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1.
Molecules ; 28(11)2023 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-37298904

RESUMO

This study identified phytochemicals in Argemone mexicana (A. mexicana) extracts that are responsible for its medicinal properties, and the best solvent for their extraction. The extracts of the stem, leaves, flowers, and fruits of A. mexicana were prepared at low (corresponding to room temperature) and high temperatures (corresponding to the boiling points) in various solvents, viz., hexane, ethyl acetate, methanol, and H2O. The UV-visible absorption spectra of various phytoconstituents in the isolated extracts were determined through spectrophotometry. Qualitative tests for the screening of phytoconstituents in the extracts were performed to identify various phytochemicals. We identified the presence of terpenoids, alkaloids, cardiac glycosides, and carbohydrates in the plant extracts. The antioxidant and anti-human immunodeficiency virus type 1 reverse transcriptase (anti-HIV-1RT) potential, as well as the antibacterial activity of various A. mexicana extracts were determined. These extracts showed strong antioxidant activities. The extracts exhibited antimicrobial activities against Salmonella typhi, Staphylococcus epidermis, Citrobacter, Neisseria gonorrhoeae, and Shigella flexineri. These extracts significantly inhibited HIV-1 reverse transcriptase activity. The aqueous leaf extract prepared at a temperature equivalent to the boiling point, i.e., 100 °C, was identified to be the most active against pathogenic bacteria and HIV-1 RT.


Assuntos
Anti-Infecciosos , Argemone , Argemone/química , Antioxidantes/farmacologia , Anti-Infecciosos/farmacologia , Anti-Infecciosos/química , Extratos Vegetais/química , Antibacterianos/farmacologia , Antibacterianos/química , Solventes , Compostos Fitoquímicos/química
2.
Indian J Clin Biochem ; 38(2): 251-261, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37025430

RESUMO

Reserpine, a bioactive compound isolated from the roots of Rauwolfia serpentine, is known to deplete dopamine, a neurotransmitter. The clinical application of reserpine has been associated to manage hypertension, insanity, insomnia and schizophrenia. However, the usage of reserpine as a drug is restricted because of its ability of inducing excess free radicals production and oxidative stress resulting into damage to liver and other organs. Here, we have explored the antioxidative potential of extract of garlic prepared using ethanol (EEG) against reserpine-induced hepatic damage in the albino Wister rats.The animals were divided into four different groups containing 6 animals in each: (1) control + placebo, (2) control + EEG, (3) reserpine and (4) reserpine with EEG. The reserpine treatment resulted into sharp increase in the level of MDA and significant reduction in the activitiesof key antioxidative enzymes (SOD, GST, and CAT) in the rat liver. It also caused sharp perturbations in the levels of certain hepatic transaminases (ALT, AST) and glycolytic LDH. The histopathological results revealed hepatic necrosis, which could have occurred due to reserpine induced lipid peroxidation as well as reduction in the levels of antioxidant species.The administration of EEG, however, significantly ameliorated reserpine induced hepatotoxicity. These results reflected the ameliorative property of EEG, which was probably mediated via its antioxidant function as it contains several bioactive molecules with free radical quenching potential.This study suggestedthe prospective application of EEG as a supplement to combat the side effects of reserpine.

3.
Indian J Clin Biochem ; : 1-9, 2023 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-37360645

RESUMO

Arthritis is a clinical condition, which mainly affects the structure and function joints. During this condition the joints gets swelled and stiffed resulting into development of pain and morbidity. Corticosteroids are frequently prescribed to manage various clinical conditions including the chronic inflammatory diseases such as arthritis. The steroidal drug also causes certain adverse effects depending on the dose, the route of administration and duration of treatment. However, a systematic investigation on the biochemical consequences of steroids as a therapeutic has not been carried out. In the present study we analyzed certain parameters associated to oxidative stress, liver function and energy metabolism has been done in the blood plasma of the arthritis patients who were using steroidal drugs (methylprednisolone and deflazacort) up to 168 days for the treatment of the disease. The results indicated increase in level of MDA and decrease in the activities of SOD, CAT and LDH. The activities of AST and ALT were found to be significantly enhanced over the increase in the treatment period. These results suggested that corticosteroids may induce lipid peroxidation, oxidative stress and liver toxicity in the arthritis patients in the dose and duration dependent manner. The use of antioxidants as supplements to the anti-arthritis agents could play a role in suppressing the oxidative stress mediated adverse effects. However, extensive research is required to explore for safer medication devoid of steroids to cure arthritis.

4.
Indian J Clin Biochem ; 37(1): 51-59, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35125693

RESUMO

Exposure to pesticides can pose a greater threat to multiple organs of nontarget animals. Cartap is a thiocarbamate pesticide, broadly used in agricultural fields. The assessment of neurotoxicity of cartap has not been properly studied in the mammalian systems. The present investigation unveils the toxic effects of cartap in the brain of Wistar rats its amelioration by using aqueous extract of Aloe vera leaves. We have used 4 groups of animals comprising six in each: Group 1- control, Group 2- control with Aloe vera, Group 3- cartap, Group 4- cartap with Aloe vera treated. After 15 days of treatment, biochemical investigations were conducted. Wistar rats orally exposed to sublethal doses of cartap, showed significant variations in the levels of prooxidants i.e. MDA and GSH (an oxidative stress marker) and enzymatic antioxidants i.e. SOD, CAT, GST, GPx. The decreased levels of CAT, SOD, GST and increased levels of GPx were detected in the experimental rats treated with cartap. The significant alterations were recorded with the declined activities of LDH and AChE, considered as the biomarker of energy metabolism and altered cholinergic function, respectively. However, the pre-administration of aqueous extract of Aloe vera leaves was found to markedly ameliorate the toxic effects of cartap by shielding the levels of aforesaid oxidative markers near to the control. The ameliorative impact of Aloe vera, might be due to the presence of several antioxidant molecules in it which were able to counter the oxidative stress generated by cartap stress. These results suggested that Aloe vera could be utilized as a possible supplement with the relevant therapeutics in the suitable management of cartap toxicity in association.

5.
Indian J Clin Biochem ; 37(4): 410-422, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36262781

RESUMO

The identification and pharmacological validation of plant-based lead compounds for the cure of different diseases including cancer have always been globally strived. In addition to possessing numerous medicinal properties, many of the phytochemicals display antioxidant potential activities. Reactive oxygen species (ROS) causeoxidative stress leading to several severe diseases such as cancer. The antioxidants are substances that fight against ROS to protect the cells from their damaging effects. In the present study, the effects of methanol extract of Euglena tuba(ETME) have been evaluated for its antioxidant and antitumor potential against Dalton's lymphoma (DL) introduced in BALB/cmice. After 24 h of intraperitoneal inoculation of DL cells in mice, ETME (300 mg kg-1 body weight) was administered intraperitoneally upto18 alternative days. On the 18th day, the mice were sacrificed; the blood and tissues (liver and brain) were collected to determine the tumor growth parameters including morphological, behavioural, haematological profile, and antioxidant indices. The results indicated that ETME exhibited significant antioxidative and antitumor properties when compared with the data from DL bearing mice. The results from the present study indicated that ETME contained remarkable antitumor efficacy, which was mediated through amelioration of oxidative stress. The data suggested that ETME could be used as a potential natural anticancer agent.

6.
Molecules ; 26(10)2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34070179

RESUMO

Conifers have long been recognized for their therapeutic potential in different disorders. Alkaloids, terpenes and polyphenols are the most abundant naturally occurring phytochemicals in these plants. Here, we provide an overview of the phytochemistry and related commercial products obtained from conifers. The pharmacological actions of different phytochemicals present in conifers against bacterial and fungal infections, cancer, diabetes and cardiovascular diseases are also reviewed. Data obtained from experimental and clinical studies performed to date clearly underline that such compounds exert promising antioxidant effects, being able to inhibit cell damage, cancer growth, inflammation and the onset of neurodegenerative diseases. Therefore, an attempt has been made with the intent to highlight the importance of conifer-derived extracts for pharmacological purposes, with the support of relevant in vitro and in vivo experimental data. In short, this review comprehends the information published to date related to conifers' phytochemicals and illustrates their potential role as drugs.


Assuntos
Florestas , Compostos Fitoquímicos/uso terapêutico , Traqueófitas/química , Animais , Ensaios Clínicos como Assunto , Humanos , Neuroproteção/efeitos dos fármacos , Compostos Fitoquímicos/química , Extratos Vegetais/uso terapêutico
7.
Semin Cancer Biol ; 56: 128-134, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-29100957

RESUMO

Ras proteins have been reported to play key role in oncologic diseases. Ras proteins are associated with cellular membranes for its carcinogenic activities through post-translational modifications, including farnesylation. Farnesyltransferase is responsible for a type of Ras membrane targeting, which leads to cancer origin and progression. Inhibitors of farnesyltransferase have been developed as novel anticancer agents. In this review, the role of farnesyltransferase in cancer progression and development has been discussed. Further, the current status of development of farnesyltransferase inhibitors for cancer prevention and treatment has also been reviewed.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Farnesiltranstransferase/antagonistas & inibidores , Farnesiltranstransferase/metabolismo , Neoplasias/metabolismo , Animais , Antineoplásicos/uso terapêutico , Ensaios Clínicos como Assunto , Inibidores Enzimáticos/uso terapêutico , Regulação Neoplásica da Expressão Gênica , Genes ras , Humanos , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Neoplasias/etiologia , Neoplasias/patologia , Ligação Proteica , Transdução de Sinais , Resultado do Tratamento
8.
Phytother Res ; 34(11): 2889-2910, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32515528

RESUMO

Essential oils (EOs) are regarded as alternative therapeutic agents for many diseases. In phytotherapy research areas, it is now well reported that conifers are the rich source of EOs. This review aims to update information on the biological sources and the best extraction processes of the significant constituents along with the traditional and therapeutic properties of the EOs from selected conifers of Himachal Pradesh, Northwestern Himalaya. In the present review, ten conifer species of high values have been selected. Results from several studies suggest that the conifers contain monoterpenes, sesquiterpenes, diterpenes, ketones, alcohols, and esters, which are used in medicines, food products, and cosmetics as well as other commercial and industrial products. Traditionally, the EOs from the conifers have been reported to be used against fever, cough, bronchitis, skin diseases, gastrointestinal disorders, and asthma. The pharmacological studies suggest that these EOs can be used as antirheumatic, antiseptic, antispasmodic, anticancer, anti-inflammatory, antitoxic, aphrodisiac, and astringent agents. It is, therefore, concluded that the EOs from the conifers might be one of the promising tools for the treatment of various diseases. Extensive research is required to ascertain the efficacy of the EOs from unstudied conifers.


Assuntos
Óleos Voláteis/uso terapêutico , Traqueófitas/química , Humanos , Óleos Voláteis/farmacologia
9.
J Cell Physiol ; 234(10): 18329-18343, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30891764

RESUMO

Exposure to mixture of pesticides in agricultural practices pose a serious threat to the nontarget animals. In present work, we have evaluated the synergistic effect of cartap and malathion on rat liver followed by impact of Aloe vera leaves aqueous extract, which is not known. The animals in eight groups were used; each containing six rats: Group 1 acted as a control, Group 2-control with A. vera leaves aqueous extract, Group 3-with cartap, Group 4-with malathion, Group 5-with mixture of cartap and malathion, Group 6-cartap with the pretreatment of A. vera leaf extract, Group 7-malathion with the pretreatment of A. vera leaf extract, Group 8-mixture of cartap and malathion with the pretreatment of A. vera leaf extract . The animals treated for 15 days were killed after 24hr of last treatment. The biochemical studies in the rat liver demonstrated significant perturbations in the levels of nonenzymatic (glutathione and malondialdehyde) and enzymatic (superoxide dismutase, catalase, and glutathione- S-transferase) antioxidative indices. The histopathological examination of liver revealed serious congestion in central vein and the disorganization of hepatic cords due to pesticide treatment. The administration of A. vera leaves aqueous extract was able to markedly protect rat liver from the pesticides-induced toxicity. The data indicated that pesticides were able to significantly induce oxidative stress which was substantially reduced by the application of plant extract .


Assuntos
Aloe/química , Fígado/efeitos dos fármacos , Malation/efeitos adversos , Extratos Vegetais/farmacologia , Substâncias Protetoras/farmacologia , Tiocarbamatos/efeitos adversos , Animais , Antioxidantes/metabolismo , Catalase/metabolismo , Glutationa/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Masculino , Malondialdeído/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo
10.
Chem Res Toxicol ; 31(10): 1009-1021, 2018 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-30178661

RESUMO

The effects of lead exposure on mammals are reported to be devastating. Lead is present in all the abiotic environmental components such as brass, dust, plumbing fixtures, soil, water, and lead mixed imported products. Its continuous use for several industrial and domestic purposes has caused a rise in its levels, thereby posing serious threats to human health. The mechanisms involved in lead-induced toxicity primarily include free-radical-mediated generation of oxidative stress which directly imbalances the prooxidants and the antioxidants in body. The toxicity of lead involves damage primarily to major biomolecules (lipid, protein, and nucleic acids) and liver (hepatotoxicity), nervous system (neurotoxicity), kidney (nephrotoxicity) and DNA (genotoxicity), present in animals and humans. The activation of c-Jun NH2-terminal kinase, phosphoinositide 3-kinase, or Akt and p38 mitogen activated protein kinase signaling pathways are important for lead cytotoxicity. Lead increased apoptosis through signaling cascade and associated factors and significantly impairs cell differentiation and maturation. In addition, lead has great impact on metabolic pathways such as heme synthesis, thereby leading to the onset of anemia in lead exposed people. This review encompasses an updated account of varied aspects of lead-induced oxidative stress and the biomolecular consequences such as perturbations in physiological processes, apoptosis, carcinogenesis, hormonal imbalance, loss of vision, and reduced fertility and their possible remediation through synthetic (chelators) and natural compounds (plant-based principles). This paper is primarily concerned with the biomedical implications of lead-induced generation of free radical and the toxicity management in the mammalian system.


Assuntos
Chumbo/toxicidade , Transdução de Sinais/efeitos dos fármacos , Animais , Dano ao DNA/efeitos dos fármacos , Gastroenteropatias/metabolismo , Gastroenteropatias/patologia , Humanos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo
11.
J Therm Biol ; 69: 149-154, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29037376

RESUMO

Heat shock proteins are important for maintaining protein homeostasis and cell survival. Among different classes of highly conserved Hsps, low molecular weight Hsps (sHsps) have significant place, particularly Hsp27, whose role has been demonstrated in wide range of biological processes, including development, immunity, diseases and therapy. In this review, the structure and functions of Hsp27 and related genes, their role in different cellular processes as well as in stress tolerance, is highlighted.


Assuntos
Proteínas de Choque Térmico HSP27/metabolismo , Envelhecimento , Animais , Apoptose , Evolução Molecular , Variação Genética , Proteínas de Choque Térmico HSP27/análise , Proteínas de Choque Térmico HSP27/genética , Homeostase , Humanos , Conformação Proteica , Transdução de Sinais , Estresse Fisiológico
12.
J Biochem Mol Toxicol ; 28(7): 320-7, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24865641

RESUMO

Pesticides cause oxidative stress and adversely influence Na(+)-K(+)-ATPase activity in animals. Since impact of carbofuran has not been properly studied in the mammalian brain, the ability of carbofuran to induce oxidative stress and modulation in Na(+)-K(+)-ATPase activity and its amelioration by vitamin E was performed. The rats divided into six groups received two different doses of carbofuran (15% and 30% LD50) for 15 days. The results suggested that the carbofuran treatment caused a significant elevation in levels of malonaldehyde and reduced glutathione and sharp inhibition in the activities of super oxide dismutase, catalase, and glutathione-S-transferase; the effect being dose dependent. Carbofuran at different doses also caused sharp reduction in the activity of Na(+)-K(+)-ATPase. The pretreatment of vitamin E, however, showed a significant recovery in these indices. The pretreatment of rats with vitamin E offered protection from carbofuran-induced oxidative stress.


Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Carbofurano/toxicidade , Estresse Oxidativo/efeitos dos fármacos , ATPase Trocadora de Sódio-Potássio/metabolismo , Vitamina E/farmacologia , Animais , Antioxidantes/metabolismo , Encéfalo/enzimologia , Catalase/metabolismo , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Glutationa Transferase/metabolismo , Masculino , Malondialdeído/metabolismo , Ratos Wistar , Superóxido Dismutase/metabolismo
13.
Biol Trace Elem Res ; 2024 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-38592566

RESUMO

Cadmium, a highly toxic heavy metal, can cause severe damage to several vital organs including the kidney, liver, and brain. Many of the natural compounds found in aromatic plants have beneficial pharmacological properties. Eugenol is one such compound reported to have anti-inflammatory and antioxidant properties. The aim of this study is to investigate whether eugenol, a natural compound found in aromatic plants known for its anti-inflammatory and antioxidant properties, can mitigate the detrimental effects of cadmium exposure on cardiac inflammation, oxidative stress, and dyslipidemia. Male albino rats were subjected to randomization into four groups, each comprising six animals, to investigate the potential of eugenol in mitigating cadmium-induced toxicity. All groups received oral gavage treatment for 21 days. Following the treatment regimen, cardiac tissue specimens were collected for analysis. The assessment of cardiac antioxidant status entailed the determination of enzymatic activities including catalase, SOD, GST, and GPx. Additionally, levels of lipid peroxidation, reduced glutathione, protein carbonyl oxidation, and thiol levels were quantified in the cardiac tissue samples. To evaluate cardiac damage, marker enzymes such as LDH and CK-MB were measured. Furthermore, the inflammatory response in the cardiac tissue induced by cadmium exposure was assessed through the quantification of NO, TNF-α, and IL-6 levels. Additionally, molecular docking and dynamics studies were conducted utilizing autodock and GLIDE methodologies. Cadmium administration markedly enhanced the activities of LDH and CK-MB, prominent cardiac markers. Furthermore, cadmium treatment also demonstrated a significant decrease in the reduced glutathione levels and antioxidant enzyme activities. Significant elevation of the inflammatory markers was also observed in the cadmium-treated group. Eugenol treatment effectively ameliorates cadmium-induced biochemical changes. This study underscores the potent anti-inflammatory and antioxidant attributes of eugenol. Co-administration of eugenol alongside cadmium exhibited remarkable protective efficacy against cadmium-induced cardio-toxicity. Eugenol demonstrated the capability to reinstate the cellular redox equilibrium of rats subjected to cadmium treatment to levels akin to those of the normal control group.

14.
J Biomol Struct Dyn ; 42(4): 1765-1777, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-37097971

RESUMO

Depressive disorders are among most common psychiatric diseases and second most common form of psychiatric illness globally. Commonly available chemical drugs used for treatment of nervous system disorders exert undesirable effects. Therefore, there is a growing need towards exploring novel antidepressants of herbal origin. Earlier, the antidepressant effect of methanolic extract of garlic has been shown. In this study, the ethanolic extract of garlic was prepared and chemically analysed using Gas Chromatography - Mass Spectrometry (GC-MS) screening. A total of 35 compounds were found to be present, which might act as antidepressant. Using computational analyses, these compounds were screened as potential inhibitors (selective serotonin reuptake inhibitor (SSRI)) against serotonin transporter (SERT)/leucine receptor (LEUT). In silico docking studies and other physicochemical, bioactivity and ADMET studies resulted in the selection of compound 1 ((2-Cyclohexyl-1-methylpropyl) cyclohexane) as potential SSRI (binding energy -8.1 kcal/mol) compared to known reference SSRI fluoxetine (binding energy -8.0 kcal/mol). Analysis of conformational stability, residue flexibility, compactness, binding interactions, solvent accessible surface area (SASA), dynamic correlation, and binding free energy predicted from molecular mechanics (MD) with generalised Born and surface area solvation (MM/GBSA) studies revealed formation of a more stable SSRI like complex with compound 1 having strong inhibitory interaction compared to known SSRI fluoxetine/reference complex. Thus, compound 1 may act as an active SSRI leading to discovery of potential antidepressant drug.Communicated by Ramaswamy H. Sarma.


Assuntos
Fluoxetina , Alho , Fluoxetina/farmacologia , Simulação de Dinâmica Molecular , Antidepressivos/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Cicloexanos , Simulação de Acoplamento Molecular
15.
Nat Prod Res ; : 1-7, 2024 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-38723184

RESUMO

Seaweeds are sources of bioactive compounds with medicinal properties, which make them attractive candidates for natural therapeutic agents. Marine brown algae are known to possess anti-inflammatory, hepatoprotective, anticancer properties, etc. Present study was carried out to identify the phytochemical constituents, antioxidant and cytotoxic activities of Sargassum prismaticum in two different solvents viz., chloroform and methanol. Chloroform was found to be the superior solvent for phenol and flavonoid extraction. Antioxidant activity was determined using DPPH and ABTS assays; however, the methanolic extract demonstrated better antioxidant potential. The highest cell cytotoxicity with an IC50 value of 7.6 ± 0.02 µg/mL was observed in methanolic extract, while the chloroform extract had an IC50 value of 9.6 ± 0.03 µg/mL against U937 cell line. These finding suggest that Sargassum prismaticum possesses potent antioxidant and cytotoxic properties, making it a potential candidate for further study as a novel antioxidant drug source.

16.
J Biomol Struct Dyn ; 42(3): 1533-1543, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-37079006

RESUMO

Human Lymphatic filariasis is caused by parasitic nematodes Wuchereria bancrofti, Brugia malayi, and Brugia timori. Protein disulfide isomerase (PDI), a redox-active enzyme, helps to form and isomerize the disulfide bonds, thereby acting as a chaperone. Such activity is essential for activating many essential enzymes and functional proteins. Brugia malayi protein disulfide isomerase (BmPDI) is crucial for parasite survival and an important drug target. Here, we used a combination of spectroscopic and computational analysis to study the structural and functional changes in the BmPDI during unfolding. Tryptophan fluorescence data revealed two well-separated transitions during the unfolding process, suggesting that the unfolding of the BmPDI is non-cooperative. The binding of the fluorescence probe 8-anilino-1-naphthalene sulfonic acid dye (ANS) validated the results obtained by the pH unfolding. The dynamics of molecular simulation performed at different pH conditions revealed the structural basis of BmPDI unfolding. Detailed analysis suggested that under different pH, both the global structure and the conformational dynamics of the active site residues were differentially altered. Our multiparametric study reveals the differential dynamics and collective motions of BmPDI unfolding, providing insights into its structure-function relationship.Communicated by Ramaswamy H. Sarma.


Assuntos
Brugia Malayi , Animais , Humanos , Isomerases de Dissulfetos de Proteínas , Desdobramento de Proteína , Domínio Catalítico , Relação Estrutura-Atividade
17.
J Biol Chem ; 287(45): 38110-23, 2012 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-22955279

RESUMO

Rilpivirine (RPV) is a second generation nonnucleoside reverse transcriptase (RT) inhibitor (NNRTI) that efficiently inhibits HIV-1 resistant to first generation NNRTIs. Virological failure during therapy with RPV and emtricitabine is associated with the appearance of E138K and M184I mutations in RT. Here we investigate the biochemical mechanism of RT inhibition and resistance to RPV. We used two transient kinetics approaches (quench-flow and stopped-flow) to determine how subunit-specific mutations in RT p66 or p51 affect association and dissociation of RPV to RT as well as their impact on binding of dNTP and DNA and the catalytic incorporation of nucleotide. We compared WT with four subunit-specific RT mutants, p66(M184I)/p51(WT), p66(E138K)/p51(E138K), p66(E138K/M184I)/p51(E138K), and p66(M184I)/p51(E138K). Ile-184 in p66 (p66(184I)) decreased the catalytic efficiency of RT (k(pol)/K(d)(.dNTP)), primarily through a decrease in dNTP binding (K(d)(.dNTP)). Lys-138 either in both subunits or in p51 alone abrogated the negative effect of p66(184I) by restoring dNTP binding. Furthermore, p51(138K) reduced RPV susceptibility by altering the ratio of RPV dissociation to RPV association, resulting in a net reduction in RPV equilibrium binding affinity (K(d)(.RPV) = k(off.RPV)/k(on.RPV)). Quantum mechanics/molecular mechanics hybrid molecular modeling revealed that p51(E138K) affects access to the RPV binding site by disrupting the salt bridge between p51(E138) and p66(K101). p66(184I) caused repositioning of the Tyr-183 active site residue and decreased the efficiency of RT, whereas the addition of p51(138K) restored Tyr-183 to a WT-like conformation, thus abrogating the Ile-184-induced functional defects.


Assuntos
Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/enzimologia , Nitrilas/farmacologia , Pirimidinas/farmacologia , Substituição de Aminoácidos , Sítios de Ligação/genética , Farmacorresistência Viral/genética , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Transcriptase Reversa do HIV/química , Transcriptase Reversa do HIV/genética , HIV-1/genética , Humanos , Modelos Moleculares , Mutação , Nitrilas/química , Ligação Proteica , Estrutura Terciária de Proteína , Pirimidinas/química , Rilpivirina
18.
Curr Med Chem ; 2023 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-37818563

RESUMO

BACKGROUND: Indomethacin is a non-steroidal anti-inflammatory drug (NSAID) used for medication to reduce fever, spondylitis, or shoulder pain. It mainly works by the inhibition of prostaglandins, the endogenous signaling molecules. METHODS: Fifteen indomethacin derivatives have been analyzed in relation to their physicochemical and molecular properties. Two-dimensional (2D) structures of fifteen indomethacin derivatives were drawn using the ACD Lab Chem Sketch version. Most of the topological parameters, such as wiener index (W), mean wiener index (Wa), Balaban indices (J), Balaban centric index (BAC), and molecular connectivity (χ), were calculated by using E Dragon software. The most common molecular file formats accepted in E-Dragon software were SMILES notations created online by Babel software and 2D structures of various derivatives, which were converted into 3D optimized structures using online CORINA, provided by Molecular Networks GMBH. 3D structures of compounds were also drawn on Gauss View software for calculations of various density functional theory (DFT) based quantum chemical descriptors, such as total energy (TE), softness (S), hardness (η), chemical potential (µ), highest occupied molecular orbital energy (HOMO), and lowest unoccupied molecular orbital energy (LUMO). All species were fully optimized in the gas phase with a 6-31+G* basis set. The harmonic vibrational frequency calculations were used to confirm that the optimized structures were minima, as characterized by positive vibrational frequencies. RESULTS: Combinations of various descriptors, such as D, ID, IOR, Log P, Mr, Mv, Mw, Pc, BAC, Pz, St, W, Wa, 0χ, 1χ, 2χ,3χ,4χ, 5χ, and Xeq have been found to be significant for modeling of activity. QSAR model no. 2: pIC50= -20.605 (±6.600) IOR - 0.747 (±0.454) I1 -5.083 (±3.478) Xeq + 51.647 optimized with empirical parameters with high statistical quality (R= 0.921, R2=0.848) was found to be the best model obtained. CONCLUSION: The QSAR model obtained suggests that substituents with a lesser value of the index of refraction and less electronegative groups were favourable for the activity, whereas indomethacin derivatives with a CH2CH2NHCONH (CH2)3ONO2 group at R1 position were unfavourable for the activity. The results were critically discussed based on regression data and cross-validation techniques. Pogliani factor Q and the results of the LOO (leave-one-out) method confirmed the reliability and predictability of the proposed models that could be highly beneficial for the future designing of new analogues with higher potency.

19.
Mini Rev Med Chem ; 23(2): 217-229, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-35658879

RESUMO

The Coronavirus Disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus type 2 (SARS-CoV-2), belongs to emerging and reemerging diseases, which was first identified and reported in Wuhan, China, in December 2019. The genetic sequence of SARS-CoV-2 was similar to the SARS virus, a ß-coronavirus. The epidemiological studies suggest that the transmission of SARS-CoV-2 mainly occurs from an infected person to others through close contact with the respiratory droplets or by having contact with SARS-CoV-2 adhering to objects and surfaces. The incubation period ranges from 5 to14 days. The symptoms include fever, dry cough, tiredness, aches, chest pain, conjunctivitis, diarrhea, headache, difficulty in breathing or short breath, loss of taste, smell, rashes on the skin, and sore throat. Some reports indicated that males exhibited lower scores than females, the younger populations displayed increased symptoms, Chinese/Taiwanese people registered only scarce symptoms, and Canadians experienced more symptoms. The results of several studies suggested that while COVID-19 had a significant effect on depression, job instability affected anxiety and depression. The diagnostics to detect the presence of coronavirus involve ELISA and RT-PCR. There is no specific treatment available to eradicate COVID-19. The therapeutics used to treat COVID 19 exhibited severe side effects. Recently, some Indian traditional medicinal plants have shown promise in reducing the risk of viral infection and also boosting the immunity of an individual. This paper presents an overview of the current status of depression in the SARS CoV2 infected people and the measures required to overcome COVID-19 induced depression in patients even after recovery.


Assuntos
COVID-19 , Feminino , Humanos , Masculino , Canadá , Depressão/tratamento farmacológico , RNA Viral/genética , SARS-CoV-2
20.
Cancers (Basel) ; 15(23)2023 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-38067358

RESUMO

Skin cancer is the 5th most common cancer in Western countries with a surge in case occurrences making it a global burden on healthcare systems. The present study aims to evaluate the cancer-preventive activity of an ethanolic extract of Argemone mexicana Linn leaves (AML). The DMBA/TPA method was used to induce skin cancer in mice. Experimental animals were divided into three pretreatment groups of 100 mg/kg BW, 250 mg/kg BW, and 500 mg/kg BW of AML extract, and feeding was continued during the induction process. In the fourth group, 500 mg/kg BW AML extract treatment was started along with the cancer induction. The analyses were performed on the basis of the time period of in-tumour induction incidence, haematological parameters, histopathology and augmentation of TNF-α secretion and the NF-κB (p65 subunit) signalling pathway. The AML extract resisted and delayed tumour formation for up to 8 weeks in the 500 mg/kg BW pretreated group as compared to 4 weeks in the negative control group. The tumour burden varied in a dose-dependent manner in the different groups. On the 60th day, a significantly high burden (p < 0.001) was observed in the negative control group and the 100 mg/kg BW group. The study was validated by investigating the expression of TNF-α and the p65 subunit of the NF-κB signalling pathway, which were found to be reduced significantly in a dose-dependent manner and significantly reduced (p < 0.001) in the 500 mg/kg BW group as compared to negative control group. The 500 mg/kg BW pretreated group was found to have significant results in comparison to the 500 mg/kg BW post-treatment group. The study revealed the effective cancer preventive activity of Argemone mexicana Linn leaves (AML) in the mouse model and paved a pathway for molecular approaches which could be explored more in future studies.

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