Insights Into the Role of Copper in Neurodegenerative Diseases and the Therapeutic Potential of Natural Compounds.

Neurodegenerative diseases encompass a collection of neurological disorders originating from the progressive degeneration of neurons, resulting in the dysfunction of neurons. Unfortunately, effective therapeutic interventions for these diseases are presently lacking. Copper (Cu), a crucial trace element within the human body, assumes a pivotal role in various biological metabolic processes, including energy metabolism, antioxidant defense, and neurotransmission. These processes are vital for the sustenance, growth, and development of organisms. Mounting evidence suggests that disrupted copper homeostasis contributes to numerous age-related neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), Wilson's disease (WD), Menkes disease (MD), prion diseases, and multiple sclerosis (MS). This comprehensive review investigates the connection between the imbalance of copper homeostasis and neurodegenerative diseases, summarizing pertinent drugs and therapies that ameliorate neuropathological changes, motor deficits, and cognitive impairments in these conditions through the modulation of copper metabolism. These interventions include Metal-Protein Attenuating Compounds (MPACs), copper chelators, copper supplements, and zinc salts. Moreover, this review highlights the potential of active compounds derived from natural plant medicines to enhance neurodegenerative disease outcomes by regulating copper homeostasis. Among these compounds, polyphenols are particularly abundant. Consequently, this review holds significant implications for the future development of innovative drugs targeting the treatment of neurodegenerative diseases.

Harnessing the Therapeutic Potential of Ginsenoside Rd for Activating SIRT6 in Treating a Mouse Model of Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is a prevalent global condition and a common precursor to liver cancer, yet there is currently no specific medication available for its treatment. Ginseng, renowned for its medicinal and dietary properties, has been utilized in NAFLD management, although the precise underlying mechanism remains elusive. To investigate the effectiveness of ginsenoside Rd, we employed mouse and cell models to induce NAFLD using high-fat diets, oleic acid, and palmitic acid. We explored and confirmed the specific mechanism of ginsenoside Rd-induced hepatic steatosis through experiments involving mice with a liver-specific knockout of SIRT6, a crucial protein involved in metabolic regulation. Our findings revealed that administration of ginsenoside Rd significantly reduced the inflammatory response, reactive oxygen species (ROS) levels, lipid peroxide levels, and mitochondrial stress induced by oleic acid and palmitic acid in primary hepatocytes, thereby mitigating excessive lipid accumulation. Moreover, ginsenoside Rd administration effectively enhanced the mRNA content of key proteins involved in fatty acid oxidation, with a particular emphasis on SIRT6 and its target proteins. We further validated that ginsenoside Rd directly binds to SIRT6, augmenting its deacetylase activity. Notably, we made a significant observation that the protective effect of ginsenoside Rd against hepatic disorders induced by a fatty diet was almost entirely reversed in mice with a liver-specific SIRT6 knockout. Our findings highlight the potential therapeutic impact of Ginsenoside Rd in NAFLD treatment by activating SIRT6. These results warrant further investigation into the development of Ginsenoside Rd as a promising agent for managing this prevalent liver disease.

Modulating endoplasmic reticulum stress in APP/PS1 mice by Gomisin B and Osthole in Bushen-Yizhi formula: Synergistic effects and therapeutic implications for Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is a prevalent neurodegenerative disorder with no effective cure. Targeting endoplasmic reticulum (ER) stress pathway may offer a novel approach to ameliorate cognitive deficits in AD. Bushen-Yizhi formula (BSYZ), a traditional Chinese medicine (TCM) prescription, has shown potential benefits for AD. To facilitate the development of new therapeutic agents for AD, it is important to identify the active components and the underlying mechanisms of BSYZ against AD. PURPOSE: The aim of this study was to systematically screen the active components of BSYZ that could improve learning and memory impairment in AD by modulating ER stress pathway. METHODS: A drug-target (D-T) network was constructed to analyze the herbal components of BSYZ. Network proximity method was used to identify the potential anti-AD components that targeted ER stress and evaluate their synergistic effects. The absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties and the literature evidence were considered to select promising candidates for further validation. The selected components were tested in vitro using an AD cell model (APPswe-SH-SY5Y). In vivo anti-AD effects of the components were assessed in APP/PS1 double-transgenic mice. RESULTS: 58 potential anti-AD components targeting ER stress were detected by network proximity analysis, and 13 out of them were selected based on ADMET properties and literature evidence. In vitro experiments confirmed that 5 components, namely gomisin B, ß-Carotene, imperatorin, chrysophanol, and osthole (OST), exhibited anti-AD effects on the APPswe-SH-SY5Y model. Moreover, network proximity analysis suggested that OST and Gomisin B might have synergistic effects on modulating ER stress. In vivo experiments demonstrated that OST, Gomisin B, OST+Gomisin B, and BSYZ all improved learning and memory function in APP/PS1 mice. Gomisin B and OST also restored cellular morphology and tissue structure in APP/PS1 mice. Thioflavine-S (Th-S) staining revealed that they reduced amyloid plaque deposition in the brain tissue of AD model mice. The qPCR results indicated that BSYZ, OST, and Gomisin B differentially regulated IRE1α, PERK, EIF2α, DDIT3, and Caspase 12 expression levels, while the OST and Gomisin B co-administration group showed better efficacy. This trend was further confirmed by immunofluorescence experiments. CONCLUSION: This study identified the active components of BSYZ that could ameliorate learning and memory impairment in AD by targeting ER stress pathway. OST and Gomisin B exhibited synergistic effects on modulating ER stress and reducing amyloid plaque deposition in vivo. Overall, our study elucidated the molecular mechanisms of BSYZ and its active components in attenuating AD symptoms which suggested the therapeutic potential of TCM for AD.

Network Pharmacology and Mechanism Studies of the Protective Effect of Ginseng against Alzheimer's Disease Based on Aß Pathogenesis.

Alzheimer's disease (AD) is a critical neurodegenerative disease that manifests as progressive intellectual decline and is pathologically characterized by a progressive loss of neurons in the brain. Despite extensive research on this topic, the pathogenesis of AD is not fully understood, while the beta-amyloid (Aß) hypothesis remains the dominant one and only a few symptomatic drugs are approved for the treatment of AD. Ginseng has been widely reported as an effective herbal medicine for the treatment of neurodegenerative diseases such as dementia. Therefore, we explore the protective effects of ginseng in AD by a network pharmacological approach based on the pathogenesis of Aß. Twenty-one major ginsenosides are screened based on ultraperformance liquid chromatography-mass spectrometry/mass spectrometry (HPLC-MS/MS) data. Among them, MAPK8, MAPK9, BACE1, FLT1, CDK2, and CCR5 are the core targets. By molecular docking and validation with the in vitro cell model APPswe-SH-SY5Y, we find that ginsenosides Rg3 and Ro have good neuroprotective effects and can reduce the expression of Aß 1 - 42 in APPswe-SH-SY5Y. Finally, through RT-qPCR experiment, we find that ginsenoside Rg3 targeted MAPK8, FLT1, and CCR5, while ginsenoside Ro targeted MAPK8, MAPK9, FLT1, and CCR5 for its potential anti-AD efficacy.