Alzheimer’s
disease (AD) is characterized by progressive
neurodegeneration and impaired cognitive functions. Fascaplysin is
a β-carboline alkaloid isolated from marine sponge Fascaplysinopsis
bergquist in 1988. Previous studies have shown that fascaplysin
might act on acetylcholinesterase and β-amyloid (Aβ) to
produce anti-AD properties. In this study, a series of fascaplysin
derivatives were synthesized. The cholinesterase inhibition activities,
the neuronal protective effects, and the toxicities of these compounds
were evaluated in vitro. Compounds 2a and 2b, the two most powerful compounds in
vitro, were further selected to evaluate their cognitive-enhancing
effects in animals. Both 2a and 2b could
ameliorate cognitive dysfunction induced by scopolamine or Aβ
oligomers without affecting locomotor functions in mice. We also found
that 2a and 2b could prevent cholinergic
dysfunctions, decrease pro-inflammatory cytokine expression, and inhibit
Aβ-induced tau hyperphosphorylation in vivo. Most importantly, pharmacodynamics studies suggested that 2b could penetrate the blood–brain barrier and be retained
in the central nervous system. All these results suggested that fascaplysin
derivatives are potent multitarget agents against AD and might be
clinical useful for AD treatment.
Non-small cell lung carcinoma (NSCLC) metastasis is responsible for most of cancer-related mortality. The tumor associated macrophages (TAMs) are known to be crucial cells in lung cancer and are usually divided into two antagonistic types, M1 and M2. Puerarin has a wide spectrum of pharmacological properties. The present study explores puerarin on macrophage polarization and metastasis of NSCLC. The results demonstrated that puerarin inhibited tumor growth and tumor volumes in NSCLC xenograft model, increased M1 markers [CD197+, inducible nitric oxide synthase (iNOS)+, CD40+)] and reduced M2 markers (CD206+, Arg-1+ and CD163+). Besides, puerarin elevated the level of pro-inflammatory cytokine interferon (IFN)-γ, tumor necrosis factor (TNF)-α and interleukin (IL)-12, decreased the expression of pro-tumor cytokines IL-10, IL-4 and transforming growth factor (TGF)-β. To explore whether puerarin directly acts on macrophages, we purified macrophages from NSCLC model, the results showed that puerarin inhibited macrophages polarized to M2 phenotype and did not require the auxiliary of other cells. In addition, puerarin suppressed the invasion and migration of NSCLC macrophages, restrained the expression of angiogenesis factors. Puerarin also inhibited the activation of mitogen-activated extracellular signal-regulated kinase (MEK)/extracellular signal-regulated kinase (ERK) 1/2 pathway through inhibition of ERK nucleus translocation. Finally, IL-4 induced M2 macrophage polarization and metastasis were partially offset by puerarin through inactivating the MEK/ERK 1/2 pathway. Taken together, this study validated that puerarin is able to skew macrophage populations back to M1 subsets to stimulate antitumor effects and suggests puerarin is a negative metastatic regulator of NSCLC.
The
marine natural product fucoxanthin has been reported previously
to produce anti-Alzheimer’s disease (AD) neuroprotective effects
in vitro and in vivo. Fucoxanthin was also demonstrated to be safe
in preclinical and small population clinical studies, but the low
bioavailability of fucoxanthin in the central nervous system (CNS)
has limited its clinical applications. To overcome this, poly lactic-co-glycolic acid-block-polyethylene glycol
loaded fucoxanthin (PLGA-PEG-Fuc) nanoparticles with diameter at around
200 nm and negative charge were synthesized and suggested to penetrate
into the CNS. Loaded fucoxanthin could be liberated from PLGA-PEG
nanoparticles by sustained released in the physiological environment.
PLGA-PEG-Fuc nanoparticles were shown to significantly inhibit the
formation of Aβ fibrils and oligomers. Moreover, these nanoparticles
were taken up by both neurons and microglia, leading to the reduction
of Aβ oligomers-induced neurotoxicity in vitro. Most importantly,
intravenous injection of PLGA-PEG-Fuc nanoparticles prevented cognitive
impairments in Aβ oligomers-induced AD mice with greater efficacy
than free fucoxanthin, possibly via acting on Nrf2 and NF-κB
signaling pathways. These results altogether suggest that PLGA-PEG
nanoparticles can enhance the bioavailability of fucoxanthin and potentiate
its efficacy for the treatment of AD, thus potentially enabling its
future use for AD therapy.
Non-small cell lung carcinoma (NScLc) accounts for 85% of all lung cancers and the five-year survival rate is ~1% in the late stage. circular RNAs (circRNAs) were reported to be involved in the progression of diverse human cancers. However, the role of circ-ACACA in NSCLC progression remains elusive. Quantitative polymerase chain reaction was conducted to detect the expression levels of circ-ACACA and microRNA (miR)-1183 in NScLc tissues and cells. A Cell Counting Kit-8 assay and transwell assay were employed to check proliferation and migration, respectively. Metabolic alternations in NSCLC cells were monitored by the Seahorse XFe96 analyzer. The protein levels of cellular myelocytomatosis, matrix metallopeptidase 9, glucose transporter 1, phosphatase and tensin homolog, phosphoinositide 3-kinases (PI3K), phosphorylated PI3K (p-PI3K), protein kinase B (PKB) and p-PKB in samples were measured by western blotting. The interaction between circ-AcAcA and miR-1183 was predicted by circular RNA Interactome, which was verified by dual-luciferase reporter assay, RNA immunoprecipitation assay and RNA pull-down assay. Xenograft tumor model was established to investigate the biological roles of circ-ACACA in vivo. The level of circ-ACACA was markedly upregulated in NSCLC tissues and cells, which was contrary to the expression of miR-1183. Knockdown of circ-AcAcA inhibited proliferation and migration of NScLc cells and also reduced the glycolysis rate. In addition, miR-1183 was a target of circ-ACACA and its downregulation reversed circ-ACACA silencing-mediated inhibitory impact on NSCLC progression. Further studies indicated that circ-AcAcA regulated the PI3K/PKB pathway through interacting with miR-1183 and downregulation of circ-AcAcA suppressed tumor growth. Knockdown of circ-ACACA impeded NSCLC progression by sponging miR-1183 and inactivating the PI3K/PKB signaling pathway.
Objectives. Retina abnormalities are related to cognitive disorders in patients with Alzheimer’s disease (AD). Retinal amyloid beta (Aβ) can be labeled by curcumin. We measured Aβ content in the cerebrum and retina of APPswe/PS1dE9 (APP) transgenic mice with early age to investigate the correlation between cerebrum and retina. Methods. APP mice and age-matched wild-type mice were investigated every month from age 2 months to 6 months to assess changes in Aβ content in the retina and cerebrum. At the beginning of each month, mice were fed a curcumin diet (50 mg/kg/day) for 7 consecutive days. The Aβ levels in the retina and cerebrum were measured by ELISAs. Correlations were identified between retinal and cerebral Aβ contents using Pearson’s correlation. Results. In the absence of curcumin, there was a significant correlation between Aβ contents in the retina and cerebrum of APP mice (r=0.7291, P=0.0014). With increasing age, Aβ-mediated degenerative change in the cerebrum (P<0.001 in 5 months) and retina (P<0.01 in 5 months) increased significantly. The inhibitory effect of curcumin on the Aβ level was significant in the cerebrum (P<0.001) and retina (P<0.01) of older APP mice in the early stage of life. Conclusion. We observed a significant correlation between the Aβ content in the retina and Aβ content in the cerebrum of APP mice. Our data suggest an appropriate time to measure retinal Aβ. Although curcumin can label Aβ in the retina, it also suppresses Aβ levels and weakens the degree of correlation between Aβ in cerebrum and retina tissues.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.