Oxidative stress is believed to be one of the main causes of neurodegenerative diseases such as Alzheimer’s disease (AD). The pathogenesis of AD is still not elucidated clearly but oxidative stress is one of the key hypotheses. Here, we found that artemisinin, an anti-malarial Chinese medicine, possesses neuroprotective effects. However, the antioxidative effects of artemisinin remain to be explored. In this study, we found that artemisinin rescued SH-SY5Y and hippocampal neuronal cells from hydrogen peroxide (H₂O₂)-induced cell death at clinically relevant doses in a concentration-dependent manner. Further studies showed that artemisinin significantly restored the nuclear morphology, improved the abnormal changes in intracellular reactive oxygen species (ROS), reduced the mitochondrial membrane potential, and caspase-3 activation, thereby attenuating apoptosis. Artemisinin also stimulated the phosphorylation of the adenosine monophosphate -activated protein kinase (AMPK) pathway in SH-SY5Y cells in a time- and concentration-dependent manner. Inhibition of the AMPK pathway attenuated the protective effect of artemisinin. These data put together suggested that artemisinin has the potential to protect neuronal cells. Similar results were obtained in primary cultured hippocampal neurons. Cumulatively, these results indicated that artemisinin protected neuronal cells from oxidative damage, at least in part through the activation of AMPK. Our findings support the role of artemisinin as a potential therapeutic agent for neurodegenerative diseases.

The pathogenesis of Alzheimer's disease (AD) is complex, resulting in unsatisfactory effects of single-target therapeutic drugs. Accumulation evidence suggests that low toxicity multi-target drugs may play effective roles in AD. Ginseng is the root and rhizome of Panax ginseng Meyer, which can be used not only as herbal medicine but also as a functional food to support body functions. Ginsenoside RK1 (RK1), obtained from ginseng plants through high-temperature treatment, has antiapoptotic, antioxidant, anti-inflammatory effects and these events are involved in the development of AD. So, we believe that RK1 may be an effective drug for the treatment of AD. We aimed to investigate the potential protective effects and mechanisms of RK1 in AD. Neuronal damage was detected by MTT assay, LDH assay, immunofluorescence and western blotting. Oxidative stress was measured by JC-1 staining, reactive oxygen species (ROS) staining, superoxide dismutase (SOD) and malonaldehyde (MDA). The cognitive deficit was measured through morris water maze (MWM) and novel object recognition (NOR) tests. RK1 attenuated Aβ-induced apoptosis, restored mitochondrial membrane potential (ΔΨm), and reduced intracellular levels of ROS in both PC12 cells and primary cultured neurons. In vivo, RK1 significantly improved cognitive deficits and mitigated AD-like pathological features. Notably, RK1 demonstrated superior efficacy compared to the positive control drug, donepezil. Mechanistically, our study elucidates that RK1 modulates the phosphorylation of AMP-activated protein kinase (AMPK) and its downstream target, NF-E2-related factor 2 (Nrf2), leading to the optimization of mitochondrial membrane potential, reduction of ROS levels, and mitigation of AD-like pathology. It's noteworthy that blocking the AMPK signaling pathway attenuated the protective effects of RK1. RK1 demonstrates superior efficacy in alleviating cognitive deficits and mitigating pathological changes compared to donepezil. These findings suggest the potential utility of RK1-based therapies in the development of treatments for AD.

The abnormal immune response is an early change in the pathogenesis of Alzheimer’s disease (AD). Microglial activation is a crucial regulator of the immune response, which contributes to progressive neuronal injury by releasing neurotoxic products. Therefore, finding effective drugs to regulate microglial homeostasis and neuroinflammation has become a new AD treatment strategy. Artemisinin has potent anti-inflammatory and immune activities. However, it is unclear whether Artemisinin contributes to the regulation of microglial activation, thereby improving AD pathology. This study found that Artemisinin significantly reduced amyloid beta-peptide 1–42 (Aβ_1–42)-induced increases in nitric oxide and reactive oxygen species and inflammatory factors in BV2 cells. In addition, Artemisinin inhibited the migration of microglia and prevented the expansion of the inflammatory cascade. The mechanical studies showed Artemisinin inhibited neuroinflammation and exerted neuroprotective effects by regulating the Toll-like receptor 4 (TLR4)/Nuclear factor-kappa B (NF-κB) signaling pathway. Similar results were obtained in AD model mice, in which Artemisinin administration attenuated Aβ_1–42-induced neuroinflammation and neuronal injury, reversing spatial learning and memory deficits. The anti-inflammatory effect of Artemisinin is also accompanied by the activation of the TLR4/NF-κB signaling pathway in the animal model. Our results indicate that Artemisinin attenuated Aβ_1–42-induced neuroinflammation and neuronal injury by stimulating the TLR4/NF-κB signaling pathway. These findings suggest that Artemisinin is a potential therapeutic agent for AD.

Cognitive deficit is the main clinical feature of Alzheimer's disease (AD), and the massive death of neuronal cells is the leading cause of cognitive deficits. So, there is an urgent clinical need to discover effective drugs to protect brain neurons from damage in order to treat AD. Naturally-derived compounds have always been an important source of new drug discovery because of their diverse pharmacological activities, reliable efficacy and low toxicity. Magnoflorine is a quaternary aporphine alkaloid, which naturally exist in some commonly used herbal medicines, and has good anti-inflammatory and antioxidant effects. However, magnoflorine has not been reported in AD. To investigate the therapeutic effect and mechanism of magnoflorine on AD. Neuronal damage was detected by flow cytometry, immunofluorescence and western blotting. Oxidative stress was measured by detection of SOD and MDA, as well as JC-1 and reactive oxygen species (ROS) staining. The APP/PS1 mice were given drugs by intraperitoneal injection (I.P.) every day for one month, and then the new object recognition and Morris water maze were used to detect the cognitive ability of the mice. We demonstrated that magnoflorine reduced Aβ-induced PC12 cell apoptosis and intracellular ROS generation. Further studies found that magnoflorine significantly improved cognitive deficits and AD-type pathology. Most interestingly, the efficacy of magnoflorine was better than that of the clinical control drug donepezil. Mechanistically, based on RNA-sequencing analysis, we found that magnoflorine significantly inhibited phosphorylated c-Jun N-terminal kinase (JNK) in AD models. This result was further validated using a JNK inhibitor. Our results indicate that magnoflorine improves cognitive deficits and pathology of AD through inhibiting of JNK signaling pathway. Thus, magnoflorine may be a potential therapeutic candidate for AD.

Alzheimer's disease (AD) has become a major public health problem affecting the elderly population, and there is currently no effective treatment. Although the pathogenesis of AD is unclear, neurotoxicity induced by oxidative stress plays an important role in the progression of AD. Ginseng, the root and rhizome of Panax ginseng C. A. Meyer, is used not only as an herbal medicine but also as a functional food to support bodily functions. Ginsenoside Rk3 (Rk3), the main bioactive component in ginseng, has a strong antioxidant effect and has not been reported in AD. In this study, we showed that Rk3 improved neuronal apoptosis, decreased intracellular reactive oxygen species (ROS) production and restored mitochondrial membrane potential in PC12 and primary neuronal cells. In vivo, we found that Rk3 improved spatial learning and memory deficit in precursor protein (APP)/presenilin 1 (PS1) double transgenic mouse model of AD. Additionally, Rk3 increases glutathione reductase (GSH) and superoxide dismutase (SOD) levels while inhibits malondialdehyde (MDA) production, apoptosis and activation of glial cells in APP/PS1 mice. Mechanistically, we found that the protective effect of Rk3 is in correlation with the activation of AMPK/Nrf2 signaling pathway. In conclusion, the findings of this study provide support for Rk3 as a new strategy for the treatment of AD.

Background: Cardiac remodeling in heart failure involves macrophage-mediated immune responses. Recent studies have shown that a PRR (pattern recognition receptor) called dectin-1, expressed on macrophages, mediates proinflammatory responses. Whether dectin-1 plays a role in pathological cardiac remodeling is unknown. Here, we identified a potential role of dectin-1 in this disease. Methods: To model aberrant cardiac remodeling, we utilized mouse models of chronic Ang II (angiotensin II) infusion. In this model, we assessed the potential role of dectin-1 through using D1KO (dectin-1 knockout) mice and bone marrow transplantation chimeric mice. We then used cellular and molecular assays to discover the underlying mechanisms of dectin-1 function. Results: We found that macrophage dectin-1 is elevated in mouse heart tissues following chronic Ang II administration. D1KO mice were significantly protected against Ang II–induced cardiac dysfunction, hypertrophy, fibrosis, inflammatory responses, and macrophage infiltration. Further bone marrow transplantation studies showed that dectin-1 deficiency in bone marrow–derived cells prevented Ang II–induced cardiac inflammation and dysfunction. Through detailed molecular studies, we show that Ang II binds directly to dectin-1, causing dectin-1 homodimerization and activating the downstream Syk (spleen tyrosine kinase)/NF-κB (nuclear factor kappa B) signaling pathway to induce expression of inflammatory and chemoattractant factors. Mutagenesis studies identified R184 in the C-type lectin domain to interact with Ang II. Blocking dectin-1 in macrophages suppresses Ang II–induced inflammatory mediators and subsequent intercellular cross talk with cardiomyocytes and fibroblasts. Conclusions: Our study has discovered dectin-1 as a new nonclassical receptor of Ang II and a key player in cardiac remolding and dysfunction. These studies suggest that dectin-1 may be a new target for treating hypertension-related heart failure.