Soluble TGF-ß decoy receptor TGFBR3 exacerbates Alzheimer's disease pathology by modifying microglial function.

Alzheimer's disease (AD) is a major cause of progressive dementia characterized by memory loss and progressive neurocognitive dysfunction. However, the molecular mechanisms are not fully understood. To elucidate the molecular mechanism contributing to AD, an integrated analytical workflow was deployed to identify pivotal regulatory target within the RNA-sequencing (RNA-seq) data of the temporal cortex from AD patients. Soluble transforming growth factor beta receptor 3 (sTGFBR3) was identified as a critical target in AD, which was abnormally elevated in AD patients and AD mouse models. We then demonstrated that sTGFBR3 deficiency restored spatial learning and memory deficits in amyloid precursor protein (APP)/PS1 and streptozotocin (STZ)-induced neuronal impairment mice after its expression was disrupted by a lentiviral (LV) vector expressing shRNA. Mechanistically, sTGFBR3 deficiency augments TGF-ß signaling and suppressing the NF-κB pathway, thereby reduced the number of disease-associated microglia (DAMs), inhibited proinflammatory activity and increased the phagocytic activity of DAMs. Moreover, sTGFBR3 deficiency significantly mitigated acute neuroinflammation provoked by lipopolysaccharide (LPS) and alleviated neuronal dysfunction induced by STZ. Collectively, these results position sTGFBR3 as a promising candidate for therapeutic intervention in AD.

An inhibitor with GSK3ß and DYRK1A dual inhibitory properties reduces Tau hyperphosphorylation and ameliorates disease in models of Alzheimer's disease.

Since Alzheimer's disease (AD) is a complex and multifactorial neuropathology, the discovery of multi-targeted inhibitors has gradually demonstrated greater therapeutic potential. Neurofibrillary tangles (NFTs), the main neuropathologic hallmarks of AD, are mainly associated with hyperphosphorylation of the microtubule-associated protein Tau. The overexpression of GSK3ß and DYRK1A has been recognized as an important contributor to hyperphosphorylation of Tau, leading to the strategy of using dual-targets inhibitors for the treatment of this disorder. ZDWX-12 and ZDWX-25, as harmine derivatives, were found good inhibition on dual targets in our previous study. Here, we firstly evaluated the inhibition effect of Tau hyperphosphorylation using two compounds by HEK293-Tau P301L cell-based model and okadaic acid (OKA)-induced mouse model. We found that ZDWX-25 was more effective than ZDWX-12. Then, based on comprehensively investigations on ZDWX-25 in vitro and in vivo, 1) the capability of ZDWX-25 to show a reduction in phosphorylation of multiple Tau epitopes in OKA-induced neurodegeneration cell models, and 2) the effect of reduction on NFTs by 3xTg-AD mouse model under administration of ZDWX-25, an orally bioavailable, brain-penetrant dual-targets inhibitor with low toxicity. Our data highlight that ZDWX-25 is a promising drug for treating AD.

Correction to Design, Synthesis, and Biological Evaluation of Notopterol Derivatives as Triple Inhibitors of AChE/BACE1/GSK3ß for the Treatment of Alzheimer's Disease.

[This corrects the article DOI: 10.1021/acsomega.2c03368.].

Design, Synthesis, and Biological Evaluation of Notopterol Derivatives as Triple Inhibitors of AChE/BACE1/GSK3ß for the Treatment of Alzheimer's Disease.

The pathogenesis of Alzheimer's disease (AD) is very complex, and there are many hypotheses. Therefore, the development of a multi-target-directed-ligand may be an effective therapeutic strategy. Our previous study showed that notopterol (a natural product from Notopterygium) is a dual BACE1/GSK3ß inhibitor. In this study, we designed and synthesized 48 notopterol derivatives with furacoumarin as a scaffold in order to enhance their balanced AChE/BACE1/GSK3ß inhibitory activity. Fortunately, 1c showed effective inhibitory activity against AChE (58.7% at 1.0 µM), BACE1 (48.3% at 20 µM), and GSK3ß (40.3% at 10 µM). Furthermore, 1c showed good blood-brain barrier penetrability, suitable bioavailability, and oral safety. More importantly, 1c could ameliorate the impaired learning and memory in Aß-induced AD mice. In conclusion, we reported the triple inhibitor of AChE/BACE1/GSK3ß lead compounds based on a furocoumarin scaffold of notopterol for the first time, which provides a potential new strategy for the treatment of AD.

Periodic density as an endpoint of customized plankton community responses to petroleum hydrocarbons: A level of toxic effect should be matched with a suitable time scale.

As an endpoint of community response to contaminants, average periodic density of populations (APDP) has been introduced to model species interactions in a community with 4 planktonic species. An ecological model for the community was developed by means of interspecific relationship including competition and predation to calculate the APDP. As a case study, we reported here the ecotoxicological effects of petroleum hydrocarbons (PHC) collected from Bohai oil field on densities of two algae, Platymonas subcordiformis and Isochrysis galbana, a rotifer, Brachionus plicatilis, and of a cladocera, Penilia avirostris, in single species and a microcosm experiment. Time scales expressing toxic effect increased with increasing levels of toxic effect from molecule to community. Remarkable periodic changes in densities were found during the tests in microcosm experiment, revealing a strong species reaction. The minimum time scale characterizing toxic effect at a community level should be the common cycle of population densities of the microcosm. In addition, the cycles of plankton densities shortened in general with increasing PHC, showing an evident toxic effect on the microcosm. Using APDP as the endpoint, a threshold concentration for the modeled microcosm was calculated to be 0.404 mg-PHC L-1. The APDP was found to be more sensitive and reliable than the standing crops of populations as the endpoint. This indicated that the APDP, an endpoint at the community level, could be quantitatively related to the endpoints at the population level, and led to the quantitative concentration-toxic effect relationship at the community level.

A light-limited growth model considering the nutrient effect for improved understanding and prevention of macroalgae bloom.

A useful growth process model for Ulva prolifera with light limitation considering the nutrient effect was proposed to better understand the development of macroalgae bloom. The interrelationship between light and nutrient limitation was demonstrated to obtain the mechanism. As a case study, thresholds of light and nutrients for different stages of Ulva prolifera growth were estimated using the proposed model. Limits of light intensity, nitrate, and phosphate concentration on the initial growth were found to be 40.0 W m-2, 6.5 µmol L-1, and 0.27 µmol L-1, respectively. The minimal light intensity for initial growth was found to increase monotonously with decrease in the nutrient concentration. It was also observed that the minimal light intensity for growth increases as the density of Ulva prolifera increases and the nutrient concentration decreases. Similarly, the minimal nutrient concentration for initial growth increases monotonously with decrease in the light intensity. In addition, the minimal nutrient concentration for growth increases with increase in the density of Ulva prolifera and decrease in the light intensity. It was demonstrated that the phosphate limitation on the initial growth of Ulva prolifera seedling can occur in most coastal waters of the southern Yellow Sea and a tendency of approaching the phosphate limitation on the growth of the floating thalli of Ulva prolifera exists. Evidence was provided to support the argument that the macroalgae thalli from aquaculture rafts, rather than that from seedlings or spores, can contribute to the original biomass of the floating green Ulva prolifera in the southern Yellow Sea. The model presented in this study can provide new insights into the interrelationship between the light and nutrient limitation, as well as into the growth mechanism of floating seaweeds. It can also provide a more accurate prediction of seaweed growth in light- and nutrient-limited environments.

A toxic effect at molecular level can be expressed at community level: A case study on toxic hierarchy.

This study demonstrated hierarchical toxicity and addressed the relevance and differences of toxic effects at the molecular, individual, population, and community levels. Superoxide dismutase (SOD) activity, photosynthetic oxygen production, filtration rate, life span and densities of Platymonas helgolandica var. tsingtaoensis, Isochrysis galbana, and Brachionus plicatilis in single-species tests and customized community tests were examined in response to a concentration gradient of aniline ranging from 0 to 50.0 mg L-1. The SOD activity was the most sensitive endpoint with the fastest response to aniline according to the calculated no-detection of toxic effect concentration (NDEC) and the EC50. The individual- and population-level endpoints, showing a lower response to aniline, could be constructed from the SOD activity in a stepwise manner. A multi-scale hierarchical model with endpoints at 4 levels was used to characterize toxic effects, at the scales of time and size. Linkage of SOD activity to toxic effects at a community level was established level by level to express the change in the customized community with the concentration of aniline. The calculated threshold concentration of aniline for the customized community was nearly equal to the minimum NDEC, demonstrating as great an impact on interactions by the toxic effect at subpopulation-level as that at the community level. However, we identified a trend of higher sensitivities of measured endpoints at sub-population level, decreasing sensitivity at higher levels but a great variety of sensitivities at community level. Although the characteristics of toxic effects are different at different levels, the structure and process of endpoints at adjacent levels are related to and interact with each other. The resulted indirect effects, together with direct effect, determine the toxic effect at every levels of biological complexity. The toxic effects at adjacent levels should be studied at the same time to better understand the ecological risk of contaminants.