Abstract Amyloid beta (Aβ) accumulates within neurons in the brains of early stage Alzheimer’s disease (AD) patients. However, mechanism underlying its toxicity remains unclear. Here, a triple omics approach was used to integrate transcriptomic, proteomic, and metabolomic data collected from nerve cell model toxic intracellular aggregation Aβ. It found that Aβ induces profound changes landscape cells are associated with pro-inflammatory, metabolic reprogramming predisposes die via...

Alzheimer's disease (AD) is the most frequent age-associated dementia with no treatments that can prevent or slow its progression. Since age by far major risk factor for AD, there a strong rationale an alternative approach to drug discovery based upon biology of aging. Phenotypic screening assays reflect multiple, neurotoxicity pathways rather than single molecular targets identify compounds have therapeutic efficacy targeting aspects aging contribute AD pathology. And, while suitability any...

The global increase in the aging population has led to a rise many age-related diseases with continuing unmet therapeutic needs. Research into molecular mechanisms underlying both and neurodegeneration identified promising targets, such as oxytosis/ferroptosis cell death pathway, which mitochondrial dysfunction plays critical role. This study focused on sterubin fisetin, two flavonoids from natural pharmacopeia previously strong inhibitors of pathway. Here, we investigated effects compounds...

Alzheimer's disease (AD) is the most common brain disorder worldwide. Aberrant tau hyperphosphorylation and accumulation play critical roles in formation of neurofibrillary tangles highly associated with neuronal dysfunction cognitive impairment AD pathogenesis. Glycogen synthase kinase-3β (GSK3β) a key kinase responsible for hyperphosphorylation. Selective inhibition GSK3β promising strategy therapy. Corn silks (CS, Zea mays L.) have been traditionally used as medicinal herb recently noted...

The oxytosis/ferroptosis regulated cell death pathway is an emerging field of research owing to its pathophysiological relevance a wide range neurological disorders, including Alzheimer's and Parkinson's diseases traumatic brain injury. Developing novel neurotherapeutics inhibit offers exciting opportunities for the treatment these other diseases. Previously, we discovered cannabinol (CBN) as unique, potent inhibitor by targeting mitochondria modulating their function in neuronal cells. To...

Glycogen synthase kinase-3β (GSK-3β) is a key enzyme responsible for tau hyperphosphorylation and viable therapeutic target of Alzheimer's disease (AD). We developed new class GSK-3β inhibitors based on the 6-C-glycosylflavone isoorientin (1). The are passive membrane permeable constitutively attenuate mediated amyloid neurotoxicity in an AD cellular model. Enzymatic assays kinetic studies demonstrated that compound 30 substrate-competitive inhibitor with distinct kinase selectivity,...

A novel approach is developed for coordinated expression of multiple proteins from a single transgene in plants. An Ssp DnaE mini-intein variant engineered hyper-N-terminal autocleavage covalently linked to the foot-and-mouth disease virus 2A (F2A) peptide with unique ribosome skipping property, via linker, create an 'IntF2A' self-excising fusion protein domain. This IntF2A domain acts, cis, direct highly effective release its flanking interest (POIs) 'polyprotein' precursor successfully...

Alzheimer's disease (AD) is the most common neurodegenerative disorder. Neuroinflammation a prevalent pathogenic stress leading to neuronal death in AD. Targeting neuroinflammation keep neurons alive an attractive strategy for AD therapy. 1-Trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) potent inhibitor of soluble epoxide hydrolase (sEH) and can enter into brain. It has good efficacy on wide range chronic inflammatory diseases preclinical animal models. However,...

Two new polycyclic alkaloids, neopetrocyclamines A and B (1 2), along with the known metabolites papuamine (3) haliclonadiamine (4), were isolated from Indonesian sponge Neopetrosia cf exigua. Neopetrocyclamine contains a formamidinium moiety, rare functional group. While these compounds share same basic biosynthetic building blocks, size of ring system differs in 1 2 because moiety. Biological evaluations 1–4 revealed that is cytotoxic against glioblastoma SF-295 cells (GI50 = 0.8 μM).

J147 is a novel drug candidate developed to treat neurological dysfunction. Numerous studies have demonstrated the beneficial effects of in cellular and animal models disease which has led transitioning compound into human clinical trials. However, no biomarkers for its target engagement been identified. Here, we determined if specific metabolites plasma could be indicative J147's activity vivo. Plasma lipidomics data from three independent rodent were assessed along with liver one studies....

Flavonoids are characteristic in maize and have diverse biological functions. C-Glycosylflavones neuroprotective against β-amyloid-induced tau hyperphosphorylation neurotoxicity SH-SY5Y cells, which is relevant to Alzheimer's disease prevention treatment. The content of the flavonoids eriodictyol, luteolin, isoorientin, maysin varied pollens, silks, tassels, seeds among five varieties. Eriodictyol was high (51-322 ng/g dw) while luteolin low (0.2-106 all four tissues. isoorientin...

Abstract Being able to coordinate co-expression of multiple proteins is necessary for a variety important applications such as assembly protein complexes, trait stacking and metabolic engineering. Currently only few options are available recombinant most them not applicable both prokaryotic eukaryotic hosts. Here, we report new polyprotein vector system that based on pair self-excising mini-inteins fused in tandem, termed the dual-intein (DI) domain, achieve synchronized proteins. The DI...

Plants, in particular those with a history traditional medicine, hold enormous potential as sources of new therapies for dementias such Alzheimer's disease (AD). The largest collections plants can be found herbaria all over the world, but value these to AD drug discovery has been significantly neglected. As proof principle, we investigated neuroprotective activity herbarium specimens Eriodictyon (yerba santa), genus long usage by indigenous tribes California treat respiratory and age-related...

A versatile and environmentally friendly synthetic method for the formation of acyl phosphates is reported.

Alzheimer's disease (AD) is the most frequent age-associated with no treatments that can prevent, delay, slow, or stop its progression. Thus, new approaches to drug development are needed. One promising approach use of phenotypic screening assays identify compounds have therapeutic efficacy in target pathways relevant aging and cognition, as well AD pathology. Using this approach, we identified flavanone sterubin, from Yerba santa (Eriodictyon californicum), a potential candidate for...

An extensive study of the secondary metabolites produced by a new Sticta sp. lichen has led to isolation three compounds containing 4-amino-3-hydroxy-5-phenylpentanoic acid residue (Ahppa). The structures stictamides A-C (1-3) were assigned 2D NMR spectroscopic and chemical methods. Due epimerization Ahppa observed after hydrolysis, configuration this unit was deduced through conversion 1 an appropriate derivative application our recently developed statine database. Evaluation stictamide A...