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Transcription Termination Factor 1 (TTF1) is a multifunctional mammalian protein with vital roles in various cellular processes, including Pol I-mediated transcription initiation and termination, pre-rRNA processing, chromatin remodelling, DNA damage repair, and polar replication fork arrest. It comprises of two distinct functional regions; the N-terminal regulatory region (1-445 aa), and the C-terminal catalytic region (445-859 aa). The Myb domain located at the C-terminal region is a conserved DNA binding domain spanning from 550 to 732 aa (183 residues). Despite its critical role in various cellular processes, the physical structure of TTF1 remains unsolved. Attempts to purify the functional TTF1 protein have been unsuccessful till date. Therefore, we focused on characterizing the Myb domain of this essential protein. We started with predicting a 3-D model of the Myb domain using homology modelling, and ab-initio method. We then determined its stability through MD simulation in an explicit solvent. The model predicted is highly stable, which stabilizes at 200ns. To experimentally validate the computational model, we cloned and expressed the codon optimized Myb domain into a bacterial expression vector and purified the protein to homogeneity. Further, characterization of the protein shows that, Myb domain is predominantly helical (65%) and is alone sufficient to bind the Sal Box DNA. This is the first-ever study to report a complete in-silico model of the Myb domain, which is physically characterized. The above study will pave the way towards solving the atomic structure of this essential mammalian protein.
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During embryonic development the placental vasculature acts as a major hematopoietic niche, where endothelial to hematopoietic transition ensures emergence of hematopoietic stem cells (HSCs). However, the molecular mechanisms that regulate the placental hematoendothelial niche are poorly understood. Using a parietal trophoblast giant cell (TGC)-specific knockout mouse model and single-cell RNA-sequencing, we show that the paracrine factors secreted by the TGCs are critical in the development of this niche. Disruptions in the TGC-specific paracrine signaling leads to the loss of HSC population and the concomitant expansion of a KDR+/DLL4+/PROM1+ hematoendothelial cell-population in the placenta. Combining single-cell transcriptomics and receptor-ligand pair analyses, we also define the parietal TGC-dependent paracrine signaling network and identify Integrin signaling as a fundamental regulator of this process. Our study elucidates novel mechanisms by which non-autonomous signaling from the primary parietal TGCs maintain the delicate placental hematopoietic-angiogenic balance and ensures embryonic and extraembryonic development.
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The physiological parameters such as growth, Chl a content, and photosynthetic performance of the experimental cyanobacterium Anabaenopsis circularis HKAR-22 were estimated to evaluate the cumulative effects of photosynthetically active radiation (PAR) and ultraviolet (UV) radiation. Maximum induction of UV-screening molecules, MAAs, was observed under the treatment condition of PAR + UV-A + UV-B (PAB) radiations. UV/VIS absorption spectroscopy and HPLC-PDA detection primarily confirmed the presence of MAA-shinorine (SN) having absorption maxima (λmax) at 332.3 nm and retention time (RT) of 1.47 min. For further validation of the presence of SN, HRMS, FTIR and NMR were utilized. UV-stress elevated the in vivo ROS scavenging and in vitro enzymatic antioxidant capabilities. SN exhibited substantial and concentration-dependent antioxidant capabilities which was determined utilizing 2,2-diphenyl-1-picryl-hydrazyl (DPPH), 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonate (ABTS), ferric reducing power (FRAP) and superoxide radical scavenging assay (SRSA). The density functional theory (DFT) method using B3LYP energy model and 6-311G++(d,p) basis set was implied to perform the quantum chemical calculation to systematically investigate the antioxidant nature of SN. The principal pathways involved in the antioxidant reactions along with the basic molecular descriptors affecting the antioxidant potentials of a compound were also studied. The results favor the potential of SN as an active ingredient to be used in cosmeceutical formulations.
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Antioxidantes , Cianobactérias , Teoria da Densidade Funcional , Raios Ultravioleta , Antioxidantes/química , Cianobactérias/química , Cianobactérias/metabolismo , Aminoácidos/química , Aminoácidos/metabolismo , Cicloexanonas/química , Fotossíntese , Espécies Reativas de Oxigênio/metabolismo , Clorofila A/química , Clorofila A/metabolismo , Compostos de Bifenilo/química , Picratos/antagonistas & inibidores , Picratos/química , Sequestradores de Radicais Livres/química , Cicloexilaminas , Glicina/análogos & derivados , Ácidos Sulfônicos , BenzotiazóisRESUMO
Methyltransferase-like 3 (METTL3), the catalytic enzyme of methyltransferase complex for m6A methylation of RNA, is essential for mammalian development. However, the importance of METTL3 in human placentation remains largely unexplored. Here, we show that a fine balance of METTL3 function in trophoblast cells is essential for successful human placentation. Both loss-of and gain-in METTL3 functions are associated with adverse human pregnancies. A subset of recurrent pregnancy losses and preterm pregnancies are often associated with loss of METTL3 expression in trophoblast progenitors. In contrast, METTL3 is induced in pregnancies associated with fetal growth restriction (FGR). Our loss of function analyses showed that METTL3 is essential for the maintenance of human TSC self-renewal and their differentiation to extravillous trophoblast cells (EVTs). In contrast, loss of METTL3 in human TSCs promotes syncytiotrophoblast (STB) development. Global analyses of RNA m6A modification and METTL3-RNA interaction in human TSCs showed that METTL3 regulates m6A modifications on the mRNA molecules of critical trophoblast regulators, including GATA2, GATA3, TEAD1, TEAD4, WWTR1, YAP1, TFAP2C and ASCL2, and loss of METTL3 leads to depletion of mRNA molecules of these critical regulators. Importantly, conditional deletion of Mettl3 in trophoblast progenitors of an early post-implantation mouse embryo also leads to arrested self-renewal. Hence, our findings indicate that METLL3 is a conserved epitranscriptomic governor in trophoblast progenitors and ensures successful placentation by regulating their self-renewal and dictating their differentiation fate.
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Peripartum cardiomyopathy and hypertensive disorders of pregnancy are not very uncommon in routine practice, but when associated with abruptio placentae and significant hypotension, survival of both child and mother becomes challenging. We report a case of a 20-year-old primigravida who presented in the gynecology emergency unit of our hospital with an ejection fraction of < 20%, severe preeclampsia with abruptio placentae leading to fetal demise, and renal failure in the immediate postoperative period. Challenges faced during decision making regarding the mode of delivery and grave concerns during intraoperative and postoperative periods are discussed. In this case, prompt termination of pregnancy, various point-of-care sonographic measurements, and post-operative emergency dialysis played vital roles in the complete recovery of this patient with a failing heart and grossly jeopardized hemodynamics. Hence, multidisciplinary team-based management is crucial for managing such cases to prevent maternal mortality and morbidity.
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New 2-(4-benzothiazol-2-yl-phenoxy)-1-(3,5-diphenyl-4,5-dihydro-pyrazol-1-yl)-ethanones (9a-o) have been designed and synthesized. All the synthesized compounds were characterized by thin layer chromatography and spectral analysis. The antiepileptic potential of the synthesized compounds has been tested by following standard animal screening models, including maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) models. The neurotoxic and antidepression effects of the synthesized compounds were checked by utilizing rotarod apparatus, and motor impairment test (by actophotometer) respectively. The study concluded that compounds 9c, 9d, 9f, 9i, 9n, and 9o possessed good antiepileptic potential compared to standard drugs like carbamazepine and phenytoin. The results of the rotarod performance test also established them without any neurotoxicity. The motor impairment test revealed that the synthesized compounds are also good antidepressants. In-silico studies have been performed for calculation of pharmacophore pattern, prediction of pharmacokinetic properties which determine the eligibility of synthesized compounds as orally administered molecules and interactions with the target proteins. The result of in-silico studies reinforced results obtained by inâ vivo study of the synthesized compounds and their possible mechanism of antiepileptic action i. e. via inhibiting voltage-gated sodium channels (VGSCs) and gamma-aminobutyric acid-A receptor.
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The versatile basic structure of piperazine allows for the development and production of newer bioactive molecules that can be used to treat a wide range of diseases. Piperazine derivatives are unique and can easily be modified for the desired pharmacological activity. The two opposing nitrogen atoms in a six-membered piperazine ring offer a large polar surface area, relative structural rigidity, and more acceptors and donors of hydrogen bonds. These properties frequently result in greater water solubility, oral bioavailability, and ADME characteristics, as well as improved target affinity and specificity. Various synthetic protocols have been reported for piperazine and its derivatives. In this review, we focused on recently published synthetic protocols for the synthesis of the piperazine and its derivatives. The structure-activity relationship concerning different biological activities of various piperazine-containing drugs has also been highlighted to provide a good understanding to researchers for future research on piperazines.
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Química Farmacêutica , Piperazinas , Piperazinas/química , Piperazinas/síntese química , Humanos , Relação Estrutura-Atividade , AnimaisRESUMO
Aim: The objective of the present investigation was to design and synthesize new heterocyclic hybrids comprising benzothiazole and indenopyrazolone pharmacophoric units in a single molecular framework targeting α-amylase and α-glucosidase enzymatic inhibition. Materials & methods: 20 new benzothiazole-appended indenopyrazoles, 3a-t, were synthesized in good yields under environment-friendly conditions via cycloaddition reaction, and assessed for antidiabetic activity against α-amylase and α-glucosidase, using acarbose as the standard reference. Results: Among all the hydroxypyrazolones, 3p and 3r showed the best inhibition against α-amylase and α-glucosidase, which finds support from molecular docking and dynamic studies. Conclusion: Compounds 3p and 3r have been identified as promising antidiabetic agents against α-amylase and α-glucosidase and could be considered valuable leads for further optimization of antidiabetic agents.
[Box: see text].
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Benzotiazóis , Inibidores de Glicosídeo Hidrolases , Hipoglicemiantes , Simulação de Acoplamento Molecular , alfa-Amilases , alfa-Glucosidases , alfa-Glucosidases/metabolismo , Benzotiazóis/química , Benzotiazóis/síntese química , Benzotiazóis/farmacologia , alfa-Amilases/antagonistas & inibidores , alfa-Amilases/metabolismo , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/farmacologia , Inibidores de Glicosídeo Hidrolases/química , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Hipoglicemiantes/síntese química , Humanos , Pirazóis/química , Pirazóis/farmacologia , Pirazóis/síntese química , Relação Estrutura-Atividade , Estrutura Molecular , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese químicaRESUMO
The five-membered 1,3,4-oxadiazole heterocyclic ring has received considerable attention because of its unique bio-isosteric properties and an unusually wide spectrum of biological activities. After a century since 1,3,4-oxadiazole was discovered, its uncommon potential attracted medicinal chemist's attention, leading to the discovery of a few presently accessible drugs containing 1,3,4-oxadiazole units, and a large number of patents have been granted on research related to 1,3,4-oxadiazole. It is worth noting that interest in 1,3,4-oxadiazoles' biological applications has doubled in the last few years. Herein, this review presents a comprehensive overview of the recent achievements in the synthesis of 1,3,4-oxadiazole-based compounds and highlights the major advances in their biological applications in the last 10 years, as well as brief remarks on prospects for further development. We hope that researchers across the scientific streams will benefit from the presented review articles for designing their work related to 1,3,4-oxadiazoles.
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Oxidiazóis , Oxidiazóis/química , Oxidiazóis/farmacologia , HumanosRESUMO
Norm-based accounts of social behavior in economics typically reflect tradeoffs between maximization of own consumption utility and conformity to social norms. Theories of norm-following tend to assume that there exists a single, stable, commonly known injunctive social norm for a given choice setting and that each person has a stable propensity to follow social norms. We collect panel data on 1468 participants aged 11-15 years in Belfast, Northern Ireland and Bogotá, Colombia in which we measure norms for the dictator game and norm-following propensity twice at 10 weeks apart. We test these basic assumptions and find that norm-following propensity is stable, on average, but reported norms show evidence of change. We find that individual-level variation in reported norms between people and within people across time has interpretable structure using a series of latent transition analyses (LTA) which extend latent class models to a panel setting. The best fitting model includes five latent classes corresponding to five sets of normative beliefs that can be interpreted in terms of what respondents view as "appropriate" (e.g. equality vs. generosity) and how they view deviations (e.g. deontological vs. consequentialist). We also show that a major predictor of changing latent classes over time comes from dissimilarity to others in one's network. Our application of LTA demonstrates how researchers can engage with heterogeneity in normative perceptions by identifying latent classes of beliefs and deepening understanding of the extent to which norms are shared, stable, and can be predicted to change. Finally, we contribute to the nascent experimental literature on the economic behavior of children and adolescents. Supplementary Information: The online version contains supplementary material available at 10.1007/s10683-024-09821-5.
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The most common heterocyclic aromatic molecule with potential uses in industry and medicine is quinoline. Its chemical formula is C9H7N, and it has a distinctive double-ring structure with a pyridine moiety fused with a benzene ring. Various synthetic approaches synthesize quinoline derivatives. These approaches include solvent-free synthetic approach, mechanochemistry, ultrasonic, photolytic synthetic approach, and microwave and catalytic synthetic approaches. One of the important synthetic approaches is a catalyst-based synthetic approach in which different catalysts are used such as silver-based catalysts, titanium-based nanoparticle catalysts, new iridium catalysts, barium-based catalysts, iron-based catalysts, gold-based catalysts, nickel-based catalyst, some metal-based photocatalyst, α-amylase biocatalyst, by using multifunctional metal-organic framework-metal nanoparticle tandem catalyst etc. In the present study, we summarized different catalyst-promoted reactions that have been reported for the synthesis of quinoline. Hopefully, the study will be helpful for the researchers.
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Clathrate hydrates (CHs), host-guest compounds of water forming hydrogen-bonded cages around guest molecules, are now known to exist under interstellar conditions. Experimental evidence demonstrated that prolonged thermal treatment of a solid mixture of water and CO2/CH4 produces CHs at 10-30 K under simulated interstellar conditions. However, in the current study, we show that CO2 produced photochemically by vacuum ultraviolet irradiation of H2O-CO mixtures at 10 K and â¼10-10 mbar, gets partitioned into its CH phase and a matrix phase embedded in amorphous ice. The process occurring under simulated interstellar conditions was studied at different temperatures and H2O-CO compositions. The formation of CO2 CH and other photoproducts was confirmed using reflection absorption infrared spectroscopy. The UV-induced photodesorption event of CO2 may provide the mobility required for the formation of CHs, while photoproducts like methanol can stabilize such CH structures. Our study suggests that new species originating during such energetic processing in ice matrices may form CH, potentially altering the chemical composition of astrophysical environments.
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The escalating prevalence of Alzheimer's disease (AD) has prompted extensive research into potential therapeutic interventions, with a specific focus on molecular targets such as amyloid beta (Aß) and tau protein aggregation. In this study, a series of α-ketoamide derivatives was synthesized from ß,γ-unsaturated α-keto thioesters, achieving high purity and good yield. Thioflavin T based Aß aggregation assay identified four promising compounds (BD19, BD23, BD24, and BD27) that demonstrated significant inhibitory effects on Aß aggregation. BD23, selected for its better solubility (0.045 ± 0.0012 mg/ml), was further subjected to in vitro Parallel Artificial Membrane Permeability Assay to determine the Blood-Brain-Barrier permeability and emerged as BBB permeable with permeability rate (Pe) of 10.66 ± 8.11 × 10-6 cm/s. In addition to its Aß inhibitory properties, BD23 exhibited significant inhibition of heparin-induced tau aggregation and demonstrated non-toxicity in SHSY5Y cell lines. Subsequent in vivo assays were conducted, administering compound BD23 to an Aß induced mouse model of AD at various doses (1, 2, & 5 mg/kg). The results revealed a noteworthy enhancement in cognitive functions, particularly when BD23 was administered at a dosage of 5 mg/kg, comparable to the effects observed with the standard dose of Donepezil (DNP). In silico investigations, including molecular docking, molecular dynamics simulations, and Density Functional Theory calculations provided insights into BD23's interactions with the targets and electronic properties. These analyses contribute to the understanding of the therapeutic potential of the lead compounds BD23 which further pave the way for further exploration of its therapeutic potential in the context of AD.
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Doença de Alzheimer , Amidas , Peptídeos beta-Amiloides , Relação Dose-Resposta a Droga , Agregados Proteicos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Humanos , Animais , Camundongos , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Amidas/química , Amidas/farmacologia , Amidas/síntese química , Agregados Proteicos/efeitos dos fármacos , Relação Estrutura-Atividade , Estrutura Molecular , Simulação de Acoplamento Molecular , Proteínas tau/metabolismo , Proteínas tau/antagonistas & inibidores , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , MasculinoRESUMO
The heat shock protein 90 kDa (Hsp90) molecular chaperone machinery is responsible for the folding and activation of hundreds of important clients such as kinases, steroid hormone receptors, transcription factors, etc. This process is dynamically regulated in an ATP-dependent manner by Hsp90 co-chaperones including a group of tetratricopeptide (TPR) motif proteins that bind to the C-terminus of Hsp90. Among these TPR containing co-chaperones, FK506-binding protein 51 kDa (FKBP51) is reported to play an important role in stress-related pathologies, psychiatric disorders, Alzheimer's disease, and cancer, making FKBP51-Hsp90 interaction a potential therapeutic target. In this study, we report identification of potent and selective inhibitors of FKBP51-Hsp90 protein-protein interaction using a structure-based virtual screening approach. Upon in vitro evaluation, the identified hits show a considerable degree of selectivity towards FKBP51 over other TPR proteins, particularly for highly homologous FKBP52. Tyr355 of FKBP51 emerged as an important contributor to inhibitor's specificity. Additionally, we demonstrate the impact of these inhibitors on cellular energy metabolism, and neurite outgrowth, which are subjects of FKBP51 regulation. Overall, the results from this study highlight a novel pharmacological approach towards regulation of FKBP51 function and more generally, Hsp90 function via its interaction with TPR co-chaperones.
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Proteínas de Choque Térmico HSP90 , Proteínas de Ligação a Tacrolimo , Humanos , Ligação Proteica , Proteínas de Ligação a Tacrolimo/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo , Chaperonas Moleculares , Fatores de Transcrição/metabolismoRESUMO
The versatile basic structure of piperazine allows for the development and production of newer bioactive molecules that can be used to treat a wide range of diseases. Piperazine derivatives are unique and can easily be modified for the desired pharmacological activity. The two opposing nitrogen atoms in a six-membered piperazine ring offer a large polar surface area, relative structural rigidity, and more acceptors and donors of hydrogen bonds. These properties frequently result in greater water solubility, oral bioavailability, and ADME characteristics, as well as improved target affinity and specificity. Various synthetic protocols have been reported for piperazine and its derivatives. In this review, we focused on recently published synthetic protocols for the synthesis of the piperazine and its derivatives. The structure-activity relationship concerning different biological activities of various piperazine-containing drugs was also highlighted to provide a good understanding to researchers for future research on piperazines.
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BACKGROUND: Thiazolidine-2,4-dione (2,4-TZD) is a flexible pharmacophore and a privileged platform and contains a five-membered ring with a 2-oxygen atom with double bond 2,4- position and one nitrogen atom as well as sulphur containing in the heterocyclic compound. A famous electron-rich nitrogen transporter combines invigorating electronic properties with the prospective for elemental applications. Thiazolidine-2,4-dione analogues have been synthesized using a variety of methods, all of which have shown to have a strong biological effect. OBJECTIVES: The study of the biological activity of Thiazolidine-2,4-dione derivatives has been a fascinating field of pharmaceutical chemistry and has many purposes. This derivative described in the literature between 1995 to 2023 was the focus of this study. Thiazolidine-2,4-diones have been discussed in terms of their introduction, general method, synthetic scheme and antidiabetic significance in the current review. CONCLUSION: Thiazolidine-2,4-diones are well-known heterocyclic compounds. The synthesis of Thiazolidine-2,4-diones has been described using a variety of methods. Antidiabetic activity has been discovered in several Thiazolidine-2,4-dione derivatives, which enhance further research. The use of Thiazolidine-2,4-diones to treat antidiabetics has piqued researchers' interest in learning more about thiazolidine-2,4-diones.
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Hipoglicemiantes , Tiazolidinedionas , Tiazolidinedionas/química , Tiazolidinedionas/síntese química , Tiazolidinedionas/farmacologia , Hipoglicemiantes/química , Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacologia , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , AnimaisRESUMO
To study the best substrate for the Indian subcontinent, four different substrates (sawdust + wheat bran, wheat straw + wheat bran + corn cobs, sawdust + corn cobs and wheat straw + wheat bran) were screened for six different Flammulina velutipes strains. The antioxidant and antibacterial properties were studied for these strains. In study it was found that the strain DMRX-767 and DMRX-768 were the most promising for yield and biological efficiency in all substrates and wheat straw + wheat bran being the best with respect to BE. To corroborate the findings, the best strain and best substrate trails were repeated. DMRX-767 and DMRX-768 were the most promising for yield and biological efficiency in all substrates, with wheat straw+wheat bran were again found the best. The methanolic extract of strain DMRX-166 showed highest antibacterial properties as highest inhibition is found for Bacillus subtilis and Pseudomonas syringae. However, DMRO-253 inhibited Ralstonia solanacearum and Xanthomonas campestris. DMRX-768 has the best scavenging ability followed by DMRO-253.
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Agaricales , Flammulina , Antioxidantes/farmacologia , Fibras na Dieta , Bactérias , Antibacterianos/farmacologiaRESUMO
The placenta establishes a maternal-fetal exchange interface to transport nutrients and gases between the mother and the fetus. Establishment of this exchange interface relies on the development of multinucleated syncytiotrophoblasts (SynT) from trophoblast progenitors, and defect in SynT development often leads to pregnancy failure and impaired embryonic development. Here, we show that mouse embryos with conditional deletion of transcription factors GATA2 and GATA3 in labyrinth trophoblast progenitors (LaTPs) have underdeveloped placenta and die by ~embryonic day 9.5. Single-cell RNA sequencing analysis revealed excessive accumulation of multipotent LaTPs upon conditional deletion of GATA factors. The GATA factor-deleted multipotent progenitors were unable to differentiate into matured SynTs. We also show that the GATA factor-mediated priming of trophoblast progenitors for SynT differentiation is a conserved event during human placentation. Loss of either GATA2 or GATA3 in cytotrophoblast-derived human trophoblast stem cells (human TSCs) drastically inhibits SynT differentiation potential. Identification of GATA2 and GATA3 target genes along with comparative bioinformatics analyses revealed that GATA factors directly regulate hundreds of common genes in human TSCs, including genes that are essential for SynT development and implicated in preeclampsia and fetal growth retardation. Thus, our study uncovers a conserved molecular mechanism, in which coordinated function of GATA2 and GATA3 promotes trophoblast progenitor-to-SynT commitment, ensuring establishment of the maternal-fetal exchange interface.
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Regulação da Expressão Gênica no Desenvolvimento , Troca Materno-Fetal , Gravidez , Feminino , Humanos , Animais , Camundongos , Placenta , Trofoblastos , Diferenciação Celular/fisiologia , Desenvolvimento Fetal , Fatores de Transcrição GATARESUMO
Kinase is an enzyme that helps in the phosphorylation of the targeted molecules and can affect their ability to react with other molecules. So, kinase influences metabolic reactions like cell signaling, secretory processes, transport of molecules, etc. The increased activity of certain kinases may cause various types of cancer, i.e. leukemia, glioblastoma, and neuroblastomas. So, the growth of particular cancer cells can be prevented by the inhibition of the kinase responsible for those cancers. Natural products are the key resources for the development of new drugs where approximately 60% of anti-tumor drugs are being developed with the same including specific kinase dwellers. This study comprised molecular interactions of various molecules (obtained from natural sources) as kinase inhibitors for the treatment of cancer. It is expected that by analyzing the skeleton behavior, the process of action, and the body-related activity of these organic products, new cancer-avoiding molecules can be developed.
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Antineoplásicos , Produtos Biológicos , Neoplasias , Inibidores de Proteínas Quinases , Humanos , Produtos Biológicos/farmacologia , Produtos Biológicos/química , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Estrutura Molecular , Neoplasias/tratamento farmacológico , Antineoplásicos/farmacologia , Antineoplásicos/químicaRESUMO
Chronic pain is a common and debilitating condition with a huge social and economic burden worldwide. Currently, available drugs in clinics are not adequately effective and possess a variety of severe side effects leading to treatment withdrawal and poor quality of life. Recent findings highlight the potential role of autotaxin (ATX) as a promising novel target for chronic pain management, extending beyond its previously established involvement in arthritis and other neurological disorders, such as Alzheimer's disease. In the present study, we used a virtual screening strategy by targeting ATX against commercially available natural compounds (enamine- phenotypic screening library) to identify the potential inhibitors for the treatment of chronic pain. After initial identification using molecular docking based virtual screening, molecular mechanics (MM/GBSA), ADMET profiling and molecular dynamics simulation were performed to verify top hits. The computational screening resulted in the identification of fifteen top scoring structurally diverse hits that have free energy of binding (ΔG) values in the range of -25.792 (for compound Enamine_1850) to -74.722 Kcal/mol (for compound Enamine_1687). Moreover, the top-scoring hits have favourable ADME properties as calculated using in-silico algorithms. Additionally, the molecular dynamics simulation revealed the stable nature of protein-ligand interaction and provided information about amino acid residues involved in binding. This study led to the identification of potential autotaxin inhibitors with favourable pharmacokinetic properties. Identified hits may further be investigated for their safety and efficacy potential using in-vitro and in-vivo models of chronic pain.Communicated by Ramaswamy H. Sarma.