Discovery of novel melatonin-mydroxyquinoline hybrids as multitarget strategies for Alzheimer's disease therapy.

Alzheimer's disease (AD) is a neurodegenerative disease that seriously affects human health, and current treatment strategies are far from meeting clinical needs. Inspired by multi-target drug design strategies, a series of novel natural products-based melatonin-hydroxyquinoline hybrids were designed and synthesized, targeting anti-oxidation and metal-chelating at the same time. Most of the compounds showed significant oxygen radical absorbance capacity and Aß1-42 aggregation inhibition. Moreover, the compounds possess good blood-brain barrier permeability. 6b and 6c have a good ability to alleviate oxidative stress induced by hydrogen peroxide. 6b and 6c possess metal-chelating properties with the chelation ratio being 2:1. Furthermore, 6b can significantly mitigate metal-induced Aß aggregation. This work may provide a new multi-target treatment strategy for Alzheimer's disease.

Non-coding RNAs expression in SARS-CoV-2 infection: pathogenesis, clinical significance, and therapeutic targets.

The coronavirus disease 2019 (COVID-19) pandemic has been looming globally for three years, yet the diagnostic and treatment methods for COVID-19 are still undergoing extensive exploration, which holds paramount importance in mitigating future epidemics. Host non-coding RNAs (ncRNAs) display aberrations in the context of COVID-19. Specifically, microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) exhibit a close association with viral infection and disease progression. In this comprehensive review, an overview was presented of the expression profiles of host ncRNAs following SARS-CoV-2 invasion and of the potential functions in COVID-19 development, encompassing viral invasion, replication, immune response, and multiorgan deficits which include respiratory system, cardiac system, central nervous system, peripheral nervous system as well as long COVID. Furthermore, we provide an overview of several promising host ncRNA biomarkers for diverse clinical scenarios related to COVID-19, such as stratification biomarkers, prognostic biomarkers, and predictive biomarkers for treatment response. In addition, we also discuss the therapeutic potential of ncRNAs for COVID-19, presenting ncRNA-based strategies to facilitate the development of novel treatments. Through an in-depth analysis of the interplay between ncRNA and COVID-19 combined with our bioinformatic analysis, we hope to offer valuable insights into the stratification, prognosis, and treatment of COVID-19.

Research progress on lncRNAs in Alzheimer's disease.

Alzheimer's disease (AD) is the common neurodegenerative disease in the center never system and the typical dementia in old people. The major pathological changes of AD are the accumulation of amyloid-ß (Aß) plaques, neurofibrillary tangles, loss of cholinergic neurons, inflammation and metabolism dysfunction. However, the molecular mechanism leading to AD pathogenesis is not clear. More and more studies reported that long non-coding RNAs (lncRNAs) play important roles in AD. In this review, we briefly introduce the recent research progress on lncRNAs in AD, including their regulation of clearance of the Aß plaques, synaptic function, inflammation reaction and mitochondrial function, and thus providing the references for that lncRNAs can serve as a potential diagnostic biomarker and therapeutic target in AD.

CircGRIA1 shows an age-related increase in male macaque brain and regulates synaptic plasticity and synaptogenesis.

Circular RNAs (circRNAs) are abundant in mammalian brain and some show age-dependent expression patterns. Here, we report that circGRIA1, a conserved circRNA isoform derived from the genomic loci of α-mino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor subunit Gria1, shows an age-related and male-specific increase in expression in the rhesus macaque prefrontal cortex and hippocampus. We show circGRIA1 is predominantly localized to the nucleus, and find an age-related increase in its association with the promoter region of Gria1 gene, suggesting it has a regulatory role in Gria1 transcription. In vitro and in vivo manipulation of circGRIA1 negatively regulates Gria1 mRNA and protein levels. Knockdown of circGRIA1 results in an age-related improvement of synaptogenesis, and GluR1 activity-dependent synaptic plasticity in the hippocampal neurons in males. Our findings underscore the importance of circRNA regulation and offer an insight into the biology of brain aging.

DL0410 Ameliorates Memory and Cognitive Impairments Induced by Scopolamine via Increasing Cholinergic Neurotransmission in Mice.

Deficiency of the cholinergic system is thought to play a vital role in cognitive impairment of dementia. DL0410 was discovered as a dual inhibitor of acetylcholinesterase (AChE) and butyrylcholinestease (BuChE), with potent efficiency in in-vitro experiments, but its in vivo effect on the cholinergic model has not been evaluated, and its action mechanism has also not been illustrated. In the present study, the capability of DL0410 in ameliorating the amnesia induced by scopolamine was investigated, and its effect on the cholinergic system in the hippocampus and its binding mode in the active site of AChE was also explored. Mice were administrated DL0410 (3 mg/kg, 10 mg/kg, and 30 mg/kg), and mice treated with donepezil were used as a positive control. The Morris water maze, escape learning task, and passive avoidance task were used as behavioral tests. The test results indicated that DL0410 could significantly improve the learning and memory impairments induced by scopolamine, with 10 mg/kg performing best. Further, DL0410 inhibited the AChE activity and increased acetylcholine (ACh) levels in a dose-dependent manner, and interacted with the active site of AChE in a similar manner as donepezil. However, no difference in the activity of BuChE was found in this study. All of the evidence indicated that its AChE inhibition is an important mechanism in the anti-amnesia effect. In conclusion, DL0410 could be an effective therapeutic drug for the treatment of dementia, especially Alzheimer's disease.