Modulation of the oxidative stress in malaria infection by clotrimazole

Antimycotic clotrimazole (CTZ) has demonstrated remarkable activity against Plasmodium falciparum in vitro and in vivo. Hemoglobin degradation by Plasmodium parasites makes amino acids available for protein synthesis, inducing oxidative stress in infected cells and producing free heme. These events represent biochemical targets for potential antimalarials. In this study, we have tested the ability of CTZ to modify the oxidative status in Plasmodium berghei-infected erythrocytes. After hemolysis, activities of superoxide dismutase (SOD), catalase (CAT), glutathione cycle and NADPH+H+-producing dehydrogenases were investigated using UV-visible spectrophotometry. Thiobarbituric acid reactive substances (TBARS) were evaluated as a marker of lipid damage. Results showed that CTZ significantly decreased the overall activity of 6-phosphagluconate dehydrogenase (6PGD) compared to infected and non-treated cells; consequently, the glutathione cycle was inhibited, leaving the parasite vulnerable to the oxidative stress originating from hemoglobin degradation. As a compensatory response, CTZ prevented some loss of SOD and CAT activities in infected cells. The infection triggered lipid peroxidation in erythrocytes, which was decreased by CTZ. These results suggest the presence of a redox unbalance in cells treated with CTZ, discussing a possible effect of this compound disturbing the oxidative status in a Plasmodium berghei-infection.O antifúngico clotrimazol (CTZ) tem demonstrado notável atividade contra Plasmodium falciparum. A degradação da hemoglobina por Plasmodium para a obtenção dos aminoácidos necessários à síntese protéica induz estresse oxidativo em eritrócitos devido à liberação de hemos oxidantes. Estes eventos representam alvos bioquímicos para a produção de antimaláricos potenciais. Neste estudo, testamos a capacidade do CTZ para modificar o estado oxidativo em eritrócitos infectados com Plasmodium berghei. Depois da hemólise, as atividades da superóxido dismutase (SOD), catalase (CAT), desidrogenases produtoras de NADPH+H+ e do ciclo de glutationa (GSH) foram investigados. A produção das espécies reativas ao ácido tiobarbitúrico (TBARS) foi avaliada como marcador de dano lipídico. Os resultados mostraram que o CTZ diminuiu a atividade da 6-fosfogliconato desidrogenase (6PGD), em comparação com eritrócitos infectados e não tratados. Consequentemente, o ciclo da GSH foi inibido, tornando os parasitas vulneráveis ao estresse oxidativo resultante da degradação da hemoglobina. Como resposta compensatória, CTZ impediu a perda de atividade da SOD e CAT nas células infectadas. A infecção induz peroxidação lipídica nos eritrócitos, sendo esta diminuída pelo CTZ. Estes resultados sugerem a existência de desequilíbrio redox nas células tratadas com CTZ, interferindo, assim, com o estado oxidativo verificado durante a infecção malárica

Formate overflow drives toxic folate trapping in MTHFD1 inhibited cancer cells

Cancer cells fuel their increased need for nucleotide supply by upregulating one-carbon (1C) metabolism, including the enzymes methylenetetrahydrofolate dehydrogenase-cyclohydrolase 1 and 2 (MTHFD1 and MTHFD2). TH9619 is a potent inhibitor of dehydrogenase and cyclohydrolase activities in both MTHFD1 and MTHFD2, and selectively kills cancer cells. Here, we reveal that, in cells, TH9619 targets nuclear MTHFD2 but does not inhibit mitochondrial MTHFD2. Hence, overflow of formate from mitochondria continues in the presence of TH9619. TH9619 inhibits the activity of MTHFD1 occurring downstream of mitochondrial formate release, leading to the accumulation of 10-formyl-tetrahydrofolate, which we term a 'folate trap'. This results in thymidylate depletion and death of MTHFD2-expressing cancer cells. This previously uncharacterized folate trapping mechanism is exacerbated by physiological hypoxanthine levels that block the de novo purine synthesis pathway, and additionally prevent 10-formyl-tetrahydrofolate consumption for purine synthesis. The folate trapping mechanism described here for TH9619 differs from other MTHFD1/2 inhibitors and antifolates. Thus, our findings uncover an approach to attack cancer and reveal a regulatory mechanism in 1C metabolism.In this study, Green, Marttila, Kiweler et al. characterize one-carbon metabolism rewiring in response to a dual MTHFD1 and MTHFD2 inhibitor. This work provides insight into one-carbon fluxes, and reveals a previously uncharacterized vulnerability in cancer cells created by folate trapping

Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress

The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors

Calcined eggshell as a cost effective material for removal of dyes from aqueous solution

Abstract The removal of Rhodamine B, Eriochrome black T and Murexide dyes from aqueous solutions using calcined eggshell powder were investigated. In this study, calcined eggshell powder was applied for its potential use as an adsorbent for the removal of Rhodamine B, Eriochrome black T and Murexide dyes from their aqueous solutions. The calcined eggshell powder obtained was characterized by Fourier Transform Infrared Spectroscopy (FT-IR), Thermogravimetric Analysis (TGA), Scanning Electron Microscopy (SEM) and X-ray Diffraction (XRD). The various parameters such as initial concentration, pH, adsorbent dose and contact time were studied. Various isotherms including Langmuir, Freundlich, Temkin and Dubinin-Radushkevich isotherm models were applied for the equilibrium adsorption data. The kinetic study of Rhodamine B, Eriochrome black T and Murexide dyes on calcined eggshell powder follows pseudo-second order kinetics

Synthesis, crystal structure and characterization of Na_2.02Ag_5.98[GaSiO₄]₆(NO₂)₂and Na_3.12K_4.88[GaSiO₄]₆(NO₂)₂ sodalites

563-567Partially exchanged silver and potassium derivatives of Na8[GaSiO4]6(NO2)2 sodalite, Na2.02Ag5.98[GaSiO4]6(NO2)2 and Na3.12K4.88[GaSiO4]6(NO2)2, have been studied. The nitrite sodalite of the composition, Na8[GaSiO4]6(NO2)2 was prepared at low temperature by hydrothermal technique and the derivatives Na2.02Ag5.98[GaSiO4]6(NO2)2 and Na3.12K4.88[GaSiO4]6(NO2)2, were obtained by cation exchange method at 373 K. These products crystallize with the cubic sodalite structure in the space group P43n and profile refinement of powder X-ray data has been completed. The products obtained were studied by different investigative techniques like IR spectroscopy, X-ray powder diffraction, UV-DRS and SEM. FTIR study shows shift in absorption frequency for the exchange of silver and potassium derivatives. The unit cell parameters (a) are found to be 8.9328, 8.9838 and 9.0409 Å for silver, sodium and potassium sodalites, respectively, while the bond distances and bond angles are modified considerably. UV-DRS study shows shift in bands and change in band gap energy of these sodalite derivatives. SEM shows surface morphology of these sodalites

Synthesis and characterization of gallosilicate halide sodalites using organic solvent

1047-1051The crystallization of gallosilicate sodalite containing halides (Cl, Br and I) in 30% ethanol have been investigated at low temperature (373 K) using one pot synthesis method. X-ray powder diffraction, IR, FAR IR, 29Si and 23Na MAS NMR, SEM and thermogravimetric data are used to characterize these sodalites. The crystal structures show cubic symmetry in a space group P3n. The crystal structures have been refined by Rietveld refinement method. The unit cell parameter, a = 8.9502, 8.9986 and 9.0779 Å and the corresponding Ga-O-Si angle are found to be 134.453, 135.252 and 136.887o for chloro, bromo and iodo sodalite respectively. The MAS NMR data confirm the alternating Ga and Si ordering of sodalite framework. TGA analysis shows stability of guest anions in the sodalite framework

INTRUSION DETECTION SYSTEM BASED ON HASHING TECHNIQUE

Security is the main issue in all the sectors but now a days attackers are doing a lot of work to breach this security for their insider trading purpose.They find the number of sources to stole the non public information.In today’s life the confidential information is on high risk and become more susceptible for attack.There are many solutions against different types of attack but attacker always try to break the security using new techniques.so here we tried to develop the new technique to resist the attack at much extent.In the proposed work we have implemented Intrusion detection system which is based on hash map.It uses the principle of hashing which stores the object as key-value pair. Keywords: Security, Intrusion, Intrusion Detection System.Hash Map,Hashing,Object