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1.
Bioinformation ; 19(10): 995-998, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37969663

RESUMO

Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), and epilepsy, pose a growing global health challenge due to an aging population. These conditions share common processes, including protein accumulation, oxidative stress, and neuro-inflammation, making their treatment complex and costly. Network pharmacology, an innovative approach integrating systems biology and computational biology, offers insights into multi-target formulations and the repurposing of existing medications for neurodegenerative diseases. We shortlisted 730 bioactive compounds from 25 traditional Himalayan plants, assessed their drug-like properties using ADME criteria, and predicted their potential target proteins through reverse docking and pharmacophore mapping. Our study identified 287 compounds with high gastrointestinal absorption and good blood-brain barrier permeability. These compounds were subjected to target prediction, yielding a list of 171 potential target proteins. Functional annotation and pathway enrichment analysis highlighted their involvement in steroid hormone-related pathways, MAPK signaling, FOXO signaling, TNF signaling, VEGF signaling, and neurotrophin signaling. Importantly, one plant, Valeriana jatamansi, exhibited an association with beta-amyloid binding activity, a potential therapeutic approach for AD. From our study we could understand how these plants modulate our body to manage these diseases. However, further in vitro and in vivo validation is needed before commercial and public use of this data.

2.
Cell Rep ; 42(9): 113058, 2023 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-37656621

RESUMO

Neuropeptides and peptide hormones are ancient, widespread signaling molecules that underpin almost all brain functions. They constitute a broad ligand-receptor network, mainly by binding to G protein-coupled receptors (GPCRs). However, the organization of the peptidergic network and roles of many peptides remain elusive, as our insight into peptide-receptor interactions is limited and many peptide GPCRs are still orphan receptors. Here we report a genome-wide peptide-GPCR interaction map in Caenorhabditis elegans. By reverse pharmacology screening of over 55,384 possible interactions, we identify 461 cognate peptide-GPCR couples that uncover a broad signaling network with specific and complex combinatorial interactions encoded across and within single peptidergic genes. These interactions provide insights into peptide functions and evolution. Combining our dataset with phylogenetic analysis supports peptide-receptor co-evolution and conservation of at least 14 bilaterian peptidergic systems in C. elegans. This resource lays a foundation for system-wide analysis of the peptidergic network.


Assuntos
Neuropeptídeos , Hormônios Peptídicos , Animais , Caenorhabditis elegans/metabolismo , Filogenia , Neuropeptídeos/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Hormônios Peptídicos/genética
4.
J Ayurveda Integr Med ; 14(1): 100558, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-35659739

RESUMO

Picrorhiza kurroa Royle ex Benth, Kutki (P.kurroa) is an important medicinal plant, traditionally recommended and used in Ayurveda for millennia, with certain cautions. There has been a significant revival of keen interest in its pharmacology, pharmacognosy, and phytochemistry for the last few decades. The evidence of its hepatoprotective activity, in experimental and clinical studies, accelerated the correlation of the specific phytochemical constituents of P.kurroa with precise pharmacological activities. Iridoid glycosides, particularly picrosides, emerged as the active molecules. For effective translation of traditional remedies into modern therapy, value addition by mechanistic understanding of molecular actions, drug targets, the degrees of efficacy and safety as well as convenient dosage forms is needed. Reverse pharmacology approach and phytopharmaceutical drug category facilitate such a translation. The present review illustrates how a potential translation of traditional practices of using P.kurroa into a phytochemically standardized, clinically targeted natural product for global unmet medical needs viz. Fatty liver disease can be attained.

5.
Biology (Basel) ; 11(10)2022 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-36290318

RESUMO

The importance of traditional and indigenous knowledge is acknowledged on a worldwide scale for its coexistence principles and sustainable use techniques. In view of this, the present study is an attempt to document the ethno-veterinary plants used by the tribal communities of Western Himalaya. This study also provides the scientific validation of herbal medicines used in ethno-veterinary practices through a reverse pharmacological approach. A total of 59 informants were selected through a non-probability sampling method. Detailed information on the medicinal plants used in ethno-veterinary practices along with their habits and habitats, part/s used, remedy preparation methods, additives/ingredients used during preparation and administration, dosages administered, and route of administration was collected. Data was analyzed for the Relative Frequency of Citations (RFC), Use Values (UV), Informant Consensus Factor (ICF), and Jaccard Index (JI). Further, a reverse pharmacological approach was used for scientific validations of the documented herbal knowledge of plant species. During the study, 56 plant species belonging to 54 genera and 39 families were documented. Asteraceae was the dominant family followed by Lamiaceae, Amaranthaceae and Fabaceae. Life forms were dominated by herbaceous species and leaves were the most common plant parts used. The highest Relative Frequency of Citations (RFC) and Use Values (UV) were recorded for Brassica rapa L. (Brassicaceae). The Pearson correlation coefficient between RFC and UV shows a strong positive correlation between the proportion of uses of a plant species within a sample of informants and the number of times that a particular use of a plant species was mentioned by the informant. Studies of the biological activity of ethno-veterinary plants can provide clues of promising leads for the isolation and identification of useful compounds that may be developed into pharmaceuticals for human welfare.

6.
Front Pharmacol ; 12: 720873, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34899290

RESUMO

Pulmonary arterial hypertension (PAH) is characterized by pulmonary artery remodeling that may subsequently culminate in right heart failure and premature death. Although there are currently both non-pharmacological (lung transplantation, etc.) and pharmacological (Sildenafil, Bosentan, and new oral drugs on trial) therapies available, PAH remains a serious and fatal pulmonary disease. As a unique medical treatment, traditional herbal medicine (THM) treatment has gradually exerted its advantages in treating PAH worldwide through a multi-level and multi-target approach. Additionally, the potential mechanisms of THM were deciphered, including suppression of proliferation and apoptosis of pulmonary artery smooth muscle cells, controlling the processes of inflammation and oxidative stress, and regulating vasoconstriction and ion channels. In this review, the effects and mechanisms of the frequently studied compound THM, single herbal preparations, and multiple active components from THM are comprehensively summarized, as well as their related mechanisms on several classical preclinical PAH models. It is worth mentioning that sodium tanshinone IIA sulfonate sodium and tetramethylpyrazine are under clinical trials and are considered the most promoting medicines for PAH treatment. Last, reverse pharmacology, a strategy to discover THM or THM-derived components, has also been proposed here for PAH. This review discusses the current state of THM, their working mechanisms against PAH, and prospects of reverse pharmacology, which are expected to facilitate the natural anti-PAH medicine discovery and development and its bench-to-bedside transformation.

7.
Phytomedicine ; 91: 153718, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34531099

RESUMO

BACKGROUND: Longstanding, successful use of combinations of phytopharmaceuticals in traditional Chinese medicine (TCM) has caught the attention of several pharmacologists to natural medicines. However, the development and popularisation of TCM is mainly limited because of the unavailability of reports clarifying the mechanisms of action and pharmacologically active ingredients in such formulations. Previous studies on natural medicines have mostly focused on their dominant components using forward pharmacology which often neglects trace components. It is necessary to assess the pharmacological and therapeutic superiority of many such trace components in comparison with single constituents. PURPOSE: In this study, we aimed to propose a new pharmacological research strategy for TCM. In particular, we presented the possibility that the effective mechanism of action of trace components of TCM is based on synthetic lethality. We sincerely hope to explore this theory further. METHOD: We obtained retrieve published research information related to synthetic lethality, phytochemicals and Chinese medicine from PubMed and Google scholar. Based on the inclusion criteria, 71 studies were selected and discussed in this review. RESULTS: As an interaction among genes, synthetic lethality can amplify co-regulatory biological effects exponentially. Synthetic strategies have been successfully applied for research and development of anti-tumour agents, including poly ADP-ribose polymerase inhibitors and clinical combination of chemotherapeutic agents for efficacy enhancement and toxicity reduction. TCM drugs contain several secondary metabolites to combat environmental stresses, providing a multi-component basis for corresponding synergistic targets. Therefore, we aimed to study whether this method could be used to identify active components present in trace amounts in TCM drugs. Based on a reverse concept of target-component-effect and identified synergistic targets, we explored the mechanisms of action of weakly active components present in trace amounts in TCM drugs to assess combinations of potential synergistic components. CONCLUSION: This pattern of synthetic lethality not only elucidated the mechanisms of action of TCM drugs from a new perspective but also inspired future studies on discovering naturally occurring active components.


Assuntos
Medicamentos de Ervas Chinesas , Compostos Fitoquímicos , Mutações Sintéticas Letais , Medicamentos de Ervas Chinesas/farmacologia , Medicina Tradicional Chinesa , Compostos Fitoquímicos/farmacologia
8.
J Ayurveda Integr Med ; 12(3): 465-473, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34353693

RESUMO

BACKGROUND: Accumulation of free fatty acids (FFAs) in hepatocytes is a hallmark of liver dysfunction and non-alcoholic fatty liver disease (NAFLD). Excessive deposition of FFAs alters lipid metabolism pathways increasing the oxidative stress and mitochondrial dysfunction. Attenuating hepatic lipid accumulation, oxidative stress, and improving mitochondrial function could provide potential targets in preventing progression of non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH). Earlier studies with Picrorhiza kurroa extract have shown reduction in hepatic damage and fatty acid infiltration in several experimental models and also clinically in viral hepatitis. Thus, the effect of P. kurroa's phytoactive, picroside II, needed mechanistic investigation in appropriate in vitro liver cell model. OBJECTIVE(S): To study the effect of picroside II on FFAs accumulation, oxidative stress and mitochondrial function with silibinin as a positive control in in vitro NAFLD model. MATERIALS AND METHODS: HepG2 cells were incubated with FFAs-1000µM in presence and absence of Picroside II-10 µM for 20 hours. RESULTS: HepG2 cells incubated with FFAs-1000µM lead to increased lipid accumulation. Picroside II-10µM attenuated FFAs-induced lipid accumulation (33%), loss of mitochondrial membrane potential (ΔΨm), ATP depletion, and production of reactive oxygen species (ROS). A concomitant increase in cytochrome C at transcription and protein levels was observed. An increase in expression of MnSOD, catalase, and higher levels of tGSH and GSH:GSSG ratios underlie the ROS salvaging activity of picroside II. CONCLUSION: Picroside II significantly attenuated FFAs-induced-lipotoxicity. The reduction in ROS, increased antioxidant enzymes, and improvement in mitochondrial function underlie the mechanisms of action of picroside II. These findings suggest a need to develop an investigational drug profile of picroside II for NAFLD as a therapeutic strategy. This could be evaluated through the fast-track path of reverse pharmacology.

9.
Schweiz Arch Tierheilkd ; 163(1): 27-42, 2021 Jan.
Artigo em Alemão | MEDLINE | ID: mdl-33528366

RESUMO

INTRODUCTION: Literature review on phyto-therapeutics for the treatment of bovine mastitis.


INTRODUCTION: Afin de trouver une alternative aux traitements antibiotiques conventionnels des mammites bovines, une recherche bibliographique a été menée en 2015 sur les agents phytothérapeutiques qui ont été étudiés in vitro et utilisés in vivo (sur des patients) dans le monde entier. Une recherche bibliographique est l'une des premières étapes du développement d'un agent phytothérapeutique peroral contre les mammites bovines en utilisant la méthode de «pharmacologie inverse¼. Des phytothérapies citées dans le monde entier dans tous les types d'administration ont été compilées et comptées. Un total de 935 citations pertinentes différentes ont été trouvées dans 195 publications, qui ont été séparées et comptées en fonction de leur type d'appli­cation et de l'espèce cible. La liste de toutes les plantes et les citations peuvent être téléchargés à partir de http://vets.ch/desktop/liste-des-plantes_fuchs_def_sat.pdf . On a répertorié dans la présente étude 106 plantes pour l'application perorale, 45 plantes pour l'application intra mammaire et 24 huiles essentielles (perorale, intra mammaire ou topique) pour le traitement des mammites bovines. La condition préalable à cette sélection était que les plantes soient mentionnées dans la littérature comme agent thérapeutique. En outre, il a été pris en compte si des études in vitro ou in vivo avaient déjà été menées. D'une part, cette liste devrait servir de preuve de l'utilisation traditionnelle des plantes dans le traitement des mammites bovines et, d'autre part, constituer une base pour de nouvelles recherches.


Assuntos
Mastite Bovina/terapia , Fitoterapia/veterinária , Animais , Bovinos , Feminino
10.
Mini Rev Med Chem ; 20(14): 1375-1388, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32348219

RESUMO

The scientists, and the researchers around the globe generate tremendous amount of information everyday; for instance, so far more than 74 million molecules are registered in Chemical Abstract Services. According to a recent study, at present we have around 1060 molecules, which are classified as new drug-like molecules. The library of such molecules is now considered as 'dark chemical space' or 'dark chemistry.' Now, in order to explore such hidden molecules scientifically, a good number of live and updated databases (protein, cell, tissues, structure, drugs, etc.) are available today. The synchronization of the three different sciences: 'genomics', proteomics and 'in-silico simulation' will revolutionize the process of drug discovery. The screening of a sizable number of drugs like molecules is a challenge and it must be treated in an efficient manner. Virtual screening (VS) is an important computational tool in the drug discovery process; however, experimental verification of the drugs also equally important for the drug development process. The quantitative structure-activity relationship (QSAR) analysis is one of the machine learning technique, which is extensively used in VS techniques. QSAR is well-known for its high and fast throughput screening with a satisfactory hit rate. The QSAR model building involves (i) chemo-genomics data collection from a database or literature (ii) Calculation of right descriptors from molecular representation (iii) establishing a relationship (model) between biological activity and the selected descriptors (iv) application of QSAR model to predict the biological property for the molecules. All the hits obtained by the VS technique needs to be experimentally verified. The present mini-review highlights: the web-based machine learning tools, the role of QSAR in VS techniques, successful applications of QSAR based VS leading to the drug discovery and advantages and challenges of QSAR.


Assuntos
Desenho de Fármacos , Relação Quantitativa Estrutura-Atividade , Aurora Quinases/antagonistas & inibidores , Aurora Quinases/metabolismo , Ligantes , Aprendizado de Máquina , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
11.
Methods Mol Biol ; 2127: 185-190, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32112323

RESUMO

Over the last decades, the use of heavy-chain-only antibodies has received growing attention in academia and industry as research and diagnostic tools as well as therapeutics. Their generation has improved with the help of innovative new methods such as the sybody technology; however, identifying conformation-selective compounds against membrane proteins remains a major challenge. In this chapter, we apply a thermal shift scintillation proximity assay (SPA-TS) to identify sybodies from an in vitro display campaign with the ability to selectively stabilize the inhibitor-bound conformation of the human solute carrier (SLC) family transporter SC6A9 (GlyT1). Using detergent-purified GlyT1 protein and a tritium-labeled glycine uptake inhibitor small molecule, we find sybody candidates that increase the apparent melting temperature in SPA-TS by several degrees. The thermal shift stabilizes the GlyT1-inhibitor complex and qualifies the sybodies for structural studies and inhibitor-selective small molecule screening assays. The SPA-TS assay in its current form is adaptable to any antibody discovery campaign for membrane proteins and permits the generation of highly valuable tools in most stages of drug discovery and development.


Assuntos
Bioensaio/métodos , Cadeias Pesadas de Imunoglobulinas/isolamento & purificação , Proteínas de Membrana/química , Proteínas de Membrana/imunologia , Animais , Especificidade de Anticorpos , Epitopos/química , Epitopos/imunologia , Epitopos/metabolismo , Glicina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Glicina/química , Proteínas da Membrana Plasmática de Transporte de Glicina/imunologia , Proteínas da Membrana Plasmática de Transporte de Glicina/metabolismo , Humanos , Cadeias Pesadas de Imunoglobulinas/química , Cadeias Pesadas de Imunoglobulinas/metabolismo , Cinética , Proteínas de Membrana/metabolismo , Ligação Proteica , Conformação Proteica , Especificidade por Substrato , Temperatura , Termodinâmica
12.
Trends Pharmacol Sci ; 41(3): 147-161, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31987662

RESUMO

Tetrahydroprotoberberines (THPBs) are a class of compounds that target both dopamine D1 and D2 families of receptors, making them attractive candidates for treating substance use disorder (SUD). The binding of some THPBs to serotonin and adrenergic receptors, in addition to dopamine receptors, gives rise to complex pharmacological profiles. Significant progress has been made over the last decade in examining these compounds for their therapeutic potential. Here, we evaluate recent discoveries relating to the neural mechanism and therapeutic effects of THPBs, focusing on compounds that have shown promise in animal models of SUD and preliminary clinical studies. Advancements in structure-activity relationship studies and in silico modeling of THPB binding to dopamine receptors have facilitated the synthesis of novel THPBs with enhanced therapeutic properties and provide insights regarding use of the THPB scaffold to serve as a template for innovative drug designs.


Assuntos
Alcaloides de Berberina , Berberina , Transtornos Relacionados ao Uso de Substâncias , Animais , Receptores de Dopamina D1 , Receptores de Dopamina D2 , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológico
14.
J Ethnopharmacol ; 223: 135-141, 2018 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-29758341

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Sceletium tortuosum (Mesembryanthemaceae), a succulent plant indigenous to South Africa. is consumed in the form of teas, decoctions and tinctures and is sometimes smoked and used as snuff. In recent years, Sceletium has received a great deal of commercial interest for relieving stress in healthy people, and for treating a broad range of psychological, psychiatric and inflammatory conditions. MATERIAL AND METHODS: The whole extract (Zembrin®) was tested ex vivo in the hippocampus slice preparation after one week of daily oral administration of 5 and 10 mg/kg. Four alkaloids - mesembrine, mesembranol, mesembrenol and mesembrenone - were tested directly in vitro. All four were also tested in the presence of different glutamate receptor agonists. RESULTS: Zembrin® ex vivo as well as all alkaloids in vitro attenuated the amplitude of the population spike during electric stimulation as single shock as well as theta burst stimulation. Only Mesembranol and Mesembrenol having a hydroxyl group at position C6 instead of carbonyl group as in mesembrine and mesembrenone acted by attenuation of AMPA receptor mediated transmission as documented for the whole extract. DISCUSSION: The current experimental series revealed a new physiological effect of Zembrin® on the electric activity of the hippocampus. Attenuation of AMPA mediated transmission has been related to successful adjunctive treatment of epileptic patients. Administered doses of 5 and 10 mg/kg are in line with a dosage of 50 mg/subject as tested clinically. CONCLUSION: We have discovered a new structure activity relationship for Sceletium alkaloids. Since attenuation of AMPA mediated transmission has been related to successful adjunctive treatment of epileptic patients), Mesembrenol and Mesembranol may serve as new chemical leads for the development of new drugs for the treatment of epilepsy.


Assuntos
Hipocampo/efeitos dos fármacos , Alcaloides Indólicos/farmacologia , Mesembryanthemum , Extratos Vegetais/farmacologia , Animais , Hipocampo/metabolismo , Hipocampo/fisiologia , Técnicas In Vitro , Alcaloides Indólicos/química , Masculino , Extratos Vegetais/química , Ratos Sprague-Dawley , Receptores de AMPA/metabolismo , Receptores de Glutamato , Receptores de N-Metil-D-Aspartato/metabolismo , Relação Estrutura-Atividade
15.
Clin Mol Hepatol ; 24(1): 77-87, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29254285

RESUMO

BACKGROUND/AIMS: Hepatic steatosis is caused by an imbalance between free fatty acids (FFAs) uptake, utilization, storage, and disposal. Understanding the molecular mechanisms involved in FFAs accumulation and its modulation could drive the development of potential therapies for Nonalcoholic fatty liver disease. The aim of the current study was to explore the effects of picroside II, a phytoactive found in Picrorhiza kurroa, on fatty acid accumulation vis-à-vis silibinin, a known hepatoprotective phytoactive from Silybum marianum. METHODS: HepG2 cells were loaded with FFAs (oleic acid:palmitic acid/2:1) for 20 hours to mimic hepatic steatosis. The FFAs concentration achieving maximum fat accumulation and minimal cytotoxicity (500 µM) was standardized. HepG2 cells were exposed to the standardized FFAs concentration with and without picroside II pretreatment. RESULTS: Picroside II pretreatment inhibited FFAs-induced lipid accumulation by attenuating the expression of fatty acid transport protein 5, sterol regulatory element binding protein 1 and stearoyl CoA desaturase. Preatreatment with picroside II was also found to decrease the expression of forkhead box protein O1 and phosphoenolpyruvate carboxykinase. CONCLUSIONS: These findings suggest that picroside II effectively attenuated fatty acid accumulation by decreasing FFAs uptake and lipogenesis. Picroside II also decreased the expression of gluconeogenic genes.


Assuntos
Cinamatos/farmacologia , Ácidos Graxos/metabolismo , Glucosídeos Iridoides/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipogênese/efeitos dos fármacos , Animais , Bovinos , Proteínas de Transporte de Ácido Graxo/genética , Proteínas de Transporte de Ácido Graxo/metabolismo , Ácidos Graxos/química , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Gluconeogênese/efeitos dos fármacos , Gluconeogênese/genética , Células Hep G2 , Humanos , Soroalbumina Bovina/química , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
16.
J Ayurveda Integr Med ; 7(4): 238-248, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27914754

RESUMO

BACKGROUND: An unceasing threat of drug resistance continuously poses demand for new antimalarial drugs. A scientific assessment of traditionally used antimalarial plants through reverse pharmacology is crucial for a fast track drug discovery. An Ayurvedic plant Nyctanthes arbor-tristis Linn. - (Parijat) is being used in clinical practice and had shown antimalarial activity, with a parasite clearance in 76.6% of 120 patients, in an earlier clinical study. OBJECTIVE: To further explore antimalarial potential of the plant through additional objective markers. MATERIALS AND METHODS: An open-labelled observational study was conducted at M.A. Podar Hospital - Ayurveda (MAPH-A) after ethics committee approval. Administration of a paste of 5 fresh leaves, thrice a day for a week was a standard practice for management of malaria at MAPH-A. Clinical activity of N. arbor-tristis was evaluated by monitoring pyrexia, parasitemia and morbidity score (MS) in twenty patients. In addition, immune and biochemical markers and organ functions were monitored for objective markers of response. Student's paired-'t' test was applied to assess statistical significance. RESULTS: Ten out of 20 patients showed both fever and parasite clearance, which was confirmed by polymerase chain reaction. Remaining ten patients had persistent but decreasing parasitemia. Four of them needed chloroquine as a fail-safe procedure. Irrespective of the degree of parasitemia all the patients showed decrease in MS. There was also an increase in platelet count and normalization of plasma lactic acid. There was a good clinical tolerability and an improvement in organ function. The inflammatory cytokines showed a reduction; particularly in TNF-α within a day. CONCLUSIONS: At the given dosage, N. arbor-tristis showed disease-modifying activity; early clinical recovery with a decline of TNF-α and a gradual parasite clearance. Further studies with a standardised formulation for dose-searching and optimizing the treatment schedule are needed in a larger sample size. CLINICAL TRIAL REGISTRATION NO: The process of trial registration had not begun when the study was conducted in 2000.

17.
Biomark Res ; 4: 25, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27999673

RESUMO

There is an urgent need for new anti-malaria drugs with broad therapeutic potential and novel mode of action, for effective treatment and to overcome emerging drug resistance. Plant-derived anti-malarials remain a significant source of bioactive molecules in this regard. The multicomponent formulation forms the basis of phytotherapy. Mechanistic reasons for the poly-pharmacological effects of plants constitute increased bioavailability, interference with cellular transport processes, activation of pro-drugs/deactivation of active compounds to inactive metabolites and action of synergistic partners at different points of the same signaling cascade. These effects are known as the multi-target concept. However, due to the intrinsic complexity of natural products-based drug discovery, there is need to rethink the approaches toward understanding their therapeutic effect. This review discusses the multi-target phytotherapeutic concept and its application in biomarker identification using the modified reverse pharmacology - systems biology approach. Considerations include the generation of a product library, high throughput screening (HTS) techniques for efficacy and interaction assessment, High Performance Liquid Chromatography (HPLC)-based anti-malarial profiling and animal pharmacology. This approach is an integrated interdisciplinary implementation of tailored technology platforms coupled to miniaturized biological assays, to track and characterize the multi-target bioactive components of botanicals as well as identify potential biomarkers. While preserving biodiversity, this will serve as a primary step towards the development of standardized phytomedicines, as well as facilitate lead discovery for chemical prioritization and downstream clinical development.

18.
J Bioinform Comput Biol ; 14(5): 1650026, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27431020

RESUMO

Recent molecular studies provide important clues into treatment of [Formula: see text]-thalassemia, sickle-cell anaemia and other [Formula: see text]-globin disorders revealing that increased production of fetal hemoglobin, that is normally suppressed in adulthood, can ameliorate the severity of these diseases. In this paper, we present a novel approach for drug prediction for [Formula: see text]-globin disorders. Our approach is centered upon quantitative modeling of interactions in human fetal-to-adult hemoglobin switch network using hybrid functional Petri nets. In accordance with the reverse pharmacology approach, we pose a hypothesis regarding modulation of specific protein targets that induce [Formula: see text]-globin and consequently fetal hemoglobin. Comparison of simulation results for the proposed strategy with the ones obtained for already existing drugs shows that our strategy is the optimal as it leads to highest level of [Formula: see text]-globin induction and thereby has potential beneficial therapeutic effects on [Formula: see text]-globin disorders. Simulation results enable verification of model coherence demonstrating that it is consistent with qPCR data available for known strategies and/or drugs.


Assuntos
Descoberta de Drogas/métodos , Hemoglobina Fetal/metabolismo , Hemoglobinopatias/tratamento farmacológico , Terapia de Alvo Molecular/métodos , Adulto , Aminopiridinas/farmacologia , Benzamidas/farmacologia , Butiratos/farmacologia , Proteínas de Transporte/antagonistas & inibidores , Hemoglobina Fetal/genética , Hemoglobinopatias/genética , Histona Desacetilase 1/antagonistas & inibidores , Humanos , Hidroquinonas/farmacologia , Fatores de Transcrição Kruppel-Like/antagonistas & inibidores , Modelos Teóricos , Proteínas Nucleares/antagonistas & inibidores , Piridinas/farmacologia , Quinolinas/farmacologia , Proteínas Repressoras , Fatores de Transcrição SOXD/antagonistas & inibidores , Sinvastatina/farmacologia , Globinas beta/genética , gama-Globinas/genética , gama-Globinas/metabolismo
19.
Int J Parasitol Drugs Drug Resist ; 4(3): 338-46, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25516845

RESUMO

Classical pharmacology has been the basis for the discovery of new chemical entities with therapeutic effects for decades. In natural product research, compounds are generally tested in vivo only after full in vitro characterization. However drug screening using this methodology is expensive, time-consuming and very often inefficient. Reverse pharmacology, also called bedside-to-bench, is a research approach based on the traditional knowledge and relates to reversing the classical laboratory to clinic pathway to a clinic to laboratory practice. It is a trans-disciplinary approach focused on traditional knowledge, experimental observations and clinical experiences. This paper is an overview of the reverse pharmacology approach applied to the decoction of Argemone mexicana, used as an antimalarial traditional medicine in Mali. A. mexicana appeared as the most effective traditional medicine for the treatment of uncomplicated falciparum malaria in Mali, and the clinical efficacy of the decoction was comparable to artesunate-amodiaquine as previously published. Four stages of the reverse pharmacology process will be described here with a special emphasis on the results for stage 4. Briefly, allocryptopine, protopine and berberine were isolated through bioguided fractionation, and had their identity confirmed by spectroscopic analysis. The three alkaloids showed antiparasitic activity in vitro, of which allocryptopine and protopine were selective towards Plasmodium falciparum. Furthermore, the amount of the three active alkaloids in the decoction was determined by quantitative NMR, and preliminary in vivo assays were conducted. On the basis of these results, the reverse pharmacology approach is discussed and further pharmacokinetic studies appear to be necessary in order to determine whether these alkaloids can be considered as phytochemical markers for quality control and standardization of an improved traditional medicine made with this plant.

20.
Ayu ; 35(4): 458-61, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-26195913

RESUMO

BACKGROUND: Plants occupy an important place in folk medicine all over the world for centuries and indigenous communities have developed their own specific knowledge on plant resources, uses, management, and conservation. Research interest and activities in the area of ethno medicine have increased tremendously in the last decade. Currently, scientists are evincing keen interest in the scientific evaluation of ethno medical claims. Bark powder of Arjuna (Terminalia arjuna [Roxb.] Wight and Arn) is used by tribals for the management of some painful conditions. AIM: To evaluate analgesic activity of T. arjuna bark in rodents. MATERIALS AND METHODS: For evaluation of analgesic activity, different experimental models, that is, the acetic acid-induced writhing syndrome in mice, formaldehyde-induced paw licking response and tail flick test in rats were designed. Experiments were carried out at two-dose levels, that is, therapeutically equivalent dose (TED) and TED × 2. Animals were divided into three groups (six animals in each group), first group serving as a control group, second and third group labeled as test drug group. RESULTS: Test drug at both the doses significantly decreased the writhing syndrome in comparison to control the group. In comparison to control the group, incidences of formalin-induced paw licking were reduced in test drug groups in both early and late phases of pain. In tail flick response, threshold was significantly increased in both test drug groups at every time intervals. CONCLUSION: Study showed that stem bark of T. arjuna possesses analgesic activity in all experimental models.

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