ABCA7-Associated Clinical Features and Molecular Mechanisms in Alzheimer's Disease.

Alzheimer's disease (AD) is the most common type of neurodegenerative disease and its pathogenesis is still unclear. Genetic factors are thought to account for a large proportion of the overall AD phenotypes. ATP-binding cassette transporter A7 (ABCA7) is one of the most important risk gene for AD. Multiple forms of ABCA7 variants significantly increase the risk of AD, such as single-nucleotide polymorphisms, premature termination codon variants, missense variants, variable number tandem repeat, mutations, and alternative splicing. AD patients with ABCA7 variants usually exhibit typical clinical and pathological features of traditional AD with a wide age of onset range. ABCA7 variants can alter ABCA7 protein expression levels and protein structure to affect protein functions such as abnormal lipid metabolism, amyloid precursor protein (APP) processing, and immune cell function. Specifically, ABCA7 deficiency can cause neuronal apoptosis by inducing endoplasmic reticulum stress through the PERK/eIF2α pathway. Second, ABCA7 deficiency can increase Aß production by upregulating the SREBP2/BACE1 pathway and promoting APP endocytosis. In addition, the ability of microglia to phagocytose and degrade Aß is destroyed by ABCA7 deficiency, leading to reduced clearance of Aß. Finally, disturbance of lipid metabolism may also be an important method by which ABCA7 variants influence the incidence rate of AD. In the future, more attention should be given to different ABCA7 variants and ABCA7 targeted therapies for AD.

Oxidative stress bridges the gut microbiota and the occurrence of frailty syndrome.

The incidence of frailty gradually increases with age. This condition places a heavy burden on modern society, of which the aging population is increasing. Frailty is one of the most complicated clinical syndromes; thus, it is difficult to uncover its underlying mechanisms. Oxidative stress (OS) is involved in frailty in multiple ways. The association between the gut microbiota (GM) and frailty was recently reported. Herein, we propose that OS is involved in the association between the GM and the occurrence of frailty syndrome. An imbalance between oxidation and antioxidants can eventually lead to frailty, and the GM probably participates in this process through the production of reactive oxygen species. On the other hand, OS can disturb the GM. Such dysbiosis consequently induces or exacerbates tissue damage, leading to the occurrence of frailty syndrome. Finally, we discuss the possibility of improving frailty by intervening in the vicious cycle between the imbalance of OS and dysbiosis.

A Novel Trimethylamine Oxide-Induced Model Implicates Gut Microbiota-Related Mechanisms in Frailty.

Frailty is a complicated syndrome that occurs at various ages, with highest incidence in aged populations, suggesting associations between the pathogenesis of frailty and age-related changes. Gut microbiota (GM) diversity and abundance change with age, accompanied by increased levels of trimethylamine oxide (TMAO), a systemic inflammation-inducing GM metabolite. Thus, we hypothesized that TMAO may be involved in the development of frailty. We successfully established and verified a novel model of frailty in adult mice based on a 4-week intraperitoneal injection regime of TMAO followed by LPS challenge. The frailty index significantly increased in TMAO-treated mice after LPS challenge. TMAO also decreased claudin-1 immunofluorescent staining intensity in the jejunum, ileum, and colon, indicating that the destruction of intestinal wall integrity may increase vulnerability to exogenous pathogens and invoke frailty. 16S sequencing showed that TMAO significantly reduced the GM Firmicutes/Bacteroidetes (F/B) ratio, but not α-diversity. Interestingly, after LPS challenge, more genera of bacterial taxa were differently altered in the control mice than in the TMAO-treated mice. We infer that a variety of GM participate in the maintenance of homeostasis, whereas TMAO could blunt the GM and impair the ability to recover from pathogens, which may explain the continuous increase in the frailty index in TMAO-treated mice after LPS challenge. TMAO also significantly increased serum imidazole metabolites, and led to different patterns of change in serum peptide and phenylpropanoid metabolites after LPS stimulation. These changes indicate that glucose metabolism may be one mechanism by which GM inactivation causes frailty. In conclusion, TMAO leads to frailty by destroying intestinal barrier integrity and blunting the GM response.

Polybenzyls from Gastrodia elata, their agonistic effects on melatonin receptors and structure-activity relationships.

Gastrodia elata is a famous traditional Chinese herb with medicinal and edible application. In this study, nine polybenzyls (1-9), including six new ones (2-5, 7 and 9), were isolated from the EtOAc extract of G. elata. Five compounds 1, 3, 4, 6 and 8 were found to activate melatonin receptors. Especially, compound 1 showed agonistic effects on MT1 and MT2 receptors with EC50 values of 237 and 244 µM. For better understanding their structure-activity relationships (SARs), ten polybenzyl analogs were further synthesized and assayed for their activities on melatonin receptors. Preliminary SARs study suggested that two para-hydroxy groups were the key pharmacophore for maintaining activity. Molecular docking simulations verified that compound 1 could strongly interact with MT2 receptor by bonding to Phe 118, Gly 121, His 208, Try 294 and Ala 297 residues.

Melatonin Receptors Agonistic Activities of Phenols from Gastrodia elata.

Gastrodia elata is a famous traditional Chinese herb with medicinal and edible application. In this study, three new polybenzyls, gastropolybenzylols G-I (1-3) were isolated from the EtOAc extract of G. elata. Their structures were identified by extensive spectroscopic analyses involving HRESIMS, UV, IR, 1D and 2D NMR. Compound 1 showed agonistic effects on MT1 and MT2 receptors with agonistic rates of 55.91±4.84% and 165.13±5.65% at the concentration of 0.5 mM, respectively, and an EC50 value of 76.24 µM on MT2 receptor.