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.

No abstract

No abstract