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Robotic lower-limb prostheses, with their actively powered joints, may significantly improve amputee users' mobility and enable them to obtain healthy-like gait in various modes of locomotion in daily life. However, timely recognition of the amputee users' locomotive mode and mode transition still remains a major challenge in robotic lower-limb prosthesis control. In the paper, the authors present a new multi-dimensional dynamic time warping (mDTW)-based intent recognizer to provide high-accuracy recognition of the locomotion mode/mode transition sufficiently early in the swing phase, such that the prosthesis' joint-level motion controller can operate in the correct locomotive mode and assist the user to complete the desired (and often power-demanding) motion in the stance phase. To support the intent recognizer development, the authors conducted a multi-modal gait data collection study to obtain the related sensor signal data in various modes of locomotion. The collected data were then segmented into individual cycles, generating the templates used in the mDTW classifier. Considering the large number of sensor signals available, we conducted feature selection to identify the most useful sensor signals as the input to the mDTW classifier. We also augmented the standard mDTW algorithm with a voting mechanism to make full use of the data generated from the multiple subjects. To validate the proposed intent recognizer, we characterized its performance using the data cumulated at different percentages of progression into the gait cycle (starting from the beginning of the swing phase). It was shown that the mDTW classifier was able to recognize three locomotive mode/mode transitions (walking, walking to stair climbing, and walking to stair descending) with 99.08% accuracy at 30% progression into the gait cycle, well before the stance phase starts. With its high performance, low computational load, and easy personalization (through individual template generation), the proposed mDTW intent recognizer may become a highly useful building block of a prosthesis control system to facilitate the robotic prostheses' real-world use among lower-limb amputees.
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This paper introduces a novel wearable shoe sensor named the Smart Lacelock Sensor. The sensor can be securely attached to the top of a shoe with laces and incorporates a loadcell to measure the force applied by the shoelace, providing valuable information related to ankle movement and foot loading. As the first step towards the automated balance assessment, this paper investigates the correlations between various levels of physical performance measured by the wearable Smart Lacelock Sensor and the SPPB clinical method in community-living older persons. 19 adults (age 76.84 ± 3.45 years), including those with and without recent fall history and SPPB score ranging from 4 to 12, participated in the study. The Smart Lacelock Sensor was attached to both shoes of each participant by skilled research staff, who then led them through the SPPB evaluation. The data obtained from the Smart Lacelock Sensors after the SPPB assessment were used to evaluate the deviation between the SPPB scores assigned by the research staff and the signals generated by the sensors for various participants. Results demonstrate that the standard deviation of the Smart Lacelock Sensor's loadcell response (both feet) for the side-by-side balance testing is significantly correlated (R2 = 0.68) with the SPPB score, demonstrating the capability of the Smart Lacelock Sensor in balance assessment.
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Pie , Vida Independiente , Adulto , Humanos , Anciano , Anciano de 80 o más Años , Extremidad Inferior , Articulación del Tobillo , Rendimiento Físico FuncionalRESUMEN
Phytochemicals are bioactive agents present in medicinal plants with therapeutic values. Phytochemicals isolated from plants target multiple cellular processes. In the current work, we have used fractionation techniques to identify 13 bioactive polyphenols in ayurvedic medicine Haritaki Churna. Employing the advanced spectroscopic and fractionation, structure of bioactive polyphenols was determined. Blasting the phytochemical structure allow us to identify a total of 469 protein targets from Drug bank and Binding DB. Phytochemicals with their protein targets from Drug bank was used to create a phytochemical-protein network comprising of 394 nodes and 1023 edges. It highlights the extensive cross-talk between protein target corresponding to different phytochemicals. Analysis of protein targets from Binding data bank gives a network comprised of 143 nodes and 275 edges. Taking the data together from Drug bank and binding data, seven most prominent drug targets (HSP90AA1, c-Src kinase, EGFR, Akt1, EGFR, AR, and ESR-α) were found to be target of the phytochemicals. Molecular modelling and docking experiment indicate that phytochemicals are fitting nicely into active site of the target proteins. The binding energy of the phytochemicals were better than the inhibitors of these protein targets. The strength and stability of the protein ligand complexes were further confirmed using molecular dynamic simulation studies. Further, the ADMET profiles of phytochemicals extracted from HCAE suggests that they can be potential drug targets. The phytochemical cross-talk was further proven by choosing c-Src as a model. HCAE down regulated c-Src and its downstream protein targets such as Akt1, cyclin D1 and vimentin. Hence, network analysis followed by molecular docking, molecular dynamics simulation and in-vitro studies clearly highlight the role of protein network and subsequent selection of drug candidate based on network pharmacology.Communicated by Ramaswamy H. Sarma.
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Walking in real-world environments involves constant decision-making, e.g., when approaching a staircase, an individual decides whether to engage (climbing the stairs) or avoid. For the control of assistive robots (e.g., robotic lower-limb prostheses), recognizing such motion intent is an important but challenging task, primarily due to the lack of available information. This paper presents a novel vision-based method to recognize an individual's motion intent when approaching a staircase before the potential transition of motion mode (walking to stair climbing) occurs. Leveraging the egocentric images from a head-mounted camera, the authors trained a YOLOv5 object detection model to detect staircases. Subsequently, an AdaBoost and gradient boost (GB) classifier was developed to recognize the individual's intention of engaging or avoiding the upcoming stairway. This novel method has been demonstrated to provide reliable (97.69%) recognition at least 2 steps before the potential mode transition, which is expected to provide ample time for the controller mode transition in an assistive robot in real-world use.
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Intención , Robótica , Humanos , CaminataRESUMEN
Haritaki churna (HC), a single herb ayurvedic formulations is known to be prescribed for various gastro-intestinal disorders in Ayurveda. Haritaki churna aqueous extract (HCAE) has anti-cancer activity against different types of cancer cells with an IC50 in the range of 50-97 µg/ml. Bioavailability of Haritaki Churna is very high in digestive track and treatment of colorectal cancer cells HCT-116, DLD1, HT-29 with HCAE reduces its cellular viability with anti-cancer IC50 70µg/ml. HCAE consumption is safe for human as it didn't affect the cellular viability of primary human PBMCs or non-cancerogenic HEK-293 cells. Haritaki churna was found to be stable in biological gastric fluids and bioactive agents are not losing their anti-cancer activity under such harsh conditions. The HPLC Chromatogram of HCAE is giving 13 major peaks and 11 minor peaks. Exploiting LC-MS, IR and NMR spectroscopic techniques, a total of 13 compounds were identified from HCAE namely Shikimic acid, Chebulic acid, gallic acid, 5-hydroxymethylfurfural, Protocatechuic acid, 4-O-galloyl-shikimic Acid, 5-O-galloyl-shikimic Acid, Methylgallate, corilagin, 1, 2, 6, Tri-O-galloyl ß-D-glucose, chebulagic acid, chebulinic acid, and Ellagic acid. Reconstitution and subtraction of phytochemicals from the mixture indicate that Ellagic acid significantly contribute into anti-cancer effect of HCAE. Cancer cells treated with ellagic acid from HCAE were incapable of completing their cell-cycle and halted the cell-cycle at DNA synthesis S-Phase, as demonstrated by decreased cyclin A2 expression levels with increasing ellagic acid concentration. Halting of cells at S-phase causes induction of apoptosis in cancer cells. Cancer cells exhibiting DNA fragmentation, changes in expression of several apoptotic proteins such as Bcl2, cytochrome-c and formation of cleaved products of caspase 3 and PARP-1 suggests ellagic acid induces cell death via mitochondrial pathway of apoptosis.
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Ácido Elágico , Extractos Vegetales , Humanos , Extractos Vegetales/farmacología , Extractos Vegetales/química , Ácido Elágico/farmacología , Células HEK293 , Ácido Shikímico , Fitoquímicos/farmacologíaRESUMEN
A new dimeric prenylated quinolone alkaloid, named 2,11-didemethoxy-vepridimerine A, was isolated from the root bark of Zanthoxylum rhetsa, together with twelve known compounds. The structure of the new compound was elucidated on the basis of spectroscopic investigations (NMR and Mass). The interaction of the isolated compounds with the main protease of SARS-CoV-2 (Mpro) was evaluated using molecular docking followed by MD simulations. The result suggests that 2,11-didemethoxy-vepridimerine A, the new compound, has the highest negative binding affinity against the Mpro with a free energy of binding of -8.5 Kcal/mol, indicating interaction with the Mpro. This interaction was further validated by 100 ns MD simulation. This implies that the isolated new compound, which can be employed as a lead compound for an Mpro-targeting drug discovery program, may be able to block the action of Mpro.
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Alcaloides , Antineoplásicos , COVID-19 , Quinolonas , Zanthoxylum , SARS-CoV-2 , Simulación del Acoplamiento Molecular , Alcaloides/farmacología , Polímeros , Inhibidores de Proteasas , Simulación de Dinámica MolecularRESUMEN
Tubulin inhibitors are conjugates that interfere with the dynamic equilibrium of the polymerization and depolymerization of microtubules. Among all the reported conjugates, indole moiety is one of the most significant classes for the development of new drug candidates for cancer therapy. Due to their presence in a wide range of natural as well as synthetic antitubulin agents, indole has become a versatile scaffold in research, and various synthetic and semisynthetic indole-based antitubulin agents have been identified and reported. The present article focuses on the reported indole-based tubulin inhibitors of synthetic origin from last the decade. Synthesis, structure-activity relationships and biological activities of synthetic indole derivatives along with brief updates on their antitubulin activity are presented.
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Indoles/farmacología , Moduladores de Tubulina/farmacología , Tubulina (Proteína)/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Indoles/química , Estructura Molecular , Relación Estructura-Actividad , Moduladores de Tubulina/químicaRESUMEN
Alzheimer's disease is a common and most chronic neurological disorder (NDs) associated with cognitive dysfunction. Pathologically, Alzheimer's disease (AD) is characterized by the presence of ß-amyloid (Aß) plaques, hyper-phosphorylated tau proteins, and neurofibrillary tangles, however, persistence oxidative-nitrative stress, endoplasmic reticulum stress, mitochondrial dysfunction, inflammatory cytokines, pro-apoptotic proteins along with altered neurotransmitters level are common etiological attributes in its pathogenesis. Rivastigmine, memantine, galantamine, and donepezil are FDA approved drugs for symptomatic management of AD, whereas tacrine has been withdrawn because of hepatotoxic profile. These approved drugs only exert symptomatic relief and exhibit poor patient compliance. In the current scenario, the number of published evidence shows the neuroprotective potential of naturally occurring bioactive molecules via their antioxidant, anti-inflammatory, antiapoptotic and neurotransmitter modulatory properties. Despite their potent therapeutic implications, concerns have arisen in context to their efficacy and probable clinical outcome. Thus, to overcome these glitches, many heterocyclic and cyclic hydrocarbon compounds inspired by natural sources have been synthesized and showed improved therapeutic activity. Computational studies (molecular docking) have been used to predict the binding affinity of these natural bioactive as well as synthetic compounds derived from natural sources for the acetylcholine esterase, α/ß secretase Nuclear Factor kappa- light-chain-enhancer of activated B cells (NF-kB), Nuclear factor erythroid 2-related factor 2(Nrf2) and other neurological targets. Thus, in this review, we have discussed the molecular etiology of AD, focused on the pharmacotherapeutics of natural products, chemical and pharmacological aspects and multi-targeted designed ligands (MTDLs) of synthetic and semisynthetic molecules derived from the natural sources along with some important on-going clinical trials.
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Enfermedad de Alzheimer , Productos Biológicos/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Diseño de Fármacos , Humanos , Ligandos , Simulación del Acoplamiento MolecularRESUMEN
BACKGROUND: The adenoma-carcinoma sequence in thyroid nodules is an enigmatic phenomenon. Genomics is the only definitive modality to resolve this hypothesis. Adenomas and papillary carcinomas tend to have mutations in RAS and highly specific BRAF gene respectively. In this context, we set out study the prevalence and clinical significance of these somatic mutations in surgical tissue samples. MATERIAL AND METHODS: This retrospective study was conducted on surgically managed thyroid nodule patients. Institutional ethical committee approval was obtained. Diagnosis was based on biochemical confirmation, imaging, fine needle aspiration cytology and later confirmed by histopathology. We selected 100 benign thyroid adenomas (BTA) and 100 papillary thyroid carcinoma (PTC) cases. Archived tumour tissue samples of selected cases were retrieved. After appropriate processing of samples, DNA extraction, cDNA preparation, PCR amplification, application of 4 sets of Primers were performed as part of mutational analysis of RAS (H-,K-,N-) and BRAF genes. RESULTS: Homozygous mutations in N-RAS were found in 36/100 (36%) of BTA and 7/100 (7%) of PTC cases. No H-RAS or K-RAS mutations were found in both groups. Homozygous mutations were found in BRAF gene in 4/100 (4%) of BTA cases and 52/100 (52%) of PTC cases. The differences were statistically significant. CONCLUSIONS: Similar N-RAS and BRAF mutations were prevalent in both benign and malignant thyroid nodules giving some evidence for linkage between them. Though not robust, we opine that there is possibility of adenoma-carcinoma sequence in thyroid nodules.
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In the present scenario, there has been a lot of consideration toward the field of free radical chemistry. Free radicals responsive oxygen species are produced by different endogenous frameworks, exposure to various physicochemical conditions, radiation, toxins, metabolized drug by-product, and pathological states. On the off chance that free radical overpowers the body's capacity, it generates a condition known as oxidative stress, which can alter physiological conditions of the body and results in several diseases. For appropriate physiological function, it is necessary to have a proper balance between free radicals and antioxidants. Antioxidants chemically inhibit the oxidation process; they are also known as free radical scavengers. For tackling the problem of oxidative stress application of an external source of antioxidant is helpful. A lot of antioxidants of natural, semi-synthetic and synthetic origin are in use, with time search of more effective, nontoxic, safe antioxidant is intensified. The present review, discuss different synthetic derivatives bearing various heterocyclic scaffolds as radical scavengers.
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Depuradores de Radicales Libres/química , Depuradores de Radicales Libres/farmacología , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacología , Animales , Descubrimiento de Drogas , HumanosRESUMEN
In this study, two series of imidazopyridine-linked thiazolidinone rings (5a-h and 6a-h) constituting 16 new compounds were synthesized and tested for their antiproliferative activity against a panel of three human cancer cell lines, that is, MCF-7 (human breast cancer), A549 (human lung cancer), and DU145 (human prostate cancer). Three compounds, 5h, 6f, and 6h, exhibited remarkable results against all three cell lines, but compound 6h was found to be the most active one against the breast cancer cell line. Among all the synthesized compounds, 6h displayed the highest antioxidant results. Furthermore, the potent compounds 5h, 6f, and 6h showed no signs of toxicity at doses ranging from 50 to 500 mg/kg of animal body weight. The biochemical parameters (SGOT and SGPT) of compound 6h nearly matched the control in hepatotoxicity studies. The molecular docking and MM-GBSADG binding studies are in agreement with the in vitro anticancer and antioxidant activity results. The most promising compound 6h was found to have the highest docking score and binding energy, and its absorption, distribution, metabolism, and excretion (ADME) parameters are in the acceptable range. Thus, it can be concluded that 6h, an imidazopyridine derivative endowed with a thiazolidinone ring system, has the potential to be developed as an anticancer agent.
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Antineoplásicos/farmacología , Imidazoles/farmacología , Piridinas/farmacología , Tiazolidinas/farmacología , Células A549 , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Diseño de Fármacos , Femenino , Humanos , Imidazoles/síntesis química , Imidazoles/química , Neoplasias Pulmonares/tratamiento farmacológico , Células MCF-7 , Masculino , Simulación del Acoplamiento Molecular , Neoplasias de la Próstata/tratamiento farmacológico , Piridinas/síntesis química , Piridinas/química , Ratas , Ratas Wistar , Tiazolidinas/síntesis química , Tiazolidinas/química , Pruebas de ToxicidadRESUMEN
Background: Vinclozolin (VCZ) is a widely used antifungal agent with capability to enter into the human food chain. VCZ metabolizes into seven metabolites M1-M7. Several studies have shown its effects on reprotoxicity. However, there is limited information available on the interaction of VCZ metabolites with nuclear receptors. In silico studies aimed at identifying interaction of endocrine disruptor with nuclear receptors serve a prescreening framework in risk assessment.Methods: We studied interactive potential of VCZ and its metabolites with human estrogen (ER) and androgen receptor (AR) using molecular docking method. Binding potential of VCZ and its metabolites with estrogen receptors 1GWR-α, 1QKM and androgen receptor 2AM9-ß was checked by using Schrodinger Maestro 10.5. Estradiol (E2), a natural ligand of ER and AR was taken as a reference.Results: VCZ and its metabolites showed higher or similar binding efficiency on interaction with target proteins when compared with E2. VCZ and its metabolites also exhibited agonistic effect against 1GWR-α, 1QKM and 2AM9-ß with strong binding potential to them.Conclusion: Some VCZ metabolites such as M4 and M5 showed higher binding potencies with 1GWR-α, 1QKM and 2AM9-ß than E2. Toxicity data of VCZ is well endowed. However, endocrine disrupting potential of VCZ via nuclear receptor mediated pathway is less understood. This in silico study revealing that not only VCZ but its metabolites have potential to interact with 1GWR-α, 1QKM and 2AM9-ß offers a platform for further exploration of VCZ in this direction.
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Disruptores Endocrinos/química , Disruptores Endocrinos/toxicidad , Receptor alfa de Estrógeno/química , Oxazoles/química , Oxazoles/toxicidad , Receptores Androgénicos/química , Sitios de Unión , Unión Competitiva , Cristalografía por Rayos X , Disruptores Endocrinos/metabolismo , Receptor alfa de Estrógeno/metabolismo , Humanos , Enlace de Hidrógeno , Ligandos , Simulación del Acoplamiento Molecular , Oxazoles/metabolismo , Unión Proteica , Receptores Androgénicos/metabolismoRESUMEN
Gliflozins constitute an important class of compounds useful as sodium glucose co-transporter (SGLT2) inhibitors to treat type-II diabetes. They act by blocking sodium-glucose transport protein 2 which is responsible for re-absorption of glucose in the proximal convoluted tubule (PCT) of kidney and thus its inhibition reduces blood glucose level. There are a number of gliflozins which have been approved by drug regulatory bodies like FDA, EMA and PMDA whereas some others are in pipeline in their late developmental phases. The present review article offers a detailed account of synthetic strategies employed for the synthesis, alternate synthetic routes along with Structure Activity Relationship (SAR) studies of well-established as well as newly developed SGLT2 inhibitors.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glucósidos/farmacología , Hipoglucemiantes/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Transportador 2 de Sodio-Glucosa/metabolismo , Animales , Diabetes Mellitus Tipo 2/metabolismo , Relación Dosis-Respuesta a Droga , Glucósidos/síntesis química , Glucósidos/química , Humanos , Hipoglucemiantes/síntesis química , Hipoglucemiantes/química , Estructura Molecular , Inhibidores del Cotransportador de Sodio-Glucosa 2/síntesis química , Inhibidores del Cotransportador de Sodio-Glucosa 2/química , Relación Estructura-ActividadRESUMEN
Free radicals generated due to exposure of radiation, environmental pollutants and as by-products of metabolised drugs. These free radicals are antagonized by molecules which are antioxidant in nature. Antioxidants are the substances which inhibit oxidation. They are moreover acknowledged as "free radical scavengers" as they form minor reactive species via radicals. Based on origin, they are categorised into two types: exogenous and endogenous antioxidants. An Antioxidant reduces the occurrence of different disorders like: aging, cancer, diabetes, inflammation, liver disease, cardiovascular disease, cataract and nephrotoxicity and neurodegenerative disorders. Dietary antioxidants are thought to have potential capacities to avert oxidative anxiety induced diseases. This review figures the various researches on pharmacological activity of natural along with synthetic antioxidant molecules.
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Antioxidantes/farmacología , Antioxidantes/química , Radicales Libres/química , Radicales Libres/farmacología , Humanos , Estrés Oxidativo/efectos de los fármacosRESUMEN
A series of 9-(2-(1-arylethylidene)hydrazinyl)acridine and its analogs were designed, synthesized and evaluated for biological activities. Various biochemical assays were performed to determine the free radical scavenging capacity of synthesized compounds (4a-4j). Anticancer activity of these compounds was assessed against two different human cancer cell lines viz cervical cancer cells (HeLa) and liver cancer cells (HepG2) as well as normal human embryonic kidney cell line (HEK 293). Compounds 4b, 4d and 4e showed potential anti-proliferative effects on HeLa cells. Based on results obtained from antioxidant and cytotoxicity studies, 4b, 4d and 4e were further studied in detail for different biological activities. 4b, 4d and 4e reduced the cell growth, inhibited metastatic activity and declined the potential of cell migration in HeLa cell lines. Topoisomerase1 (Top1) treated with compounds 4b, 4d and 4e exhibited inhibition of Top1 and prevented DNA replication. Molecular docking results validate that interaction of compounds 4b, 4d and 4e with Top1-DNA complex, which might be accountable for their inhibitory effects. Further it was concluded that compounds 4b, 4d and 4e arrests the cells at S phase and consequently induces cell death through DNA damage in HeLa cells.
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Acridinas/farmacología , Antineoplásicos/farmacología , ADN-Topoisomerasas de Tipo I/metabolismo , Inhibidores de Topoisomerasa I/farmacología , Acridinas/síntesis química , Acridinas/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células HEK293 , Células HeLa , Humanos , Estructura Molecular , Relación Estructura-Actividad , Inhibidores de Topoisomerasa I/síntesis química , Inhibidores de Topoisomerasa I/químicaRESUMEN
Microtubules are a protein which is made of α- and ß-heterodimer. It is one of the main components of the cell which play a vital role in cell division especially in G2/M-phase. It exists in equilibrium dynamic of polymerization and depolymerization of α- and ß-heterodimer. It is one of the best targets for developing anti-cancer drugs. Various natural occurring molecules are well known for their anti-tubulin effect such as vinca, paclitaxel, combretastatin, colchicine etc. These microtubule-targeted drugs are acted through two processes (i) inhibiting depolymerization of tubulin (tubulin stabilizing agents) and (ii) inhibiting polymerization of tubulin (tubulin destabilizing agents). Now days, various binding domains have been explore through which these molecules are binding to tubulin but the three major binding domain of tubulin are taxol, vinca and colchicine binding domain. The present article mainly focus on the classification of various naturally occurring compounds on the basis of their inhibition processes (depolymerization and polymerization) and the site of interaction (targets taxol, vinca and colchicine binding domain) which has been hitherto reported. By placing all the naturally occurring taxol, vinca and colchicine binding site analogues at one place makes a better understanding of the tubulin interactions with known natural tubulin binders that would helps in the discovery of new and potent natural, semi-synthetic and synthetic analogues for treating cancer.
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Productos Biológicos/farmacología , Colchicina/farmacología , Paclitaxel/farmacología , Tubulina (Proteína)/metabolismo , Vinca/química , Sitios de Unión/efectos de los fármacos , Productos Biológicos/síntesis química , Productos Biológicos/química , Colchicina/síntesis química , Colchicina/química , Relación Dosis-Respuesta a Droga , Estructura Molecular , Paclitaxel/síntesis química , Paclitaxel/química , Polimerizacion/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
Alzheimer, the fourth leading cause of death embodies a key responsible event including formation of ß-amyloid protein clustering to amyloid plaque on blood vessels. The origin of above events is Amyloid precursor protein (APP) which is an integral membrane protein known for its function in synapses formation. Modern research had proposed that the over expression of DYRK1A (Dual specificity tyrosine phosphorylation regulated kinase1A, a family of protein kinases, positioned within the Down's syndrome critical region (DSCR) on human chromosome 21causes phosphorylation of APP protein resulting in its cleavage to Aß 40, 42 and tau proteins (regulated by beta and gamma secretase) which plays critical role in early onset of Alzheimer's disease (AD) detected in Down's syndrome (DS), leading to permanent functional and structural deformities which results ultimately into neuro-degeneration and neuronal death. Therefore, DYRK1A emerges as a potential target for prevention of neuro-degeneration and hence Alzheimer. Presently, the treatment methods for Down's syndrome, as well as Alzheimer's disease are extremely biased and represent a major deficiency for therapeutic necessities. We hereby, focus our review on the current status of the research and contributions in the development of DYRK1A inhibitors.
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Enfermedad de Alzheimer/tratamiento farmacológico , Síndrome de Down/tratamiento farmacológico , Descubrimiento de Drogas/métodos , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/fisiopatología , Animales , Diseño Asistido por Computadora , Síndrome de Down/metabolismo , Síndrome de Down/fisiopatología , Humanos , Terapia Molecular Dirigida/métodos , Neurogénesis/efectos de los fármacos , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Quinasas DyrKRESUMEN
Graviola (Annona muricata) is a small deciduous tropical evergreen fruit tree, belonging to the Annonaceae family, and is widely grown and distributed in tropical and subtropical regions around the world. The aerial parts of graviola have several functions: the fruits have been widely used as food confectionaries, while several preparations, especially decoctions of the bark, fruits, leaves, pericarp, seeds, and roots, have been extensively used in traditional medicine to treat multiple ailments including cancers by local communities in tropical Africa and South America. The reported therapeutic benefits of graviola against various human tumors and disease agents in in vitro culture and preclinical animal model systems are typically tested for their ability to specifically target the disease, while exerting little or no effect on normal cell viability. Over 212 phytochemical ingredients have been reported in graviola extracts prepared from different plant parts. The specific bioactive constituents responsible for the major anticancer, antioxidant, anti-inflammatory, antimicrobial, and other health benefits of graviola include different classes of annonaceous acetogenins (metabolites and products of the polyketide pathway), alkaloids, flavonoids, sterols, and others. This review summarizes the current understanding of the anticancer effects of A. muricata and its constituents on diverse cancer types and disease states, as well as efficacy and safety concerns. It also includes discussion of our current understanding of possible mechanisms of action, with the hope of further stimulating the development of improved and affordable therapies for a variety of ailments.
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Annona/química , Antineoplásicos , HumanosRESUMEN
New N3-benzylidene (substituted)-2-phenyl-N4-(thiazol-2-yl)-quinazoline-3,4-(4H)-diamine derivatives were design and synthesized by a sequence of reactions starting from appropriate 6-methyl anthranilic acid. The title compounds were screened for in vitro dipeptidyl peptidase IV (DPP-4) inhibitory activity and diphenyl-2-picryl-hydrazyl (DPPH) assay and results showed significant to good activity in compared to Linagliptin for antidiabetic activity and Ascorbic acid for antioxidant activity. Compound 7g (IC50=0.76nM) exhibited most promising DPP-4 inhibitory activity and also showed good antioxid and result. Docking study was also performed to provide an insight about the binding mode into binding sites of DPP-4 enzyme. Hopefully in future, compound 7g could be used as a lead compound for developing new antidiabetic agent with good antioxidant property.
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Antioxidantes/química , Diabetes Mellitus Experimental/tratamiento farmacológico , Inhibidores de la Dipeptidil-Peptidasa IV/química , Diseño de Fármacos , Hipoglucemiantes/química , Quinazolinas/química , Animales , Antioxidantes/síntesis química , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Compuestos de Bifenilo/antagonistas & inhibidores , Diabetes Mellitus Experimental/enzimología , Dipeptidil Peptidasa 4/metabolismo , Inhibidores de la Dipeptidil-Peptidasa IV/síntesis química , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Radicales Libres/antagonistas & inhibidores , Hipoglucemiantes/síntesis química , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Simulación del Acoplamiento Molecular , Picratos/antagonistas & inhibidores , Quinazolinas/síntesis química , Quinazolinas/farmacología , Quinazolinas/uso terapéutico , Ratas Wistar , Tiazoles/síntesis química , Tiazoles/química , Tiazoles/farmacología , Tiazoles/uso terapéuticoRESUMEN
OBJECTIVE: The present review article presented a detailed account of the design strategies and the structure activity relationship of different derivatives apart from the nitrogen containing ring. These scaffolds play an important part in the drug discovery which showed anticancer activity against different human cancer cell lines through apoptosis, cell cycle arrest, inhibiting kinases, angiogenesis, disruption of cell migration, modulation of nuclear receptor responsiveness and others. Naphthalenes amides/amidines, furan, podophyllotoxin, platinum compounds, steroids, and urea, which forms the core part or along with other N-heterocyclic rings are enclosed. Some of these compounds e.g. podophyllotoxin and platinum based drugs displayed anticancer activity at nanomolar range. Various substitutions from the earlier and latest information are prerequisite in the drug synthesis process. CONCLUSION: The review focused on the recent development of these derivatives, design and anticancer properties, thus providing with the most profound knowledge for the development of targeted based anticancer drugs.