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1.
BMC Geriatr ; 24(1): 285, 2024 Mar 27.
Artículo en Inglés | MEDLINE | ID: mdl-38532328

RESUMEN

BACKGROUND: Medication management capacity is a crucial component of medication adherence, particularly among older adults. Various factors, including physical abilities, cognitive functions, sensory capabilities, motivational, and environmental factors, influence older adults' ability to manage medications. It is, therefore, crucial to identify appropriate tools that allow clinicians to determine which factors may impact medication management capacity and, consequently, nonadherence to medications. PURPOSE: 1)To identify tools that measure physical, cognitive, sensory (vision, hearing, touch), motivational, and environmental barriers to medication self-management in older adults, and 2) to understand the extent to which these tools assess various barriers. METHODS: The scoping review was conducted using Arksey and O'Malley's scoping review framework and the PRISMA Extension for Scoping Reviews checklist. In June 2022, the relevant literature was identified by searching PubMed (MEDLINE), Ovid Embase, Ovid IPA, EBSCOhost CINAHL, APA PsycINFO, and Scopus. RESULTS AND DISCUSSION: In total, 7235 studies were identified. Following the removal of duplicates, 4607 articles were screened by title and abstract, of which 4253 did not meet the inclusion criteria. Three reviewers reviewed the full texts of the remaining 354 articles; among them, 41 articles, 4 theses and 1 conference abstract met the inclusion criteria. From the included studies, 44 tools were identified that measured a combination of physical, cognitive, sensory, motivational, and environmental barriers (n=19) or only cognition (n=13), vision (n=5), environmental factors (n=3), auditory (n=1), and motivational factors (n=1). The review also examined the psychometric properties of the identified tools and found that most of them had reported validity and reliability data. Several tools have demonstrated promise in assessing a combination of barriers with validity and reliability. These tools include the Self-Medication Assessment Tool (SMAT), ManageMed Screening (MMS), Self-Medication Risk Assessment Tool (RAT), HOME-Rx revised, and Medication Management Ability Assessment (MMAA). CONCLUSION: This scoping review identified 44 validated tools to measure various challenges that older adults encounter with medication management. However, no tool measures all five barriers (physical, cognitive, sensory, motivational, and environmental) to medication-taking at home. Therefore, utilizing a combination of tools would be most appropriate to measure these different aspects comprehensively. Further research is needed to develop a new comprehensive tool that simultaneously measures various barriers to medication self-management.


Asunto(s)
Cognición , Administración del Tratamiento Farmacológico , Humanos , Anciano , Reproducibilidad de los Resultados , Automedicación
2.
Int J Mol Sci ; 25(5)2024 Mar 06.
Artículo en Inglés | MEDLINE | ID: mdl-38474306

RESUMEN

Type 2 diabetes is a chronic metabolic disorder characterized by high blood glucose levels due to either insufficient insulin production or ineffective utilization of insulin by the body. The enzyme dipeptidyl peptidase IV (DPP IV) plays a crucial role in degrading incretins that stimulate insulin secretion. Therefore, the inhibition of DPP IV is an established approach for the treatment of diabetes. Hemorphins are a class of short endogenous bioactive peptides produced by the enzymatic degradation of hemoglobin chains. Numerous in vitro and in vivo physiological effects of hemorphins, including DPP IV inhibiting activity, have been documented in different systems and tissues. However, the underlying molecular binding behavior of these peptides with DPP IV remains unknown. Here, computational approaches such as protein-peptide molecular docking and extensive molecular dynamics (MD) simulations were employed to identify the binding pose and stability of peptides in the active site of DPP IV. Findings indicate that hemorphins lacking the hydrophobic residues LVV and VV at the N terminal region strongly bind to the conserved residues in the active site of DPP IV. Furthermore, interactions with these critical residues were sustained throughout the duration of multiple 500 ns MD simulations. Notably, hemorphin 7 showed higher binding affinity and sustained interactions by binding to S1 and S2 pockets of DPP IV.


Asunto(s)
Diabetes Mellitus Tipo 2 , Inhibidores de la Dipeptidil-Peptidasa IV , Humanos , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Simulación del Acoplamiento Molecular , Dipeptidil Peptidasa 4/metabolismo , Péptidos/química , Insulina , Simulación de Dinámica Molecular
3.
Int J Mol Sci ; 25(12)2024 Jun 13.
Artículo en Inglés | MEDLINE | ID: mdl-38928234

RESUMEN

Mcl-1 (myeloid cell leukemia 1), a member of the Bcl-2 family, is upregulated in various types of cancer. Peptides representing the BH3 (Bcl-2 homology 3) region of pro-apoptotic proteins have been demonstrated to bind the hydrophobic groove of anti-apoptotic Mcl-1, and this interaction is responsible for regulating apoptosis. Structural studies have shown that, while there is high overall structural conservation among the anti-apoptotic Bcl-2 (B-cell lymphoma 2) proteins, differences in the surface groove of these proteins facilitates binding specificity. This binding specificity is crucial for the mechanism of action of the Bcl-2 family in regulating apoptosis. Bim-based peptides bind specifically to the hydrophobic groove of Mcl-1, emphasizing the importance of these interactions in the regulation of cell death. Molecular docking was performed with BH3-like peptides derived from Bim to identify high affinity peptides that bind to Mcl-1 and to understand the molecular mechanism of their interactions. The interactions of three identified peptides, E2gY, E2gI, and XXA1_F3dI, were further evaluated using 250 ns molecular dynamics simulations. Conserved hydrophobic residues of the peptides play an important role in their binding and the structural stability of the complexes. Understanding the molecular basis of interaction of these peptides will assist in the development of more effective Mcl-1 specific inhibitors.


Asunto(s)
Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , Péptidos , Unión Proteica , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/química , Humanos , Péptidos/química , Péptidos/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/metabolismo , Interacciones Hidrofóbicas e Hidrofílicas , Sitios de Unión , Secuencia de Aminoácidos , Proteína 11 Similar a Bcl2/metabolismo , Proteína 11 Similar a Bcl2/química
4.
Mar Drugs ; 20(12)2022 Dec 13.
Artículo en Inglés | MEDLINE | ID: mdl-36547924

RESUMEN

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by elevated levels of blood glucose due to insulin resistance or insulin-secretion defects. The development of diabetes is mainly attributed to the interaction of several complex pathogenic, genetic, environmental and metabolic processes. Dipeptidyl peptidase-4 (DPP-4) is a serine protease that cleaves X-proline dipeptides from the N-terminus of several polypeptides, including natural hypoglycemic incretin hormones. Inhibition of this enzyme restores and maintains glucose homeostasis, making it an attractive drug target for the management of T2DM. Natural products are important sources of bioactive agents for anti-T2DM drug discovery. Marine ecosystems are a rich source of bioactive products and have inspired the development of drugs for various human disorders, including diabetes. Here, structure-based virtual screening and molecular docking were performed to identify antidiabetic compounds from the Comprehensive Marine Natural Products Database (CMNPD). The binding characteristics of two shortlisted compounds, CMNPD13046 and CMNPD17868, were assessed using molecular dynamics simulations. Thus, this study provides insights into the potential antidiabetic activity and the underlying molecular mechanism of two compounds of marine origin. These compounds could be investigated further for the development of potent DPP-4 inhibitors.


Asunto(s)
Productos Biológicos , Bases de Datos Farmacéuticas , Inhibidores de la Dipeptidil-Peptidasa IV , Hipoglucemiantes , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores de la Dipeptidil-Peptidasa IV/química , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Ecosistema , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Productos Biológicos/química , Productos Biológicos/farmacología , Relación Estructura-Actividad , Evaluación Preclínica de Medicamentos
5.
J Dairy Sci ; 104(7): 7393-7405, 2021 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-33934858

RESUMEN

Novel antihypercholesterolemic bioactive peptides (BAP) from peptic camel whey protein hydrolysates (CWPH) were generated at different time, temperature, and enzyme concentration (%). Hydrolysates showed higher pancreatic lipase- (PL; except 3 CWPH) and cholesterol esterase (CE)-inhibiting potential, as depicted by lower half-maximal inhibitory concentration values (IC50 values) compared with nonhydrolyzed camel whey proteins (CWP). Peptide sequencing and in silico data depicted that most BAP from CWPH could bind active site of PL, whereas as only 3 peptides could bind the active site of CE. Based on higher number of reactive residues in the BAP and greater number of substrate binding sites, FCCLGPVPP was identified as a potential CE-inhibitory peptide, and PAGNFLPPVAAAPVM, MLPLMLPFTMGY, and LRFPL were identified as PL inhibitors. Molecular docking of selected peptides showed hydrophilic and hydrophobic interactions between peptides and target enzymes. Thus, peptides derived from CWPH warrant further investigation as potential candidates for adjunct therapy for hypercholesterolemia.


Asunto(s)
Camelus , Esterol Esterasa , Animales , Lipasa , Simulación del Acoplamiento Molecular , Péptidos , Hidrolisados de Proteína , Suero Lácteo , Proteína de Suero de Leche
6.
Int J Mol Sci ; 22(1)2020 Dec 28.
Artículo en Inglés | MEDLINE | ID: mdl-33379211

RESUMEN

Hemorphins are known for their role in the control of blood pressure. Recently, we revealed the positive modulation of the angiotensin II (AngII) type 1 receptor (AT1R) by LVV-hemorphin-7 (LVV-H7) in human embryonic kidney (HEK293) cells. Here, we examined the molecular binding behavior of LVV-H7 on AT1R and its effect on AngII binding using a nanoluciferase-based bioluminescence resonance energy transfer (NanoBRET) assay in HEK293FT cells, as well as molecular docking and molecular dynamics (MD) studies. Saturation and real-time kinetics supported the positive effect of LVV-H7 on the binding of AngII. While the competitive antagonist olmesartan competed with AngII binding, LVV-H7 slightly, but significantly, decreased AngII's kD by 2.6 fold with no effect on its Bmax. Molecular docking and MD simulations indicated that the binding of LVV-H7 in the intracellular region of AT1R allosterically potentiates AngII binding. LVV-H7 targets residues on intracellular loops 2 and 3 of AT1R, which are known binding sites of allosteric modulators in other GPCRs. Our data demonstrate the allosteric effect of LVV-H7 on AngII binding, which is consistent with the positive modulation of AT1R activity and signaling previously reported. This further supports the pharmacological targeting of AT1R by hemorphins, with implications in vascular and renal physiology.


Asunto(s)
Angiotensina II/metabolismo , Hemoglobinas/metabolismo , Fragmentos de Péptidos/metabolismo , Receptor de Angiotensina Tipo 1/metabolismo , Células HEK293 , Humanos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular
7.
J Dairy Sci ; 102(12): 10748-10759, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31548068

RESUMEN

Novel bioactive peptides from camel milk protein hydrolysates (CMPH) were identified and tested for inhibition of cholesterol esterase (CEase), and their possible binding mechanisms were elucidated by molecular docking. Papain-generated CMPH showed the highest degree of hydrolysis. All CMPH produced upon enzymatic degradation demonstrated a dramatic enhancement of CEase inhibition compared with intact camel milk proteins, with papain-generated hydrolysate P9 displaying the highest inhibition. Peptide identification and their modeling through PepSite 2 revealed that among 20 potential bioactive peptides in alcalase-generated hydrolysate A9, only 3 peptides, with sequences KFQWGY, SQDWSFY, and YWYPPQ, showed the highest binding toward CEase catalytic sites. Among 43 peptides in 9-h papain-generated hydrolysate P9, 4 peptides were found to be potent CEase inhibitors. Molecular docking revealed that WPMLQPKVM, CLSPLQMR, MYQQWKFL, and CLSPLQFR from P9 hydrolysates were able to bind to the active site of CEase with good docking scores and molecular mechanics-generalized born surface area binding energies. Overall, this is the first study reporting CEase inhibitory potential of peptides generated from milk proteins.


Asunto(s)
Camelus , Inhibidores Enzimáticos/aislamiento & purificación , Proteínas de la Leche/química , Péptidos/química , Esterol Esterasa/antagonistas & inhibidores , Animales , Camelus/metabolismo , Inhibidores Enzimáticos/química , Femenino , Leche/química , Simulación del Acoplamiento Molecular , Papaína/química , Péptidos/aislamiento & purificación , Hidrolisados de Proteína/química , Subtilisinas/química
8.
Crit Rev Food Sci Nutr ; 58(15): 2491-2507, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-28609132

RESUMEN

The enduring relationship between dietary patterns and human health has led us to investigate the bioactive components present in fruits and vegetables for a very long time. Berries, notably the popular ones such as strawberry, raspberry, blueberry, blackberry, and the Indian gooseberry, are among the best known dietary sources due to the presence of a wide range of bioactive nutritive components. Bioactive components in berries include phenolic compounds, flavonoids, and tannins apart from vitamins, minerals, sugars, and fibers. Individually or synergistically, these have been shown to provide protection against several disorders. Mounting evidence suggests that consumption of berries confer antioxidant and anticancer protection to humans and animals. Free radical scavenging, protection from DNA damage, induction of apoptosis, and inhibition of growth and proliferation of cancer cells are just to name a few. This review comprehensively summarizes the key phytochemicals present in berries and their biological action in preventing oxidative stress and carcinogenesis.


Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Antioxidantes/química , Antioxidantes/farmacología , Frutas/química , Animales , Humanos , Neoplasias/tratamiento farmacológico , Fitoquímicos/química , Fitoquímicos/farmacología , Fitoterapia
9.
Biomedicines ; 11(12)2023 Dec 04.
Artículo en Inglés | MEDLINE | ID: mdl-38137438

RESUMEN

Methylmalonic aciduria and homocystinuria type C protein (MMACHC) is required by the body to metabolize cobalamin (Cbl). Due to its complex structure and cofactor forms, Cbl passes through an extensive series of absorptive and processing steps before being delivered to mitochondrial methyl malonyl-CoA mutase and cytosolic methionine synthase. Depending on the cofactor attached, MMACHC performs either flavin-dependent reductive decyanation or glutathione (GSH)-dependent dealkylation. The alkyl groups of Cbl have to be removed in the presence of GSH to produce intermediates that can later be converted into active cofactor forms. Pathogenic mutations in the GSH binding site, such as R161Q, R161G, R206P, R206W, and R206Q, have been reported to cause Cbl diseases. The impact of these variations on MMACHC's structure and how it affects GSH and Cbl binding at the molecular level is poorly understood. To better understand the molecular basis of this interaction, mutant structures involving the MMACHC-MeCbl-GSH complex were generated using in silico site-directed point mutations and explored using molecular dynamics (MD) simulations. The results revealed that mutations in the key arginine residues disrupt GSH binding by breaking the interactions and reducing the free energy of binding of GSH. Specifically, variations at position 206 appeared to produce weaker GSH binding. The lowered binding affinity for GSH in the variant structures could impact metabolic pathways involving Cbl and its trafficking.

10.
JMIR Aging ; 6: e50990, 2023 Dec 19.
Artículo en Inglés | MEDLINE | ID: mdl-38113067

RESUMEN

BACKGROUND: Older adults often face challenges in self-managing their medication owing to physical and cognitive limitations, complex medication regimens, and packaging of medications. Emerging smart medication dispensing and adherence products (SMAPs) offer the options of automated dispensing, tracking medication intake in real time, and reminders and notifications. A 2021 review identified 51 SMAPs owing to the rapid influx of digital technology; an update to this review is required. OBJECTIVE: This review aims to identify new products and summarize and compare the key features of SMAPs. METHODS: Gray and published literature and videos were searched using Google, YouTube, PubMed, Embase, and Scopus. The first 10 pages of Google and the first 100 results of YouTube were screened using 4 and 5 keyword searches, respectively. SMAPs were included if they were able to store and allowed for the dispensation of medications, tracked real-time medication intake data, and could automatically analyze data. Products were excluded if they were stand-alone software applications, not marketed in English, not for in-home use, or only used in clinical trials. In total, 5 researchers independently screened and extracted the data. RESULTS: This review identified 114 SMAPs, including 80 (70.2%) marketed and 34 (29.8%) prototypes, grouped into 15 types. Among the marketed products, 68% (54/80) were available for consumer purchase. Of these products, 26% (14/54) were available worldwide and 78% (42/54) were available in North America. There was variability in the hardware, software, data collection and management features, and cost of the products. Examples of hardware features include battery life, medication storage capacity, availability of types and number of alarms, locking features, and additional technology required for use of the product, whereas software features included reminder and notification capabilities and availability of manufacturer support. Data capture methods included the availability of sensors to record the use of the product and data-syncing capabilities with cloud storage with short-range communications. Data were accessible to users via mobile apps or web-based portals. Some SMAPs provided data security assurance with secure log-ins (use of personal identification numbers or facial recognition), whereas other SMAPs provided data through registered email addresses. Although some SMAPs were available at set prices or free of cost to end users, the cost of other products varied based on availability, shipping fees, and subscription fees. CONCLUSIONS: An expanding market for SMAPs with features specific to at-home patient use is emerging. Health care professionals can use these features to select and suggest products that meet their patients' unique requirements.

11.
Front Oncol ; 11: 664403, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34055630

RESUMEN

Carnosol, a natural polyphenol abundant in edible plants such as sage, rosemary, and oregano, has shown promising anticancer activity against various types of cancers. Nonetheless, very little is known about its molecular mechanism of action or its downstream target(s). We have previously shown that carnosol inhibits cellular proliferation, migration, invasion, and metastasis as well as triggers autophagy and apoptosis in the highly invasive MDA-MB-231 breast cancer cells. Here, we report that carnosol induces histone hypoacetylation in MDA-MB-231 and Hs578T breast cancer cells. We show that, while carnosol does not affect HDACs, it promotes a ROS-dependent proteasome degradation of p300 and PCAF histone acetyl transferases (HATs) without affecting other HATs such as GCN5 and hMOF. Carnosol-induced histone hypoacetylation remains persistent even when p300 and PCAF protein levels were rescued from degradation by (i) the inhibition of the proteasome activity by the proteasome inhibitors MG-132 and bortezomib, and (ii) the inhibition of ROS accumulation by the ROS scavenger, N-acetylcysteine. In addition, we report that, in a cell-free system, carnosol efficiently inhibits histone acetyltransferase activity of recombinant p300 but not that of PCAF or GCN5. Molecular docking studies reveal that carnosol inhibits p300 HAT activity by blocking the entry of the acetyl-CoA binding pocket of the catalytic domain. The superimposition of the docked conformation of the p300 HAT domain in complex with carnosol shows a similar orientation as the p300 structure with acetyl-CoA. Carnosol occupies the region where the pantetheine arm of the acetyl-CoA is bound. This study further confirms carnosol as a promising anti-breast cancer therapeutic compound and identifies it as a novel natural p300 inhibitor that could be added to the existing panel of inhibitors.

12.
Front Genet ; 10: 17, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30838017

RESUMEN

Camels have an important role in the lives of human beings, especially in arid regions, due to their multipurpose role and unique ability to adapt to harsh conditions. In spite of its enormous economic, cultural, and biological importance, the camel genome has not been widely studied. The size of camel genome is roughly 2.38 GB, containing over 20,000 genes. The unusual genetic makeup of the camel is the main reason behind its ability to survive under extreme environmental conditions. The camel genome harbors several unique variations which are being investigated for the treatment of several disorders. Various natural products from camels have also been tested and prescribed as adjunct therapy to control the progression of ailments. Interestingly, the camel employs unique immunological and molecular mechanisms against pathogenic agents and pathological conditions. Here, we broadly review camel classification, distribution and breed as well as recent progress in the determination of the camel genome, its size, genetic distribution, response to various physiological conditions, immunogenetics and the medicinal potential of camel gene products.

13.
Sci Rep ; 9(1): 14747, 2019 10 14.
Artículo en Inglés | MEDLINE | ID: mdl-31611567

RESUMEN

Hemorphins are atypical endogenous opioid peptides produced by the cleavage of hemoglobin beta chain. Several studies have reported the therapeutic potential of hemorphin in memory enhancement, blood regulation, and analgesia. However, the mode of interaction of hemorphin with its target remains largely elusive. The decapeptide LVV-hemorphin-7 is the most stable form of hemorphin. It binds with high affinity to mu-opioid receptors (MOR), angiotensin-converting enzyme (ACE) and insulin-regulated aminopeptidase (IRAP). In this study, computational methods were used extensively to elucidate the most likely binding pose of mammalian LVV-hemorphin-7 with the aforementioned proteins and to calculate the binding affinity. Additionally, alignment of mammalian hemorphin sequences showed that the hemorphin sequence of the camel harbors a variation - a Q > R substitution at position 8. This study also investigated the binding affinity and the interaction mechanism of camel LVV-hemorphin-7 with these proteins. To gain a better understanding of the dynamics of the molecular interactions between the selected targets and hemorphin peptides, 100 ns molecular dynamics simulations of the best-ranked poses were performed. Simulations highlighted major interactions between the peptides and key residues in the binding site of the proteins. Interestingly, camel hemorphin had a higher binding affinity and showed more interactions with all three proteins when compared to the canonical mammalian LVV-hemorphin-7. Thus, camel LVV-hemorphin-7 could be explored as a potent therapeutic agent for memory loss, hypertension, and analgesia.


Asunto(s)
Hemoglobinas/metabolismo , Fragmentos de Péptidos/metabolismo , Secuencia de Aminoácidos , Animales , Hemoglobinas/química , Humanos , Modelos Moleculares , Fragmentos de Péptidos/química , Peptidil-Dipeptidasa A/química , Peptidil-Dipeptidasa A/metabolismo , Unión Proteica , Dominios y Motivos de Interacción de Proteínas , Mapas de Interacción de Proteínas , Receptores Opioides mu/química , Receptores Opioides mu/metabolismo , Alineación de Secuencia
14.
Front Pharmacol ; 10: 1258, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31708782

RESUMEN

Hemorphins are hemoglobin ß-chain-derived peptides initially known for their analgesic effects via binding to the opioid receptors belonging to the family of G protein-coupled receptor (GPCR), as well as their physiological action on blood pressure. However, their molecular mechanisms in the regulation of blood pressure are not fully understood. Studies have reported an antihypertensive action via the inhibition of the angiotensin-converting enzyme, a key enzyme in the renin-angiotensin system. In this study, we hypothesized that hemorphins may also target angiotensin II (AngII) type 1 receptor (AT1R) as a key GPCR in the renin-angiotensin system. To investigate this, we examined the effects of LVV-hemorphin-7 on AT1R transiently expressed in human embryonic kidney (HEK293) cells using bioluminescence resonance energy transfer (BRET) technology for the assessment of AT1R/Gαq coupling and ß-arrestin 2 recruitment. Interestingly, while LVV-hemorphin-7 alone had no significant effect on BRET signals between AT1R and Gαq or ß-arrestin 2, it nicely potentiated AngII-induced BRET signals and significantly increased AngII potency. The BRET data were also correlated with AT1R downstream signaling with LVV-hemorphin-7 potentiating the canonical AngII-mediated Gq-dependent inositol phosphate pathway as well as the activation of the extracellular signal-regulated kinases (ERK1/2). Both AngII and LVV-hemorphin-7-mediated responses were fully abolished by AT1R antagonist demonstrating the targeting of the active conformation of AT1R. Our data report for the first time the targeting and the positive modulation of AT1R signaling by hemorphins, which may explain their role in the physiology and pathophysiology of both vascular and renal systems. This finding further consolidates the pharmacological targeting of GPCRs by hemorphins as previously shown for the opioid receptors in analgesia opening a new era for investigating the role of hemorphins in physiology and pathophysiology via the targeting of GPCR pharmacology and signaling.

15.
Nat Prod Res ; 32(24): 2928-2931, 2018 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-29022361

RESUMEN

Lung cancer is a deadly form of cancer with high morbidity and mortality rates. Deregulated receptor tyrosine kinases (RTKs) are frequently associated with the formation and development of lung carcinoma. Quercetin is a major dietary flavonoid that has been shown to induce cell growth inhibition and apoptosis in human lung cancer cell lines. In the current study, four major overexpressed RTKs - EGFR, FGFR1, IGF1R and c-Met - involved in human lung cancer were investigated. Molecular docking was employed to identify the binding orientation and inhibitory potential of quercetin in these RTKs. Quercetin bound to the ATP binding pocket of these kinases exhibited good binding scores and interactions by establishing hydrogen, hydrophobic and π-π interactions with the hinge region and the DFG motif in the activation loop. Thus, quercetin could be further explored as a platform for developing specific or polypharmacological compounds targeting overexpressed RTKs in lung cancer.


Asunto(s)
Neoplasias Pulmonares/tratamiento farmacológico , Simulación del Acoplamiento Molecular/métodos , Quercetina/farmacología , Apoptosis/efectos de los fármacos , Bases de Datos de Proteínas , Receptores ErbB/química , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/patología , Proteínas Proto-Oncogénicas c-met/química , Proteínas Proto-Oncogénicas c-met/metabolismo , Quercetina/química , Quercetina/metabolismo , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/química , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/metabolismo , Receptor IGF Tipo 1 , Receptores de Somatomedina/química , Receptores de Somatomedina/metabolismo
16.
Artículo en Inglés | MEDLINE | ID: mdl-30533869

RESUMEN

Here, we report the draft genome sequence of Bacillus cereus strain UAEU-H3K6M1, which was isolated from petroleum sludge in the desert. It is composed of around 5.4 Mbp and has a GC content of 35%. Functional annotation and pathway modeling showed multiple genes with potential bioremediation abilities.

18.
J Mol Model ; 22(11): 272, 2016 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-27783229

RESUMEN

Phosphatidylinositols and their phosphorylated derivatives, phosphoinositides, play a central role in regulating diverse cellular functions. These phospholipids have been shown to interact with the hydrophobic TH domain of the tumor necrosis factor (TNF)-α-induced protein 8 (TIPE) family of proteins. However, the precise mechanism of interaction of these lipids is unclear. Here we report the binding mode and interactions of these phospholipids in the TH domain, as elucidated using molecular docking and simulations. Results indicate that phosphoinositides bind to the TH domain in a similar way by inserting their lipid tails in the hydrophobic cavity. The exposed head group is stabilized by interactions with critical positively charged residues on the surface of these proteins. Further MD simulations confirmed the dynamic stability of these lipids in the TH domain. This computational analysis thus provides insight into the binding mode of phospholipids in the TH domain of the TIPE family of proteins. Graphical abstract A phosphoinositide (phosphatidylinositol 4-phosphate; PtdIns4P) docked to TIPE2.


Asunto(s)
Péptidos y Proteínas de Señalización Intracelular/química , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Fosfatidilinositoles/química , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Fosfatidilinositoles/metabolismo , Unión Proteica , Dominios Proteicos
19.
Drug Des Devel Ther ; 10: 3109-3123, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27729770

RESUMEN

Polypharmacology, the discovery or design of drug molecules that can simultaneously interact with multiple targets, is gaining interest in contemporary drug discovery. Serine/threonine kinases are attractive targets for therapeutic intervention in oncology due to their role in cellular phosphorylation and altered expression in cancer. Quercetin, a naturally occurring flavonoid, inhibits multiple cancer cell lines and is used as an anticancer drug in Phase I clinical trial. Quercetin glycosides have also received some attention due to their high bioavailability and activity against various diseases including cancer. However, these have been studied to a lesser extent. In this study, the structural basis of the multitarget inhibitory activity of quercetin and isoquercitrin, a glycoside derivative, on serine/threonine kinases using molecular modeling was explored. Structural analysis showed that both quercetin and isoquercitrin exhibited good binding energies and interacted with aspartate in the highly conserved Asp-Phe-Gly motif. The results indicate that isoquercitrin could be a more potent inhibitor of several members of the serine/threonine kinase family. In summary, the current structural evaluation highlights the multitarget inhibitory property of quercetin and its potential to be a chemical platform for oncological polypharmacology.


Asunto(s)
Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Quercetina/farmacología , Humanos , Ligandos , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/metabolismo , Quercetina/química , Relación Estructura-Actividad
20.
Bioinformation ; 11(6): 316-21, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26229293

RESUMEN

Inspite of the large body of genomic data obtained from the transcriptome of Zingiber officinale, very few studies have focused on the identification and characterization of miRNAs in gingerol biosynthesis. Zingiber officinale transcriptome was analyzed using EST dataset (38169 total) deposited in public domains. In this paper computational functional annotation of the available ESTs and identification of genes which play a significant role in gingerol biosynthesis are described. Zingiber officinale transcriptome was analyzed using EST dataset (38169 total) from ncbi. ESTs were clustered and assembled, resulting in 8624 contigs and 8821 singletons. Assembled dataset was then submitted to the EST functional annotation workflow including blast, gene ontology (go) analysis, and pathway enrichment by kyoto encyclopedia of genes and genomes (kegg) and interproscan. The unigene datasets were further exploited to identify simple sequence repeats that enable linkage mapping. A total of 409 simple sequence repeats were identified from the contigs. Furthermore we examined the existence of novel miRNAs from the ESTs in rhizome, root and leaf tissues. EST analysis revealed the presence of single hypothetical miRNA in rhizome tissue. The hypothetical miRNA is warranted to play an important role in controlling genes involved in gingerol biosynthesis and hence demands experimental validation. The assembly and associated information of transcriptome data provides a comprehensive functional and evolutionary characterization of genomics of Zingiber officinale. As an effort to make the genomic and transcriptomic data widely available to the public domain, the results were integrated into a web-based Ginger EST database which is freely accessible at http://www.kaubic.in/gingerest/.

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