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Computational inference of the framework and unsafe effects of the lignin walkway in Panicum virgatum.
Energy decomposition reveals the electrostatic effect on the stability of G-quadruplex. The radial distribution function displayed the solvent shell and ion moving away from the groove. The hydrogen bond played an essential role in the binding of both ligands, especially for the charged derivative. van der Waals interaction is the only factor that is more important in binding uncharged distamycin into G-quadruplex than the charged one. The calculated ΔGbind showed the stability of both ligands within grooves and good agreement with the experimental binding free energy data. Finally, the results suggest that ligand modification improves the binding mode toward stabilizing G-quadruplexes.Despite being initially regarded as a metabolic waste product, lactate is now considered to serve as a primary fuel for the tricarboxylic acid cycle in cancer cells. At the core of lactate metabolism, lactate dehydrogenases (LDHs) catalyze the interconversion of lactate to pyruvate and as such represent promising targets in cancer therapy. However, direct inhibition of the LDH active site is challenging from physicochemical and selectivity standpoints. However, LDHs are obligate tetramers. Thus, targeting the LDH tetrameric interface has emerged as an appealing strategy. In this work, we examine a dimeric construct of truncated human LDH to search for new druggable sites. We report the identification and characterization of a new cluster of interactions in the LDH tetrameric interface. Using nanoscale differential scanning fluorimetry, chemical denaturation, and mass photometry, we identified several residues (E62, D65, L71, and F72) essential for LDH tetrameric stability. Moreover, we report a family of peptide ligands based on this cluster of interactions. We next demonstrated these ligands to destabilize tetrameric LDHs through binding to this new tetrameric interface using nanoscale differential scanning fluorimetry, NMR water-ligand observed via gradient spectroscopy, and microscale thermophoresis. Altogether, this work provides new insights on the LDH tetrameric interface as well as valuable pharmacological tools for the development of LDH tetramer disruptors.Schizophrenia is a devastating neurodevelopmental disorder. The animal model based on perinatal immune activation, as first-hit, combined with peripubertal stress, as a second hit, has gained evidence in recent years. Omega-3 polyunsaturated fatty acids (n3-PUFAs) is being a promise for schizophrenia prevention. Nevertheless, the influence of sex in schizophrenia neurobiology and prevention has been neglected. Thus, the present study evaluates the preventive effects of n3-PUFAs in both sexes' mice submitted to the two-hit model and the participation of oxidative changes in this mechanism. The two-hit consisted of polyIC administration from postnatal days (PNs) 5-7, and unpredictable stress from PNs35-43. n3-PUFAs were administered from PNs30-60. Prepulse inhibition of the startle reflex (PPI), social interaction, and Y-maze tests were conducted between PNs70-72 to evaluate positive-, negative-, and cognitive-like schizophrenia symptoms. We assessed brain oxidative changes in brain areas and plasma. Both sexes' two-hit mice presented deficits in PPI, social interaction, and working memory that were prevented by n3-PUFAs. In two-hit females, n3-PUFAs prevented increments in nitrite levels in the prefrontal cortex (PFC), hippocampus, striatum, and plasma TBARS levels. In two-hit males, n3-PUFAs prevented the increase in TBARS in the PFC, hippocampus, and striatum. Notably, male mice that received only n3-PUFAs without hit exposure presented impairments in working memory and social interaction. These results add further preclinical evidence for n3-PUFAs as an accessible and effective alternative in preventing behavioral and oxidative changes related to schizophrenia but call attention to the need for precaution in this indication due to hit- and sex-sensitive issues.Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized by progressive memory loss, declining language skills and other cognitive disorders. AD has brought great mental and economic burden to patients, families and society. However due to the complexity of AD's pathology, drugs developed for the treatment of AD often fail in clinical or experimental trials. The main problems of current anti-AD drugs are low efficacy due to mono-target method or side effects, especially high hepatotoxicity. To tackle these two main problems, multi-target-directed ligand (MTDL) based on "one molecule, multiple targets" has been studied. MTDLs can regulate multiple biological targets at the same time, so it has shown higher efficacy, better safety. Bozitinib clinical trial As a natural active small molecule, α-mangostin (α-M) has shown potential multi-factor anti-AD activities in a series of studies, furthermore it also has a certain hepatoprotective effect. The good availability of α-M also provides support for its application in clinical research. In this work, multiple activities of α-M related to AD therapy were reviewed, which included anti-cholinesterase, anti-amyloid-cascade, anti-inflammation, anti-oxidative stress, low toxicity, hepatoprotective effects and drug formulation. It shows that α-M is a promising candidate for the treatment of AD.Metaplasticity is referred to adjustment in the requirements for induction of synaptic plasticity based on the prior history of activity. Synaptic plasticity, including long-term potentiation (LTP) and long-term depression (LTD), has been considered to be the neural processes underlying learning and memory. Previous observations that cordycepin (an adenosine derivative) improved learning and memory seemed to be contradictory to the findings that cordycepin inhibited LTP. Therefore, we speculated that the conflicting reports of cordycepin might be related to metaplasticity. In the current study, population spike (PS) in hippocampal CA1 area of rats was recorded by using electrophysiological method in vivo. The results showed that cordycepin reduced PS amplitude in hippocampal CA1 with a concentration-dependent relationship, and high frequency stimulation (HFS) failed to induce LTP when cordycepin was intrahippocampally administrated but improved LTP magnitude when cordycepin was pre-treated. Cordycepin increased LTD induced by activating N-Methyl-D-aspartate (NMDA) receptors and subsequently facilitated LTP induced by HFS.
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