Metabolic brain disease最新文献

Alzheimer's disease (AD) is a progressive neurodegenerative condition marked by amyloid-beta deposits, tau pathology, chronic systemic inflammation, and metabolic disturbances. Recent evidence highlights the relevance of inflammatory markers and adipokines as practical blood-based biomarkers in AD diagnosis. In this cross-sectional study, 70 patients with probable AD and 50 healthy controls matched for age and sex were evaluated. Cognitive performance was measured using the Standardized Mini Mental Test (SMMT). Serum intelectin-1 (ITLN1) and tumor necrosis factor-alpha (TNF-α) levels were analyzed, and hematologic indices were used to calculate the Systemic Immune-Inflammation Index (SII), Systemic Inflammation Response Index (SIRI), and CALLY index. Compared to controls, individuals with AD exhibited significantly lower ITLN1, albumin, lymphocyte counts, and CALLY index, while CRP, neutrophil and monocyte counts, SII, and SIRI were notably higher. TNF-α concentrations showed no significant difference between groups. ITLN1 and CALLY levels correlated positively with SMMT scores, whereas SII and SIRI correlated negatively. ROC analysis indicated that ITLN1 (AUC = 0.764), CALLY (AUC = 0.754), SII (AUC = 0.734), and SIRI (AUC = 0.787) had moderate discriminatory ability. This study suggests that reduced ITLN1 and increased systemic inflammation indices are associated with AD and may reflect underlying metabolic and inflammatory pathways involved in disease progression. Although TNF-α levels were variable, ITLN1, SII, SIRI, and CALLY indices demonstrated potential as peripheral biomarkers to help distinguish patients with AD. Future large-scale prospective research is needed to further clarify their clinical utility.

This 2024comprehensive review examines the crucial functions of lipids in neurological health, highlighting their vital contributions to brain structure, function, and pathology. The intricate lipid composition of the brain, comprising phospholipids, sphingolipids, cholesterol, glycolipids, and polyunsaturated fatty acids, supports membrane integrity, synaptic transmission, and myelination. Lipid production, metabolism, and transport in the central nervous system are meticulously controlled, necessitating specialised interactions among neurones, glial cells, and the blood-brain barrier. Lipid homeostasis dysregulation is widely acknowledged as playing a critical role in the aetiology of neurodegenerative diseases such as Alzheimer's and Parkinson's, multiple sclerosis, and neuropsychiatric disorders like schizophrenia and depression. These disruptions result in compromised synapse function, neuroinflammation, oxidative stress, and neuronal injury. The review emphasises bioactive lipids, particularly specialised pro-resolving mediators originating from polyunsaturated fatty acids, which regulate neuroinflammation and enhance neuroprotection. Progress in lipidomics has enabled the discovery of new lipid biomarkers and therapeutic targets, presenting intriguing opportunities for disease diagnosis, prognosis, and therapy. This paper highlights the significance of lipid biology in maintaining brain health and the therapeutic potential of targeting lipid pathways to mitigate the progression of neurological diseases, integrating contemporary lipidomic discoveries and mechanistic knowledge.

Hepatic encephalopathy (HE) is a neuropsychiatric disease caused by liver failure and/or portosystemic shunting and is characterized by cognitive and motor impairments. Although it is typically thought to be reversible after liver transplantation, recent research suggests the opposite. This underscores the need for a deeper understanding of HE pathophysiology. Both motor and cognitive function impairments are characteristic of HE and these two functions are controlled by the cerebellum. Therefore, we performed behavioral and histological studies to investigate motor dysfunction and neurodegeneration in thioacetamide-induced moderate-grade hepatic encephalopathy (MoHE) rats. To further investigate the molecular changes in the cerebellum, we utilized label-free-based mass spectrometry analysis. Rotarod and gait tests indicated gross and fine motor impairment, respectively. Histological examination revealed Purkinje neuron degeneration and Bergmann glial fiber hypertrophy. Mass spectrometry analysis identified 2,002 proteins, of which 65 were significantly differentially expressed (35 upregulated and 30 downregulated). Bioinformatic analysis of these 65 proteins revealed dysregulation of calcium ion signalling, GTPase cycles, endocytosis, and apoptosis. Western blotting showed the upregulation of RheB, MPPCB, and fetuin-A, which further validated the MS results. Immunofluorescence also validated the overexpression of these proteins, along with lactadherin, and showed spatial distribution in the granular and Purkinje layers of the cerebellum. This study provides a profile of proteomic changes in the cerebellum and the associated dysregulated biological pathways that may be responsible for the pathophysiology. These findings not only highlight promising new therapeutic targets but also open the door to the development of innovative treatments that could significantly improve patient outcomes.

Parkinson's disease (PD) is a neurodegenerative disease that primarily affects motor function. Dopaminergic cell death occurs progressively in the PD brain and autophagic dysfunction is critically implicated in the neuronal death. Therefore, modulating impaired autophagic flux is a promising strategy to treat dopaminergic neurodegeneration, addressing the unmet needs in PD. This study aimed to investigate efficacy and the underlying mechanism of Paeonia lactiflora extract (PLE) focusing on autophagic dysfunction in 6-hydroxydopamine (6-OHDA)-induced PD models in vitro and in vivo for the first time. PC12 cells were treated with PLE at concentrations of 10, 30, and 100 µg/ml, followed by 6-OHDA treatment. For in vivo study, PLE was administered to ICR mice that were intrastriatally injected with 6-OHDA. As a result, in PC12 cells, PLE increased the cell viability and suppressed apoptosis against 6-OHDA. In addition, PLE improved the imbalance in the expression of autophagy-related proteins including microtubule associated protein 1 light chain 3 beta (LC3B) and sequestosome-1/p62, as well as the phosphorylation of protein kinase B (AKT)/mammalian target of rapamycin (mTOR) and extracellular signal-regulated kinase (ERK) in AKT-dependent manner. Subsequently, Behavior assessment revealed that PLE administration to 6-OHDA-induced PD mice alleviated asymmetric movement impairment. Moreover, PLE treatment significantly attenuated dopaminergic neuronal loss, mitigated the decrease in dopamine transporter expression, and reduced LC3B levels in the brain. Taken together, these results suggest that PLE can protect neuronal cells and alleviate motor dysfunction induced by 6-OHDA, by restoring autophagic dysfunction via AKT signaling pathway.

Alzheimer's disease (AD), acknowledged as the leading cause of dementia, is defined by the accumulation of amyloid plaques and neurofibrillary tangles (NFTs) in the brain. This condition presents a significant challenge to global health due to its complex and multifaceted characteristics. Pharmacological treatments for AD mainly focus on relieving symptoms instead of addressing the fundamental progression of the condition. Currently, there are three cholinesterase inhibitors (ChEIs) that can be used for the treatment of AD: donepezil, rivastigmine, and galantamine, along with the N-methyl-D-aspartate (NMDA) receptor antagonist memantine. Although these medications can improve cognitive function and assist patients in their daily activities, it is crucial to understand that they do not halt the progression of the disease itself. Recently, innovative therapeutic strategies have been introduced for the treatment of this disease. Cell and gene therapies hold remarkable potential for the treatment of AD. Gene therapy, in particular, enables the precise modulation of AD-related genes, enhances neuroprotective factors, and mitigates the accumulation of amyloid plaques. Additionally, cell-based therapies utilizing mesenchymal stromal cells (MSCs), neural stem cells (NSCs), and induced pluripotent stem cells (iPSCs) are designed to replace lost neurons, modulate immune responses, and restore functional neural networks. Together, these innovative techniques represent significant advancement in the treatment of AD, instilling hope for enhanced patient outcomes and a higher quality of life. In this review, we emphasize the innovative cell and gene strategies, along with in vitro and preclinical studies, that explore the potential of gene and cell-based therapies as treatments for AD.

Neurological disorders like Alzheimer's, Parkinson's, and stroke involve oxidative stress and inflammation. Current treatments mainly ease symptoms but have side effects. Piceatannol, a natural polyphenol, shows promise as a safer, multi-target neuroprotective agent. This review aims to compile and analyze preclinical evidence on PCN, elucidate its underlying mechanisms, and explore its therapeutic prospects in the management of neurological disorders. A comprehensive literature search was conducted using PubMed/MEDLINE and Google Scholar, incorporating in vitro and in vivo studies that evaluated PCN in relevant models. Findings indicate that PCN exerts neuroprotection through potent antioxidant effects, enhancing superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities, and activating Nrf2 signaling while suppressing proinflammatory mediators via nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein kinase (MAPK) pathway inhibition. It also stabilizes mitochondrial function, prevents neuronal apoptosis by modulating Bcl-2/Bax balance and caspase activity, and mitigates ferroptosis. Furthermore, PCN reduces disease-specific pathological markers such as amyloid-β (Aβ) and acetylcholinesterase (AChE), improving memory, motor performance, and neurobehavioral outcomes. These effects are observed in diverse models, including cerebral ischemia-reperfusion injury (CIRI), subarachnoid hemorrhage (SAH), Alzheimer's disease, chronic unpredictable stress (CUS), and prion-related neurodegeneration. In conclusion, PCN's multi-target actions and safe clinical trial position make it a strong candidate for neurodegenerative disease therapy. While preclinical data are compelling, rigorous clinical trials are essential to validate efficacy, optimize dosage, and explore its potential as a standalone or adjunctive treatment for neurological disorders.

Alzheimer's disease (AD) is the most common and irreversible type of dementia, accounting for more than half of all dementia cases. Early diagnosis of AD plays a role in slowing the progression of the disease and also preserving the quality of life of patients. However, there is often a time lag of several decades between the biological onset of the disease and the time of clinical diagnosis. At the time of diagnosis, the patient often has noticeable cognitive decline, which reduces the effectiveness of available treatments. This diagnostic time lag from onset to the onset of symptoms highlights the need to identify accessible and cost-effective screening tools, such as biomarker-based diagnostic and screening methods. Studies have implicated disorders of the oral-brain axis in the pathogenesis of neurodegenerative diseases such as AD. Oral dysbiosis has been epidemiologically associated with an increased risk of cognitive decline and AD, making the oral microbiome a potential biomarker for screening and early diagnosis of AD. Oral dysbiosis also plays a role in the pathogenesis of AD by increasing systemic inflammation and neuroinflammation. TLR/NLR signaling has been identified as a key intrinsic pathway in the pathogenesis of these neuroinflammations and systemic inflammation, which may suggest the use of inhibitors such as TAK-242/MCC950 as a potential therapeutic approach in the treatment of AD, although preclinical and clinical evidence for the use of these inhibitors in the course of AD is still very limited. In this review, we discuss oral dysbiosis in AD and review studies investigating the mouth-brain axis as an effective pathway in AD from diagnosis to treatment.

Alzheimer's disease (AD) poses significant challenges to public health and well-being, with current treatments often providing limited efficacy. Chuanzhitongluo capsule (CZTL) has neuroprotective effects, and is expected to be used for the treatment of AD. In this study, the chemical composition, pharmacological effects and underlying mechanisms of CZTL against AD were systematically investigated. We identified the major components of CZTL through ultra-high-performance liquid chromatography coupled with a quadrupole time-of-flight mass spectrometer. AD rat model was established via scopolamine injection, followed by the administration of CZTL at various dosages, and pharmacological effects were then systematically evaluated. Furthermore, the potential mechanisms were explored using metabolomics and immunohistochemistry. Seventeen chemical constituents were identified from CZTL. Pretreatment with CZTL led to significant improvements in cognitive function and reductions in neuronal loss among AD rats. CZTL administration decreased abnormal protein aggregates (Aβ and Tau), along with markers of oxidative stress and inflammation. Metabolomic and immunohistochemical analyses indicated that CZTL modulated nicotinamide metabolism and impacted levels of NAD+, UMP, nitric oxide, and SIRT1 activity. These results suggest that CZTL effectively mitigates cognitive deficits and neuronal loss in AD by regulating nicotinamide and SIRT1, while inhibiting oxidative stress and inflammation. This study lies in their contribution to the development of novel anti-AD therapies derived from traditional Chinese medicine, paving the way for new approaches in managing neurodegenerative diseases.