management of Alzheimer disease (AD) and AChE inhibitors are the mainstay drugs for its treatment. In order to discover new sources of potent AChE inhibitors, a combined strategy is presented based on AChE-inhibitory activity and chemical profiles by GC/MS, together with in silico studies. The combined strategy was applied on alkaloid extracts of five Amaryllidaceae species that grow in Colombia. Fifty-seven alkaloids were detected using GC/MS, and 21 of them were identified by comparing their mass-spectral fragmentation patterns with standard reference spectra in commercial and private library databases. The alkaloid extracts of Zephyranthes carinata exhibited a high level of inhibitory activity (IC50=5.97±0.24μg/mL). Molecular modeling, which was performed using the structures of some of the alkaloids present in this extract and the three-dimensional crystal structures of AChE derived from Torpedo cali...
Alzheimer&amp... more Alzheimer's disease (AD) is the most common senile dementia in the world. Although important progress has been made in understanding the pathogenesis of AD, current therapeutic approaches provide only modest symptomatic relief. In this study, we evaluated the neuroprotective effect of quercetin (25 mg/kg) administration via i.p. injection every 48 h for 3 months on aged (21-24 months old) triple transgenic AD model (3xTg-AD) mice. Our data show that quercetin decreases extracellular β-amyloidosis, tauopathy, astrogliosis and microgliosis in the hippocampus and the amygdala. These results were supported by a significant reduction in the paired helical filament (PHF), β-amyloid (βA) 1-40 and βA 1-42 levels and a decrease in BACE1-mediated cleavage of APP (into CTFβ). Additionally, quercetin induced improved performance on learning and spatial memory tasks and greater risk assessment behavior based on the elevated plus maze test. Together, these findings suggest that quercetin reverses histological hallmarks of AD and protects cognitive and emotional function in aged 3xTg-AD mice.
Biomédica : revista del Instituto Nacional de Salud
Dihydrofolate reductase (DHFR) has been used successfully as a drug target in the area of anti-ba... more Dihydrofolate reductase (DHFR) has been used successfully as a drug target in the area of anti-bacterial, anti-cancer and anti-malarial therapy. Although this bifunctional enzyme is also a potential drug target for treatment of leishmaniasis, there have been no reports on its efficacy against Leishmania (Viannia) species. The gene encoding the bifunctional DHFR and thymidylate synthase (TS) of Le. (V.) braziliensis was isolated and expressed in E. coli. The enzyme was purified and characterized. The inhibitory effects of antifolates and four aporphine alkaloids on its activity were evaluated. The full-length gene consists of a 1560-bp open reading frame encoding a 58 kDa translated peptide containing DHFR and TS domains linked together in a single polypeptide chain. The recombinant DHFR-TS enzyme revealed Km and Vmax values of 55.35 ± 4.02 µ M (mean ± SE) and 0.02 ± 5.34 x 10 -4 µ M/min respectively for dihydrofolic acid (H₂F). The Le. braziliensis rDHFR-TS have Ki values for antimi...
Biomédica : revista del Instituto Nacional de Salud, 2005
Protozoan parasites are important causative agents of morbidity and mortality throughout the worl... more Protozoan parasites are important causative agents of morbidity and mortality throughout the world--a problem further complicated by the emergence of drug resistance in these parasites. Mechanisms of drug resistance include the following: decreased uptake of the drug into the cell, loss of drug activation, alterations in the drug target, and over-expression of a well-known multiple drug transporter proteins. In this review, two critical components of resistance are stressed: (1) the role of ATP binding cassette proteins, such as P-glycoproteins, in mediating drug resistance in Leishmania and other protozoans, followed by development of cross-resistance to many structurally and functionally unrelated drugs, and (2) some concepts concerning the reversal mechanism of multidrug resistance by drugs and natural products. Several modulators or chemosensitizers alter the capacity of P-glycoproteins to maintain subtoxic intracellular drug concentrations. Calcium channel blockers such as vera...
In the course of from ethnobotanical or chemotaxonomical studies on biologically active substance... more In the course of from ethnobotanical or chemotaxonomical studies on biologically active substances with antiparasitic effects from Anonaceae colombian plants, substantial antiplasmodial activity was observed from the ethyl acetate extract of the stem of Rollinia pittieri and Pseudomalmea boyacana (Annonaceae), the alkaloids isolated from these were studied. Of the alkaloids, liriodenine exhibited the highest activity against chloroquine sensitive and chloroquine resistant strains of Plasmodium falciparum (CI50 = 8.0-10.0 µg/ml). In addition, inhibition of β-hematin formation (Ifb-h) by isolated compounds was evaluated (Ifß-h). O-methylmoschatoline and melosmine showed inhibition percentage >96% at 2 mg/ml. Some degree of cytotoxic to U-937 cells activity was observed by oxoporphine alkaloids.
The bulbs of Phaedranassa dubia (Amaryllidaceae) were found to contain the novel compound phaedra... more The bulbs of Phaedranassa dubia (Amaryllidaceae) were found to contain the novel compound phaedranamine, together with seven known alkaloids. The structure and stereochemistry of the alkaloids were determined by physical and spectroscopic methods. An in vitro screening against four different parasitic protozoa was carried out using the isolated compounds. The alkaloids ungeremine, pseudolycorine and haemanthamine showed good activity in in vitro assays against Trypanosoma brucei rhodesiense, T. cruzi and Plasmodium falciparum with IC50 values in the range of 3.66μM or lower.
Journal of pharmaceutical and biomedical analysis, 2015
Acetylcholinesterase (AChE) enzymatic inhibition is an important target for the management of Alz... more Acetylcholinesterase (AChE) enzymatic inhibition is an important target for the management of Alzheimer disease (AD) and AChE inhibitors are the mainstay drugs for its treatment. In order to discover new sources of potent AChE inhibitors, a combined strategy is presented based on AChE-inhibitory activity and chemical profiles by GC/MS, together with in silico studies. The combined strategy was applied on alkaloid extracts of five Amaryllidaceae species that grow in Colombia. Fifty-seven alkaloids were detected using GC/MS, and 21 of them were identified by comparing their mass-spectral fragmentation patterns with standard reference spectra in commercial and private library databases. The alkaloid extracts of Zephyranthes carinata exhibited a high level of inhibitory activity (IC50=5.97±0.24μg/mL). Molecular modeling, which was performed using the structures of some of the alkaloids present in this extract and the three-dimensional crystal structures of AChE derived from Torpedo cali...
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