Результаты поиска

Структура-ориентированное исследование ДНК-аптамера, целевого PTK7, выявляет сложную 3D-составляющую, направляющую оптимизацию функции.

DNA аптамеры вышли в качестве новых молекулярных инструментов в терапевтической и диагностической медицине благодаря своей высокой аффинности и специфичности к белковым целям, что определяется их способностью сворачиваться в отличительные трехмерные (3D) структуры. Однако при проектировании и моделировании аптамеров часто игнорируются тонкие атомные взаимодействия, формирующие 3D структуры, что приводит к неэффективной оптимизации функциональных свойств. Проблемы сохраняются при определении высокоразрешающих структур комплексов аптамер-белок. Кроме того, экспериментально определенные 3D структ

Aptamer Therapeutics in Cancer: Current and Future.

Aptamer-related technologies represent a revolutionary advancement in the capacity to rapidly develop new classes of targeting ligands. Structurally distinct RNA and DNA oligonucleotides, aptamers mimic small, protein-binding molecules and exhibit high binding affinity and selectivity. Although their molecular weight is relatively small-approximately one-tenth that of monoclonal antibodies-their complex tertiary folded structures create sufficient recognition surface area for tight interaction with target molecules. Additionally, unlike antibodies, aptamers can be readily chemically synthesize

Three- размерная структура комплекса Palbociclib-HIV TAR.

Мы представляем структуру HIV-1 элемент реакции на трансактивацию (TAR), связанный с киназным ингибитором palbociclib, однозначным лигандом nM и ингибитором с низким значением nM комплекса супер удлинения. Маленькая молекула перестраивает РНК, чтобы создать глубокий связующий карман в новой структуре ТАР. Он заменяет A22 на "интермолекулярную пару" с U40, создавая постоянно сложенную пару. 11 спираль, которая включает в себя three :: новые три базы, включая саму A22 и нуклеотиды UCU. Мутация нуклеотидов в связующем кармане или небольшие модификации малой молекулы, отменяющей связующую способно

Targeted synthesis of a trimethoxyphenyltetrahydropyrimidine analogue designed as a DNA intercalator: in silico, multi-spectroscopic, thermodynamic, and in vitro approaches.

Based on the rational design of DNA intercalators and Topo-II inhibitors and taking into consideration the main pharmacophoric features of doxorubicin (Dox) as a reference standard, we theoretically designed novel substituted tetrahydropyrimidine analogues (T1-35). The designed analogues (T1-35) were investigated for their inhibitory potential towards the hybrid DNA and Topo-II target receptor using molecular docking. Interestingly, the theoretically designed analogue T30 with a 3,4,5-trimethoxy phenyl side chain was found to be the superior candidate, achieving a binding score of -7.06 kcal m

Dual COX-2/TNF-α Inhibitors as Promising Anti-inflammatory and Cancer Chemopreventive Agents: A Review.

Cyclooxygenases (COX) play a pivotal role in inflammation and are responsible for the production of prostaglandins (PGs). Two types of COXs have been identified as key biological targets for drug design: Constitutive COX-1 and inducible COX-2. Nonsteroidal anti-inflammatory drugs (NSAIDs) target COX-1, while selective COX-2 inhibitors are designed for COX-2. These COX isoforms are involved in multiple physiological and pathological pathways throughout the body. Overproduction of tumor necrosis factor-alpha (TNF-α) plays a role in COX-2's inflammatory activity. Tumor necrosis factor-alpha can c

Unlocking the Heterogeneity in Acute Leukaemia: Dissection of Clonal Architecture and Metabolic Properties for Clinical Interventions.

Genetic studies of haematological cancers have pointed out the heterogeneity of leukaemia in its different subpopulations, with distinct mutations and characteristics, impacting the treatment response. Next-generation sequencing (NGS) and genome-wide analyses, as well as single-cell technologies, have offered unprecedented insights into the clonal heterogeneity within the same tumour. A key component of this heterogeneity that remains unexplored is the intracellular metabolome, a dynamic network that determines cell functions, signalling, epigenome regulation, immunity and inflammation. Unders

Совпадение в полном тексте источника
… Nucleotide Metabolism Cancer cell growth and proliferation depend on de novo nucleotide synthesis from intermediates in the TCA cycle, glucose-derived ribose sugars from the pentose phosphate pathway (PPP) and amino acids that generate purines and pyrimidine nucleotides. …

BET bromodomain protein inhibition is a therapeutic option for medulloblastoma.

Medulloblastoma is the most common malignant brain tumor of childhood, and represents a significant clinical challenge in pediatric oncology, since overall survival currently remains under 70%. Patients with tumors overexpressing MYC or harboring a MYC oncogene amplification have an extremely poor prognosis. Pharmacologically inhibiting MYC expression may, thus, have clinical utility given its pathogenetic role in medulloblastoma. Recent studies using the selective small molecule BET inhibitor, JQ1, have identified BET bromodomain proteins, especially BRD4, as epigenetic regulatory factors for

Изучение связи между 91 циркуляцией воспламенительных протеинов и нейродегенеративными заболеваниями: двухнаправленный анализ менделей и биоинформатики.

Циркуляция подстрекательских белков играет важную роль в патогенезе нейродегенеративных заболеваний (НДД). Однако точная причинно-следственная связь и механизмы, лежащие в основе их взаимодействия, по-прежнему остаются неясными. МЕТОДЫ: В каталоге GWAS были получены данные по 91 циркуляционному подстрекательскому протеину в рамках исследования ассоциации геномов (GWAS). Кроме того, данные GWAS о болезни Паркинсона (PD), болезни Альцгеймера (AD), амиотропическом боковом склерозе (ALS), множественном склерозе (MS) и ишемическом инсульте (IS) были получены в рамках проекта IEU Open GWAS. Для анал

A case-control study of a combination of single nucleotide polymorphisms and clinical parameters to predict clinically relevant toxicity associated with fluoropyrimidine and platinum-based chemotherapy in gastric cancer.

BACKGROUND: Fluoropyrimidine plus platinum chemotherapy remains the standard first line treatment for gastric cancer (GC). Guidelines exist for the clinical interpretation of four DPYD genotypes related to severe fluoropyrimidine toxicity within European populations. However, the frequency of these single nucleotide polymorphisms (SNPs) in the Latin American population is low (< 0.7%). No guidelines have been development for platinum. Herein, we present association between clinical factors and common SNPs in the development of grade 3-4 toxicity. METHODS: Retrospectively, 224 clinical records

Clinical relevance of a pharmacogenetic approach using multiple candidate genes to predict response and resistance to imatinib therapy in chronic myeloid leukemia.

PURPOSE: Imatinib resistance is major cause of imatinib mesylate (IM) treatment failure in chronic myeloid leukemia (CML) patients. Several cellular and genetic mechanisms of imatinib resistance have been proposed, including amplification and overexpression of the BCR/ABL gene, the tyrosine kinase domain point mutations, and MDR1 gene overexpression. EXPERIMENTAL DESIGN: We investigated the impact of 16 single nucleotide polymorphisms (SNP) in five genes potentially associated with pharmacogenetics of IM, namely ABCB1, multidrug resistance 1; ABCG2, breast-cancer resistance protein; CYP3A5, c

Drug repurposing for breast cancer therapy: Old weapon for new battle.

Despite tremendous resources being invested in prevention and treatment, breast cancer remains a leading cause of cancer deaths in women globally. The available treatment modalities are very costly and produces severe side effects. Drug repurposing that relate to new uses for old drugs has emerged as a novel approach for drug development. Repositioning of old, clinically approved, off patent non-cancer drugs with known targets, into newer indication is like using old weapons for new battle. The advances in genomics, proteomics and information computational biology has facilitated the process o

Mitochondrial Genetic and Epigenetic Regulations in Cancer: Therapeutic Potential.

Mitochondria are dynamic organelles managing crucial processes of cellular metabolism and bioenergetics. Enabling rapid cellular adaptation to altered endogenous and exogenous environments, mitochondria play an important role in many pathophysiological states, including cancer. Being under the control of mitochondrial and nuclear DNA (mtDNA and nDNA), mitochondria adjust their activity and biogenesis to cell demands. In cancer, numerous mutations in mtDNA have been detected, which do not inactivate mitochondrial functions but rather alter energy metabolism to support cancer cell growth. Increa

The Potential Role of Sildenafil in Cancer Management through EPR Augmentation.

Enhanced permeation retention (EPR) was a significant milestone discovery by Maeda et al. paving the path for the emerging field of nanomedicine to become a powerful tool in the fight against cancer. Sildenafil is a potent inhibitor of phosphodiesterase 5 (PDE-5) used for the treatment of erectile dysfunction (ED) through the relaxation of smooth muscles and the modulation of vascular endothelial permeability. Overexpression of PDE-5 has been reported in lung, colon, metastatic breast cancers, and bladder squamous carcinoma. Moreover, sildenafil has been reported to increase the sensitivity of

Role of Fibroblast Growth Factors Receptors (FGFRs) in Brain Tumors, Focus on Astrocytoma and Glioblastoma.

Despite pharmacological treatments and surgical practice options, the mortality rate of astrocytomas and glioblastomas remains high, thus representing a medical emergency for which it is necessary to find new therapeutic strategies. Fibroblast growth factors (FGFs) act through their associated receptors (FGFRs), a family of tyrosine kinase receptors consisting of four members (FGFR1-4), regulators of tissue development and repair. In particular, FGFRs play an important role in cell proliferation, survival, and migration, as well as angiogenesis, thus their gene alteration is certainly related

Биоразлагаемый электроспун PLGA Nanofibers-Encapsolated Trichinella Sphiralis Antigens защищает от повторного использования экспериментального аутоиммунного энцефаломилита и связанного с ним микробиота дисбиоз.

ЦЕЛЬ: &quot; Тричинелла спиралис &quot; создала сложные механизмы иммуномодуляции при посредничестве экскременто-секретарских продуктов (ESL1), которые позволяют ей выжить в принимающей стране. Следовательно, антигены ESL1 обладают прекрасным потенциалом для лечения аутоиммунных заболеваний, таких, как множественный склероз (MS). Однако вопрос о том, могут ли своевременные контролируемые поставки антигенов ESL1 в vivo, как и в случае естественных инфекций, повысить его терапевтический потенциал в отношении MS, до сих пор неизвестен.Для этого мы ввели антигены ESL1 в полихлорированные (лактидно

Role of Cyclin-Dependent Kinase Inhibitors in Endometrial Cancer.

Endometrial Cancer (EC) is an important cause of death in women worldwide. Despite early diagnosis and optimal treatment of localized disease, relapsed patients have few therapeutic options because after first line therapy, currently no standard of care exists. On the basis of endocrine positivity of most endometrioid ECs, Endocrine Therapy (ET) is a reasonable and widely accepted option. Better knowledge of molecular mechanisms involved in cancer highlighted the deregulated activity of Cyclin-Dependent Kinases (CDKs) in the cell cycle as a hallmark of carcinogenesis supporting the development

Реконструкция петли антикодона и форма D-стима приводят к конкретному распознаванию ANN-декодирования tRNA для модификации t6A.

N6-threonylcarbamoyladenosine (t6A) — универсальная трансфертная модификация RNA (tRNA), необходимая для перевода. Модификация устанавливается в положение 37 ANN-декодирование tRNAs (N is A, U, G или C) путем переноса треонилкарбамойла из промежуточного пути, катализированного в бактериях комплексом ЦаБД. Несмотря на строгое требование в отношении 36-UAA-38 Последовательность в субстрате tRNS, структурная основа этой специфичности остается неясной. Мы определили крио-эм-структуры "Термотога маритима Т6А" синтазы, связанные с немодифицированной и изначально модифицированной ТRNA с модификацией

FDA-Approved Small Molecule Compounds as Drugs for Solid Cancers from Early 2011 to the End of 2021.

Solid cancers are the most common types of cancers diagnosed globally and comprise a large number of deaths each year. The main challenge currently in drug development for tumors raised from solid organs is to find more selective compounds, which exploit specific molecular targets. In this work, the small molecule drugs registered by the Food and Drug Administration (FDA) for solid cancers treatment between 2011 and 2022 were identified and analyzed by investigating a type of therapy they are used for, as well as their structures and mechanisms of action. On average, 4 new small molecule agent

Ультрафиолетовое излучение и нейродегенерация: молекулярные механизмы, лежащие в основе двойного нейрозащитного и нейротоксичного воздействия.

Ультрафиолетовое излучение имеет сложную, зачастую противоречивую связь с риском/прогрессом нейродегенерации, охватывающую клинически диагностированные заболевания [Заболевания Паркинсона (PD), болезни Альцгеймера (AD), множественный склероз (MS) и амиотропический боковой склероз (ALS)] или промежуточные фенотипы (уменьшенный нейрогенесис, потеря гиппокампального объема). Цель этого обзора заключается в выявлении двойного воздействия УФ-излучения путем сбора и обобщения экспериментальных (доклинических и переводческих) данных, а также эпидемиологических данных. Нынешняя литература демонстрируе

Association of genetic polymorphisms in the influx transporter SLCO1B3 and the efflux transporter ABCB1 with imatinib pharmacokinetics in patients with chronic myeloid leukemia.

This study explored the association of 14 single nucleotide polymorphisms in three genes coding for influx transporters (SLC22A1, SLCO1B1, and SLCO1B3), two genes coding for efflux transporters (ABCB1 and ABCG2), and four genes coding for enzymes (CYP2C9, CYP2C19, CYP2D6, and CYP3A5) with the pharmacokinetics of imatinib in Japanese patients with chronic myeloid leukemia. Pharmacokinetic parameters were estimated by a population pharmacokinetic analysis based on 622 plasma samples from 34 patients at steady state. Approximately 4.6-fold variability in individual clearance was observed (range,