Neurodegenerative and mood disorders represent growing medical and social problems, many of which are produced by oxidative stress, neuroinflammation, disruption in the metabolism of various neurotransmitters, and some disturbances in lipid/carbohydrate homeostasis. Biologically active plant compounds, including flavonoids, have been shown to exert a positive impact on central nervous system function. This review assesses the studies of naturally occurring flavonoids belonging to various polyphenol subclasses and their mechanisms of neuroprotective action, especially against neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. Most of the studied phytochemicals possess anti-oxidative, anti-inflammatory, and neuroprotective properties. These phytochemicals have been considered as compounds that reduce the risk of developing Alzheimer's and Parkinson's diseases and can be used in the treatment of neurological diseases. The neuroprotective actions of some flavonoids may entail mechanisms that regulate reactive oxygen species generation and modify inflammatory pathways, and they should be considered as therapeutic agents.

Regular exercise is known to have positive effects on a variety of health outcomes, including the prevention of obesity and cognitive decline. Several recent reports have suggested that combining exercise with dietary factors such as flavonoids can amplify health functions. While the addition of dietary factors synergistically or additively enhances the beneficial effects of exercise, the addition of exercise may also reduce the amount of dietary factors needed to obtain their beneficial effects. This review describes (1) the exercise-induced improvement of health functions focusing on cognitive function, (2) several studies that investigated the effects that combining flavonoids with exercise has on obesity and cognitive function, and (3) the synergistic effect of inducing beige adipocyte formation to potentially explain the mechanism of the preventive effects of combining dietary factors and exercise on obesity, including new findings on lactate obtained through these studies. Finally, we summarize the following challenges and issues in research on developing the combination of dietary factors and exercise: clarifying the appropriate types and intensities of exercise and appropriate intake of dietary factors for obtaining the optimal combined effect, accumulating results of human interventional studies, and examining the benefits of this combination in improving the memory and learning ability of young adults and children. As scientists studying functional foods, we should focus more on exercise-replacement and exercise-complementing dietary factors in our research. This journal will play an important role in elucidating the molecular mechanisms underlying the combined effects of dietary factors and exercise.

Alzheimer's disease (AD) is the most common form of dementia globally, placing a substantial economic burden on patients and society. Exercise serves as an adjuvant therapy for AD with a low incidence of related adverse events. As a non-pharmacological intervention, it has demonstrated significant potential in the therapy of AD.

This study examines the key hotspots and emerging trends in exercise therapy for AD, offering valuable insights for researchers engaged in future research in this field.

The Web of Science Core Collection database was utilized to search for literature on exercise therapy for AD from January 1, 2000, to November 1, 2024, with 1,372 relevant articles being identified. And CiteSpace 6.2.R4 and VOSviewer were used to evaluate the bibliometric indicators.

Since 2000, the number of publications in the field of exercise therapy for AD has been increasing. In addition to the well-known areas of research, such as the impact of exercise on cognitive function, the combination of exercise and medication therapy, the effects of exercise on specific symptoms, and the exercise with music therapy, the field may also focus on more novel topics. These include the integration of the design and implementation of exercise interventions, exercise and dendritic spines, and exercise and neurophysiological mechanisms. Furthermore, an analysis of emerging keywords reveals that the current main research direction is exploring the specific physiological mechanisms through which exercise affects AD. This includes three emerging trends: the impact of exercise on cognitive impairment in AD patients, the effects of exercise on brain-derived neurotrophic factor (BDNF) and Amyloid beta, and the influence of exercise on Stress and neuroinflammation.

The research results indicate that interventions using exercise to alleviate the negative symptoms of AD, as well as combining exercise with medication for therapy, are gaining increasing attention from researchers. Meanwhile, novel topics such as exercise and music therapy, the design and implementation of exercise interventions, and neurophysiological mechanisms should also attract scholarly interest. Additionally, exploring the physiological mechanisms behind exercise therapy for AD could be a key focus for future research.

Antioxidant enzyme therapy shows promise for treating Alzheimer's disease (AD), but significant challenges remain in achieving effective blood-brain barrier (BBB) penetration and sustained therapeutic effects. We developed a novel neutrophil membrane (NM)-coated cerium-doped Prussian blue biomimetic nanozyme (NM@PB-Ce) that demonstrates outstanding enzymatic properties and targeted therapeutic efficacy. Extensive physicochemical characterization using transmission electron microscopy, X-ray photoelectron spectroscopy, and dynamic light scattering confirmed the successful synthesis of uniform nanoparticles (~ 142 nm) with preserved membrane protein functionality. In vitro studies utilizing SH-SY5Y neuroblastoma cells revealed that NM@PB-Ce effectively scavenged reactive oxygen species through multiple enzyme-mimetic activities (catalase, superoxide dismutase, and peroxidase). The nanozyme significantly suppressed NLRP3 inflammasome activation and subsequent pyroptosis, reducing inflammatory markers (IL-1β, IL-18) while attenuating Aβ aggregation. Using a sophisticated co-culture BBB model and real-time in vivo fluorescence imaging, we demonstrated NM@PB-Ce's ability to traverse the BBB and accumulate specifically in AD-affected regions. In an Aβ1-42 oligomer-induced AD mouse model, systematic administration of NM@PB-Ce (320 μg/mL, 0.01 mL/g/day for 14 days) significantly improved cognitive performance across multiple behavioral paradigms, including the Morris water maze, Y-maze, and open field tests. Molecular and histological analyses revealed decreased neuroinflammation markers (GFAP, Iba-1) in the hippocampus, reduced levels of NLRP3, caspase-1, and phosphorylated tau (demonstrated by Western blot and ELISA), and enhanced dendritic spine density (visualized through Golgi staining). This comprehensive study establishes NM@PB-Ce as a promising therapeutic platform for AD treatment, providing both mechanistic insights into its mode of action and robust evidence of its therapeutic efficacy in targeting neuroinflammation and cognitive decline.

Alzheimer's disease (AD) is the most common neurodegenerative disease, which is mainly caused by the damage of the structure and function of the central nervous system. At present, there are many adverse reactions in market-available drugs, which can't significantly inhibit the occurrence of AD. Therefore, the current focus of research is to find safe and effective therapeutic drugs to improve the clinical treatment of AD. Oxidative stress bridges different mechanism hypotheses of AD and plays a key role in AD. Numerous studies have shown that natural flavonoids have good antioxidant effects. They can directly or indirectly resist -oxidative stress, inhibit Aβ aggregation and Tau protein hyperphosphorylation by activating Nrf2 and other oxidation-antioxidation-related signals, regulating synaptic function-related pathways, promoting mitochondrial autophagy, etc., and play a neuroprotective role in AD. In this review, we summarised the mechanism of flavonoids inhibiting oxidative stress injury in AD in recent years. Moreover, because of the shortcomings of poor biofilm permeability and low bioavailability of flavonoids, the advantages and recent research progress of nano-drug delivery systems such as liposomes and solid lipid nanoparticles were highlighted. We hope this review provides a useful way to explore safe and effective AD treatments.

Brain-related disorders include neuroinflammation, neurodegenerative disorders, and demyelination, which ultimately affect the quality of life of patients. Currently, brain-related disorders represent the most challenging health problem worldwide due to complex pathogenesis and limited availability of drugs for their management. Further, the available pharmacotherapy accompanies serious side effects, therefore, much attention has been directed toward the development of alternative therapy derived from natural sources to treat such disorders. Recently, flavonoids, natural phytochemicals, have been reported as a treatment option for preventing brain aging and disorders related to this. Among these flavonoids, dietary luteolin, a flavone, is found in many plant products such as broccoli, chamomile tea, and honeysuckle bloom having several pharmacological properties including neuroprotective activities. Therefore, the objective of this paper is to compile the available literature regarding the neuroprotective potential of luteolin and its mechanism of action. Luteolin exerts notable anti-inflammatory, antioxidant, and antiapoptotic activity suggesting its therapeutic efficacy in different neurological disorders. Numerous in-vivo and in-vitro experiments have revealed that luteolin exhibits neuroprotective potential via up-regulating the ER/ERK, PI3AKT, Nrf2 pathways and down-regulating the MAPK/JAK2STAT and NFκB pathways. Taking into account of available facts regarding the neuroprotective efficacy of luteolin, the current study highlights the beneficial effects of luteolin for the prevention, management, and treatment of different neurological disorders. Thus, luteolin can be considered an alternative for the development of new pharmacophores against various brain-related disorders.

Major depressive disorder (MDD) is a common mental disorder that severely disrupts psychosocial function and decreases the quality of life. Although the pathophysiological mechanism underlying MDD is complex and remains unclear, emerging evidence suggests that autophagy dysfunction plays a role in MDD occurrence and progression. Natural products serve as a major source of drug discovery and exert tremendous potential in developing antidepressants. Recently published reports are paying more attention on the autophagy regulatory effect of antidepressant natural products. In this review, we comprehensively discuss the abnormal changes occurred in multiple autophagy stages in MDD patients, and animal and cell models of depression. Importantly, we emphasize the regulatory mechanism of antidepressant natural products on disturbed autophagy, including monomeric compounds, bioactive components, crude extracts, and traditional Chinese medicine formulae. Our comprehensive review suggests that enhancing autophagy might be a novel approach for MDD treatment, and natural products restore autophagy homeostasis to facilitate the renovation of mitochondria, impede neuroinflammation, and enhance neuroplasticity, thereby alleviating depression.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by amyloid plaques and cognitive decline, the latter of which is thought to be driven by soluble oligomeric amyloid-β (oAβ). The dysregulation of G protein-gated inwardly rectifying K+ (GIRK; also known as Kir3) channels has been implicated in rodent models of AD. Here, seeking mechanistic insights, we uncovered a sex-dependent facet of GIRK-dependent signaling in AD-related amyloid pathophysiology. Synthetic oAβ1-42 suppressed GIRK-dependent signaling in hippocampal neurons from male mice, but not from female mice. This effect required cellular prion protein, the receptor mGluR5, and production of arachidonic acid by the phospholipase PLA2. Although oAβ suppressed GIRK channel activity only in male hippocampal neurons, intrahippocampal infusion of oAβ or genetic suppression of GIRK channel activity in hippocampal pyramidal neurons impaired performance on a memory test in both male and female mice. Moreover, genetic enhancement of GIRK channel activity in hippocampal pyramidal neurons blocked oAβ-induced cognitive impairment in both male and female mice. In APP/PS1 AD model mice, GIRK-dependent signaling was diminished in hippocampal CA1 pyramidal neurons from only male mice before cognitive deficit was detected. However, enhancing GIRK channel activity rescued cognitive deficits in older APP/PS1 mice of both sexes. Thus, whereas diminished GIRK channel activity contributes to cognitive deficits in male mice with increased oAβ burden, enhancing its activity may have therapeutic potential for both sexes.

Alzheimer's disease (AD) is the leading cause of dementia, and currently, no effective treatments are available to reverse or halt its progression in clinical practice. Although a plethora of studies have highlighted the benefits of physical exercise in combating AD, elder individuals often have limited exercise capacity. Therefore, mild physical exercise and nutritional interventions represent potential strategies for preventing and mitigating neurodegenerative diseases. Our research, along with other studies, have demonstrated that platycodin D (PD) or its metabolite, platycodigenin, derived from the medicinal plant Platycodon grandiflorus, exerts neuroprotective effects against amyloid β (Aβ)-induced neuroinflammation. However, the combined effects of PD and physical exercise on alleviating AD have yet to be explored. The current study aimed to investigate whether combined therapy could synergistically ameliorate memory deficits and AD pathology in 5 × FAD mice.

Five-month-old 5 × FAD mice were randomly assigned to four groups, and received either PD (5 mg/kg/day, p.o.), voluntary running, or a combination of both for 47 days. Nest building test, locomotion test, and Morris water maze test were used to evaluate the cognitive function. Immunohistochemical and ELISA analysis was performed to determine Aβ build-up, microglia and astrocytes hyperactivation, and survival neurons in the hippocampus and perirhinal cortex. Real-time quantitative PCR analysis was used to assess the polarization of microglia and astrocytes. HPLC analysis was performed to measure monoamine neurotransmitters in the hippocampus.

The combination of PD and voluntary running synergistically restored nest-building behavior, alleviated recognition and spatial memory deficits, and showed superior effects compared to monotherapy. In addition, the PD and voluntary running combination reduced Aβ build-up, decreased hyperactivation of microglia and astrocytes in the hippocampus and perirhinal cortex, promoted the polarization of inflammatory M1 microglia and reactive astrocytes toward beneficial phenotypes, and lowered systemic circulating pro-inflammatory cytokines while increasing anti-inflammatory cytokines in 5 × FAD mice. Furthermore, combined therapy effectively protected neurons and increased levels of 5-hydroxytryptamine (5-HT) and dopamine (DA) in the hippocampus of 5 × FAD mice. In conclusion, the combination of PD and voluntary running holds great potential as a treatment for AD, offering promise for delaying onset or progression of AD.

Cognitive dysfunction can occur both in normal aging and age-related neurological disorders, such as mild cognitive impairment and Alzheimer's disease (AD). These disorders have few treatment options due to side effects and limited efficacy. New approaches to slow cognitive decline are urgently needed. Dietary interventions (nutraceuticals) have received considerable attention because they exhibit strong neuroprotective properties and may help prevent or minimize AD symptoms. Biological aging is driven by a series of interrelated mechanisms, including oxidative stress, neuroinflammation, neuronal apoptosis, and autophagy, which function through various signaling pathways. Recent clinical and preclinical studies have shown that dietary small molecules derived from natural sources, including flavonoids, carotenoids, and polyphenolic acids, can modulate oxidative damage, cognitive impairments, mitochondrial dysfunction, neuroinflammation, neuronal apoptosis, autophagy dysregulation, and gut microbiota dysbiosis. This paper reviews research on different dietary small molecules and their bioactive constituents in the treatment of AD. Additionally, the chemical structure, effective dose, and specific molecular mechanisms of action are comprehensively explored. This paper also discusses the advantages of using nanotechnology-based drug delivery, which significantly enhances oral bioavailability, safety, and therapeutic effect, and lowers the risk of adverse effects. These agents have considerable potential as novel and safe therapeutic agents that can prevent and combat age-related AD.

Alzheimer's disease (AD) is a neurodegenerative condition characterized by oxidative stress and neuroinflammation. Tanshinone IIA (Tan-IIA), a bioactive compound isolated from Salvia miltiorrhiza plants, has shown potential neuroprotective effects; however, the mechanisms underlying such a function remain unclear.

To investigate potential Tan-IIA neuroprotective effects in AD and to elucidate their underlying mechanisms.

Hematoxylin and eosin staining was utilized to analyze structural brain tissue morphology. To assess changes in oxidative stress and neuroinflammation, we performed enzyme-linked immunosorbent assay and western blotting. Additionally, the effect of Tan-IIA on AD cell models was evaluated in vitro using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Genetic changes related to the long non-coding RNA (lncRNA) nuclear-enriched abundant transcript 1 (NEAT1)/microRNA (miRNA, miR)-291a-3p/member RAS oncogene family Rab22a axis were assessed through reverse transcription quantitative polymerase chain reaction.

In vivo, Tan-IIA treatment improved neuronal morphology and attenuated oxidative stress and neuroinflammation in the brain tissue of AD mice. In vitro experiments showed that Tan-IIA dose-dependently ameliorated the amyloid-beta 1-42-induced reduction of neural stem cell viability, apoptosis, oxidative stress, and neuroinflammation. In this process, the lncRNA NEAT1 - a potential therapeutic target - is highly expressed in AD mice and downregulated via Tan-IIA treatment. Mechanistically, NEAT1 promotes the transcription and translation of Rab22a via miR-291a-3p, which activates nuclear factor kappa-B (NF-κB) signaling, leading to activation of the pro-apoptotic B-cell lymphoma 2-associated X protein and inhibition of the anti-apoptotic B-cell lymphoma 2 protein, which exacerbates AD. Tan-IIA intervention effectively blocked this process by inhibiting the NEAT1/miR-291a-3p/Rab22a axis and NF-κB signaling.

This study demonstrates that Tan-IIA exerts neuroprotective effects in AD by modulating the NEAT1/miR-291a-3p/Rab22a/NF-κB signaling pathway, serving as a foundation for the development of innovative approaches for AD therapy.

Alzheimer's disease (AD) is a neurodegenerative disease with insidious onset and progressive development. It is clinically characterized by cognitive impairment, memory impairment and behavioral change. Chinese herbal medicine and acupuncture are important components of traditional Chinese medicine (TCM), and are commonly used in clinical treatment of AD. This paper systematically summarizes the research progress of traditional Chinese medicine natural products and acupuncture treatment of AD, which combined with existing clinical and preclinical evidence, based on a comprehensive review of neuroinflammation, and discusses the efficacy and potential mechanisms of traditional Chinese medicine natural products and acupuncture treatment of AD. Resveratrol, curcumin, kaempferol and other Chinese herbal medicine components can significantly inhibit the neuroinflammation of AD in vivo and in vitro, and are candidates for the treatment of AD. Acupuncture can alleviate the memory and cognitive impairment of AD by improving neuroinflammation, synaptic plasticity, nerve cell apoptosis and reducing the production and aggregation of amyloid β protein (Aβ) in the brain. It has the characteristics of early, safe, effective and benign bidirectional adjustment. The purpose of this paper is to provide a basis for improving the clinical strategies of TCM for the treatment of AD.

Cognitive impairment is the main symptom of Alzheimer's disease (AD). Accumulating evidence implicate that immunity plays an important role in AD. Here, we investigated the effect of Qi-fu-yin (QFY) on cognitive impairment and cytokine secretion of 5xFAD mice.

We used 2.5-month-old 5xFAD transgenic mice for behavioral tests to observe the changes in cognitive function after QFY treatment. After the behavioral experiment, the whole brain, cortex and plasma of each mouse were collected for soluble Aβ analysis, immunohistochemical experiment and cytokine analysis.

Here we found that the treatment of QFY ameliorated the ability of object recognition, passive avoidance responses and the ability of spatial learning and memory in 5xFAD mice. The deposits of β_{1 - 42} and Aβ_{1 - 40} were alleviated and the ration of Aβ_{1 - 42}/Aβ_{1 - 40} was decrease in the plasma and brain of 5xFAD mice administrated with QFY. The administration of QFY promoted the secretion of anti-inflammatory cytokines, IL-5, IL-10 and G-CSF, and reduced the content of proinflammatory cytokines IFN-γ in plasma of 5xFAD mice. Notably, we found that the treatment of QFY decreased the concentration of CCL11 in the brain and plasma of 5xFAD mice.

This suggested that QFY improved cognition and reduced Aβ deposits in 5xFAD mice by regulating abnormal immunity in 5xFAD mice. QFY may be as a potential therapeutic agent for AD.