Metabolic brain disease最新文献

Multiple sclerosis (MS) is a neurological disorder characterized by damage to the myelin sheaths surrounding axons in the central nervous system, causing decreased axonal signal transmission and disability in people with MS. Epstein-Barr virus (EBV) infection and vitamin D deficiency have been put forward as causal factors for the development of MS, but their effects have not been conclusively linked to the disruption of myelin maintenance. Interestingly, both EBV infection and vitamin D deficiency increase the levels of hepcidin, an acute-phase peptide hormone that inhibits iron absorption. The current understanding of iron dysregulation in MS is that iron accumulates in deep gray matter brain structures which leads to disability progression. However, recent studies have revealed that the apparent iron influx may be an artefact of disease-related brain atrophy, and that iron is in contrast depleted in the deep gray matter in MS, which could cause iron deficiency in oligodendrocytes (the cells producing myelin), leading to their demise due to a mitochondrial energy deficit, with consequent demyelination. EBV infection, vitamin D deficiency and iron deficiency may converge as causal risk factors for MS. Dismantling the current understanding that iron excess underpins MS would improve testing and optimization of iron parameters and vitamin D as part of clinical management of MS. This review additionally explores the risk factors for lytic reactivation of EBV which is hypothesized to drive MS disease activity. Conversely, ensuring that EBV remains in a latent state by ameliorating these risk factors may prevent MS exacerbations and disease worsening.

Alzheimer's disease (AD) is the most common form of dementia, characterized by progressive cognitive decline driven by a complex interplay of genetic, environmental, and lifestyle factors. Increasing evidence highlights impaired synaptic plasticity as a major contributor to early cognitive deficits, often preceding neuronal loss. In particular, disruption of long-term potentiation (LTP) within the hippocampus, a region essential for learning and memory, plays a central role. Accumulation of amyloid β (Aβ) plaques and hyperphosphorylated tau proteins compromises synaptic integrity, leading to reduced synaptic density and altered protein expression critical for excitatory signaling. Additional mechanisms, including microglial activation and mitochondrial dysfunction, further aggravate synaptic impairment through inflammation and oxidative stress. Understanding these interconnected molecular and cellular disruptions offers crucial insight into the pathways underlying synaptic dysfunction in AD. By elucidating these mechanisms, future research can inform novel therapeutic strategies aimed at preserving synaptic function and slowing disease progression.

Type 2 Diabetes (T2D) and Alzheimer's Disease (AD) share common risk factors that can be seen through T2D nearly doubling an individual's likelihood of developing AD. Some AD patients show signs of metabolic dysfunction as well. This review focuses on the potential mechanisms associated with these two diseases, like insulin resistance, inflammation, oxidative damage, mitochondrial injury, and cell death. One of the notable elements in this connection is the "brain insulin resistance," most frequently named as "type 3 diabetes," which impairs glucose metabolism and facilitates amyloid beta (Aβ) plaque synthesis while reducing the action of insulin-degrading enzyme (IDE). Moreover, the overactivity of glycogen synthase kinase-3 beta (GSK-3β) also triggers taurine protein pathology. Raised concentrations of glucose in blood can produce advanced glycation end products (AGEs), which further exacerbate neuroinflammation in tandem with the mitigation of neurotoxic Aβ oligomers. Inflammation and subsequent damage to mitochondria lead to the dissolution of synapses. Current vascular insults include the breakdown of the blood-brain barrier (BBB) and decreased brain perfusion, along with other contributory factors to conditions conducive to neurotoxicity. Recently, novel therapies are emerging, including GLP-1 agonists, intranasal insulin, and mitochondrial antioxidants, that show surprising results for treating both conditions, but on the contrary, bioavailability and the timing of interventions remain a big challenge in the management of these diseases. Eventually, further research should center on understanding the mechanisms of integration along with the development of molecular biology, neuroimaging, and outcome-driven treatment strategies. Comprehensive strategies that exist between T2D-AD for integration and preservation of brain and metabolic health are addressed in this review.

Hereditary tyrosinemia type I (HT1) is an inborn error of metabolism (IEM), caused by deficiency of the enzyme fumarylacetoacetate hydrolase (FAH), in the catabolic pathway of the semi-essential amino acid tyrosine (TYR), causing accumulation and formation of toxic metabolites such as succinylacetone (SA), which results in kidney and liver damage. Patients are treated with a low-protein diet and restriction of TYR and phenylalanine and administration of nitisinone (NTBC), a potent inhibitor of the 4-hydroxyphenylpyruvate dioxygenase (HPD) enzyme, which minimizes the formation of toxic metabolites. The literature has demonstrated the involvement of oxidative stress in the pathophysiology of tyrosinemia, but there is no informative data on patients under treatment. In this work, we evaluated oxidative stress and inflammation in patients with HT1 under treatment with NTBC, as well their SA levels in plasma and urine. We found a significant decrease in SA plasma and urine levels in treated patients compared to untreated patients and control group. We observed a decrease in IL-2 and an increase in IL-4, and non-significant differences were observed for the other cytokines, when compared to the control group. We did not observe significant differences between groups when evaluating total antioxidant status (TAS), oxidized guanine species, which represents oxidative damage to DNA/RNA, and sulfhydryl content, which represents oxidative damage to protein. When evaluating lipoperoxidation (TBARS) we found a significant increase for untreated patients in relation to the control group. Our study was the first to evaluate these parameters in HT1 patients treated with NTBC, and our results allow to suggest that the treatment appears to protect against inflammation, DNA and protein oxidative damage by decreasing SA levels.

Portacaval anastomosis (PCA) is a model for hypometabolic liver dysfunction. Spongiform neurodegeneration has been detected in the cerebellum of PCA rats 13 weeks after surgery. This report characterizes the damage associated with spongiform degeneration by studying mitochondrial, ultrastructural, and oxidative changes in the molecular, Purkinje, and granular layers of the cerebellar cortex. Morphometry by electron microscopy determined an increase in mitochondrial presence in PCA rats. In parallel, mitochondria displayed smaller size, diminished interconnectivity, and decreased elongation. Fluorescent probes revealed that PCA cerebellar mitochondria showed a reduction in membrane potential (ΔΨ) alongside a rise in superoxide levels. In contrast, the calcium content exhibited variability across the three cerebellar layers. In addition, an elevation of intracellular reactive oxygen species in the cerebellar cortex was detected. The measurement of TBARS, conjugated dienes, and total antioxidant activity confirmed the presence of oxidative stress in the PCA cerebella. The increased number of smaller mitochondria was accompanied by an altered equilibrium between mitochondrial fission and fusion markers in PCA rats: increased FIS1 and p-DRP1, as well as OPA1, but decreased MFN1. Immunohistochemical analyses of these markers indicated that the molecular layer was the most affected in the cerebellum of PCA rats. In conclusion, we characterized the active cerebellar damage associated with dysregulated mitochondrial activity accompanied by an evident pro-oxidative condition. Ultrastructural analysis helped to strengthen the depiction of the mitochondrial and biochemical alterations associated with the spongiform vacuolization observed in the PCA cerebellar cortex, especially within the molecular layer.

Chlorpyrifos (CPF), an organophosphate pesticide, is a widely used pest control chemical. Unfortunately, pesticides are known to cause neuronal intoxication. Umbelliferone (UMB) is an antioxidant, anti-inflammatory, and neuroprotective phytochemical. We plan to investigate the effectiveness of UMB in treating CPF-induced neurotoxicity. In our investigation, rats were assigned to the control, 30 mg/kg of UMB, 10 mg/kg of untreated CPF, CPF + UMB (15 mg/kg), and CPF + UMB (30 mg/kg) groups. UMB reduced neuronal intoxication by lowering p-Tau/Tau and β-amyloid. UMB reduced CPF-induced neuronal oxidative damage by lowering MDA content and increasing GSH levels, mediated by downregulating Keap1 and upregulating Nrf2, HO-1, and SOD3. UMB decreased CPF-induced brain inflammation by lowering TNF-α and IL-6 levels by suppressing NF-κB and STAT3 activation and downregulating NLRP3 dose-dependently. Our findings indicated that UMB is a potentially effective treatment approach for reducing CPF-induced neuronal intoxication by restoring the balance between oxidants and antioxidants and reducing inflammatory responses in brain tissues.

Recent studies have demonstrated that insulin and its receptors play a vital role in the central nervous system, supporting neuronal survival, regulating energy metabolism, and facilitating synaptic plasticity-processes fundamental to learning and memory. Therefore, disruption of insulin signaling and glucose metabolism in the central nervous system impairs cognitive function and plays a role in the induction of dementia, such as AD. In the central nervous system, increased insulin sensitivity and proper insulin signaling affect the molecular cascades underlying plasticity, learning, and memory. Therefore, increasing brain insulin sensitivity is a preventive and therapeutic strategy in the prevalence and prevention of neurodegenerative disorders. It has been confirmed that in muscle, liver, and brain tissues, regular exercise training (including aerobic, resistance, and high-intensity exercise) with standard intensity and frequency, undoubtedly plays an important role in improving insulin sensitivity. The effects of exercise training on improving brain insulin sensitivity can be explained by multiple mechanisms. Since muscle contraction can have endocrine effects by secreting secretomes (especially myokines), it seems that one of the precise mechanisms of the effect of exercise training and exercise-induced muscle contraction on brain insulin sensitivity is these myokines. This review examines the roles and mechanisms of multiple myokines in enhancing brain insulin sensitivity, along with the metabolic interactions between muscle and the central nervous system. Clinical tips for the type, dose, and intensity of exercise to increase myokines related to the central nervous system are also presented.

Hepatic encephalopathy (HE) is a common decompensating event in liver cirrhosis, with a prevalence of 10-14% in newly diagnosed cirrhotic and 30-40% during the course of the disease. The study aimed to evaluate the clinical spectrum, systemic inflammation, treatment outcomes, prognostic significance, and survival probability of HE in patients with liver cirrhosis. Over five years, consecutive patients hospitalized with HE were evaluated for symptoms, signs, etiology, inflammatory markers, prognostic index, and response to treatment. Primary outcomes included reversal of HE up to 10 days of admission and mortality at 28 days. Secondary outcomes included length of hospital stay, time taken for resolution of HE, adverse events, and recurrence of HE over 28 days. 539 patients were included. The median (range) age was 46 (18-82) years, with 84.4% males. Hyponatremia (65.4%) was the most common precipitating factor. Complete reversal of HE occurred in 62.8%. Median (range) Mean hospital stay was 7(27) days, and 28-day mortality during the study period was 26.1%. The survival probability was higher in grade 2 HE than in grade 3 and grade 4 (79.79 vs. 74.31 vs. 60.22%, p = 0.0020). Patients with resolution of HE had better survival {HR 0.271 [95% C. I (0.187-0.394)], p < 0.005}. Arterial ammonia, serum IL-6, and albumin were independent prognostic factors. Patients were classified into two groups according to a prognostic index calculated from these three variables. Survival probability at 28 days was 80.67% vs. 67% (p = 0.0001), respectively, in patients with low prognostic and high prognostic indexes. Approximately one-third of patients with liver cirrhosis with acute episodes of HE have non-reversal of HE and poor survival. The development of HE and its resolution is a crucial prognostic event in liver cirrhosis patients. The prognostic significance of hepatic encephalopathy has been previously studied in unison or combination with other decompensating events. However, data on the prognostic role of systemic inflammatory markers in patients with hepatic encephalopathy have not been well evaluated. This prospective observational study assessed the systemic inflammation, short-term prognostic significance, and survival probability of patients with hepatic encephalopathy (HE) with liver cirrhosis over 5 years. This study identified a prognostic index that could stratify patients with hepatic encephalopathy into those with a high or low survival risk. The development of HE and its resolution is a crucial prognostic event in liver cirrhosis patients. These early stratifications can help in identifying patients with a high risk of death, and advanced treatment or early transplantation can be advised.