Metabolic brain disease最新文献

Angiogenesis plays a critical role in mitigating cerebral infarction injury. However, both endogenous and exogenous angiogenic responses are often insufficient to generate stable, functional blood vessels. Brain microvascular endothelial cells rely primarily on glycolysis for energy, a process that intensifies under hypoxic conditions. Therefore, enhancing energy metabolism may support angiogenesis. Tongqiao Huoxue Decoction (TQHXD) has been shown to have therapeutic effects on cerebral infarction, but its ability to promote angiogenesis by enhancing glycolysis remains unclear. We established an in vivo middle cerebral artery occlusion (MCAO) model and analyzed four postinfarction stages: hyperacute, acute, subacute and chronic. Brain injury in MCAO rats was assessed using neurobehavioral scoring, 2,3,5-triphenyltetrazolium chloride (TTC) staining, hematoxylin‒eosin (HE) staining, and brain water content measurements. The relationship between angiogenesis and glycolysis was further evaluated using enzyme-linked immunosorbent assays (ELISAs), western blotting (WB), reverse transcription polymerase chain reaction (RT‒PCR), and immunohistochemistry (IHC). TQHXD significantly alleviated brain injury and improved neurological function in MCAO rats. Treatment with TQHXD markedly increased the expressions of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF), which are potentially linked to elevated levels of glucose, pyruvate, lactate, glucose transporter 1 (GLUT1), phosphofructokinase (PFK), and lactate dehydrogenase A (LDHA). Therefore, in the early stages of cerebral infarction (hyperacute and acute stages), TQHXD activates the HIF-1α/VEGF pathway by enhancing glycolysis, thereby accelerating the formation of new blood vessels and inhibiting cerebral infarction damage.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline, oxidative stress, and neuroinflammation. Betanin, a natural antioxidant, has shown neuroprotective potential, but its clinical use is limited by poor bioavailability. This study investigates the effects of betanin-loaded nanomicelles, designed to enhance brain delivery, in a scopolamine-induced rat model of AD. Nanomicelles were synthesized and characterized using TEM, DLS, and FT-IR. Rats received either pre- or post-treatment with betanin nanomicelles, free betanin, donepezil, or saline. Cognitive performance was assessed using the Morris Water Maze. Gene expression levels of AQP4, BDNF, SIRT6, and Seladin-1 were measured using real-time PCR, and antioxidant activity was evaluated by assessing glutathione (GSH) and glutathione reductase (GR) in hippocampal tissue. Betanin nanomicelles improved spatial memory, increased BDNF and SIRT6 expression, and reduced AQP4 levels, indicating potential neuroprotection. Seladin-1 expression was notably elevated in the pre-treatment group, suggesting support for neuronal survival. Antioxidant assays showed restoration of GSH and GR activity. These findings suggest that betanin nanomicelles may enhance cognitive function and modulate neuroprotective pathways more effectively than free betanin, supporting their potential as a novel therapeutic strategy for AD.

The present study investigates the therapeutic potential of Ranolazine in cerebral ischemic stroke, focusing on its neuroprotective properties in a middle cerebral artery occlusion/reperfusion (MCAO/R) induced ischemic brain injury in a rat model. Ranolazine demonstrated neuroprotective effects by reducing infarct size and brain edema, improving cerebral blood flow, and preserving blood-brain barrier integrity, leading to improved neurological function. Mechanistically, ranolazine decreased HIF-1α and GFAP expression while enhancing BDNF levels. Ranolazine increased mitochondrial complex enzyme activities (I, II, IV, and V) and enhanced the expression of the mitochondrial Tu translation elongation factor (TUFM), NRF1, and PGC-1α levels, indicating improved mitochondrial biogenesis and decreased mitochondrial oxidative stress markers such as 4-HNE and increased catalase and SOD. Further, ranolazine treatment reduced the levels of pro-inflammatory cytokines TNF-α and IL-6 while increasing the anti-inflammatory cytokine IL-10, suggesting its anti-inflammatory potential in mitigating the stroke-associated neuroinflammation. Moreover, ranolazine suppressed apoptosis by reducing the levels of apoptotic mediators such as cytochrome c, caspase-9, and caspase-3, and flow cytometry analysis revealed a significant decline in neuronal apoptosis, which further underscores its neuroprotective efficacy. Therefore, the novelty of this research lies in demonstrating that ranolazine exerts neuroprotective effects against ischemic brain injury by simultaneously modulating apoptotic pathways, restoring vital neurological factors (BDNF, TUFM, NRF-1, PGC-1α), improving mitochondrial function, reducing oxidative stress, and attenuating neuroinflammation, offering a novel multi-targeted therapeutic approach, meriting further clinical studies.

Pharmacological treatments for major depressive disorder (MDD) have limited efficacy, underscoring the need for biomarkers to assess treatment response. Metabolomics enables characterization of metabolic alterations associated with antidepressant effectiveness. This cross-sectional study aimed to discover and validate metabolite biomarkers that can be used to screen responses to drug treatment in MDD through a metabolomics-based approach. Serum samples from drug-treated MDD patients with persistent depression (D-MDD), patients in remission (R-MDD), and healthy controls were divided into discovery (D-MDD: n=19, R-MDD: n=17, control: n=25) and validation (D-MDD: n=36, R-MDD: n=30, control: n=65) sets. Untargeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis identified candidate metabolites, which were validated using multiple reaction monitoring. L-histidine and nudifloramide were identified in the discovery phase. L-histidine increased stepwise from D-MDD to R-MDD to controls, but significance was lost in validation. Nudifloramide showed a similar trend; in validation, its concentration was significantly higher in controls than in D-MDD, with R-MDD at intermediate levels approaching controls. Alterations in nudifloramide suggest involvement of the tryptophan-kynurenine pathway and NAD⁺ homeostasis in MDD pathophysiology and treatment response. Nudifloramide may serve as a biomarker for distinguishing depressed from healthy states in treated patients. Further pathway-focused studies are warranted.

Neurodegenerative and neuropsychiatric diseases pose significant challenges to individuals' well-being and healthcare systems. These conditions share common mechanisms like oxidative stress, protein aggregation, inflammation, impaired neurotransmission, mitochondrial dysfunction, and excitotoxicity. Current treatments offer limited efficacy and often come with adverse effects. Mushrooms, recognized as a valuable cultural and nutritional resource, hold therapeutic potential. As a future superfood, they contribute to overall health and well-being. Various mushroom groups have been studied for their bioactive compounds, including polysaccharides, protein complexes, peptides, terpenoids, and phenolic compounds, demonstrating efficacy in different neurodegenerative conditions. Notably, edible mushrooms have shown promise in mitigating beta-amyloid-induced neurotoxicity. This review explores the utilization of mushroom biomolecules in treating neurodegenerative diseases, offering novel research insights with preclinical and clinical trials in both rat model and humans paving the way for the development and utilization of mushroom bioactive compounds as neuroprotective agents.

Hepatic encephalopathy (HE), complication of liver dysfunction, leads to neurocognitive impairments. Artichoke (Cynara scolymus L.) has been traditionally used for its antioxidant, anti-inflammatory and hepatoprotective properties. This study evaluates artichoke leaf and receptaculum extracts in cholestasis and HE in a rat model. Wistar rats were divided into 6 groups: sham-control, bile duct ligation (BDL), and BDL with low/high-dose leaf or receptaculum extracts. After BDL, physiological saline and extracts (250/500 mg/kg) were administered orally for 28 days. Cognitive activity was evaluated using Morris water maze and novel object recognition tests on day 28. Artichoke extract regulated liver enzymes and bilirubin at high-doses and significantly increased antioxidant enzyme activities reduced by BDL. Elevated 8-Hydroxyguanosine (8-OHdG) levels decreased in liver and brain tissues. Similarly, artichoke extracts reduced cytokine and hydroxyproline (HP) levels elevated by cholestasis. Following BDL, Na⁺/K⁺-ATPase levels in brain and liver tissues decreased, while artichoke extract reversed this. Artichoke, particularly high-dose receptaculum, improved impaired performance and increased time in the target quadrant after BDL. Both artichoke leaf and receptaculum extracts improved recognition. Artichoke treatments, especially high-dose receptaculum, reduced hepatic and neuronal damage and improved histological appearance. These findings highlight the therapeutic potential of artichoke extracts for liver fibrosis and related neurocognitive disorders.

The leaves of Linzia gerberiformis are used in traditional Cameroonian medicine for the treatment of respiratory infections and hepatitis. The present study was conducted to evaluate the anti-amnesic effects of the aqueous extract of L. gerberiformis leaves in ovariectomized rats exposed to chronic unpredictable mild stress (CUMS). A total of 42 female rats were used for this study. Thirty five ovariectomized rats were subjected to chronic unpredictable mild stress, distributed across five treatment groups, while 7 non-ovariectomized rats served as a control group receiving distilled water and were labeled as the vehicle. Ovariectomized (OVX) female rats exposed to CUMS for 1 week were treated with distilled water, estradiol valerate (1 mg/kg), and the aqueous extract of L. gerberiformis leaves (75, 150, and 300 mg/kg) for 14 days starting from the 8th day after OVX. Memory integrity was assessed using the novel object recognition test (NORT) and the Morris water maze test (MWM). Hippocampus was collected to assess the cholinergic system [acetylcholinesterase (AChE) and acetylcholine], pro-oxidants (nitric oxide (NO) and malondialdehyde (MDA)), anti-oxidants (superoxide dismutase (SOD), catalase, and, GSH (reduced glutathione)) as well as 17-β-estradiol. Plasma was also collected to measure the concentration of 17-β-estradiol. The aqueous extract of L. gerberiformis leaves at 75 mg/kg and 150 mg/kg improved short-term recognition memory and long-term spatial learning memory compared to OVX animals exposed to CUMS treated with distilled water. The aqueous extract of L. gerberiformis leaves increased plasma and hippocampal 17-β-estradiol compared to OVX + CUMS animals. In addition, L. gerberiformis significantly prevented the effect induced by the combined action of ovariectomy and CUMS in rats by preventing the decrease of estrogen, acetylcholine, SOD, CAT and GSH; and the increase in AChE, NO and MDA. Pretreatment with L. gerberiformis aqueous extract leaves protects against the combined effects of ovariectomy and CUMS-induced memory deficits, suggesting its anti-amnesic properties. These properties could be mediated through the prevention of estrogen decline, modulation of the cholinergic system and oxidative stress.

Therapeutic hypothermia (TH) is the standard treatment for neonatal hypoxia-ischemia (HI), but its efficacy is limited. Understanding the molecular pathways involved in cell death and survival, while considering sex-related differences, is essential to optimize therapeutic strategies. This study evaluated the neuroprotective effects of memantine, a non-competitive NMDA receptor antagonist, alone or in combination with TH, in male and female neonatal rats subjected to HI. Seven-day-old pups (P7) underwent right common carotid artery occlusion followed by 90 min of hypoxia (8% O₂). Memantine (20 mg/kg, i.p.) was administered immediately after hypoxia, followed by TH (32 °C for 5 h). Neurobehavioral tests were performed at P8, and animals were euthanized at P9 for assessment of brain injury and analysis of cleaved caspase-3, p-Akt, Bcl-2, and Bax levels by Western blot. The results showed that the treatments reversed the deficits in the righting reflex in females, but not in males. Memantine and TH - combined or alone - reduced infarct volume in males, while in females, memantine alone exerted a neuroprotective effect. Cleaved caspase-3 levels were reduced in both sexes in groups treated with memantine; in females, this reduction was also observed following TH alone or in combination with memantine. In males, both memantine and TH - either combined or alone - increased the Bcl-2/Bax ratio. In females, only the individual treatments (memantine or TH alone) promoted this anti-apoptotic effect. These findings highlight a sex-dependent differential effect of memantine and TH on neuroprotection.

Hepatic encephalopathy (HE) is a multifaceted neuropsychiatric syndrome frequently observed in patients with liver dysfunction. The present study aimed to evaluate the therapeutic effects of Fraxinus micrantha (F. micrantha) in thioacetamide (TAA)-induced HE model. HE was induced using TAA (200 mg/kg i.p.) for once every 48 h for 14 consecutive days in rats. Ethyl acetate fraction of F. micrantha (EAFM) (50, 100, and 200 mg/kg) was administered for 14 consecutive days (p.o.) after HE induction. TAA induced hepatotoxicity and HE, evidenced by significant alterations in liver biomarkers alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), lipid profiles (triglycerides, cholesterol), and neurotransmitter levels (serotonin, acetylcholine, dopamine, norepinephrine). Histopathological analysis revealed severe liver necrosis, inflammation, and brain damage, characterized by reduced neuronal density and hippocampal degeneration. EAFM treatment produced a significant, dose-dependent amelioration of TAA-induced liver injury, evidenced by the normalization of serum biomarkers (ALT, AST, ALP) and lipid profiles (cholesterol, triglycerides), with the 200 mg/kg dose showing efficacy comparable to silymarin. EAFM also exerted potent neuroprotective effects, restoring the altered levels of key neurotransmitters (serotonin, dopamine, norepinephrine) and reducing elevated acetylcholinesterase activity in the brain cortex and hippocampus. Furthermore, EAFM significantly mitigated oxidative stress by replenishing depleted reduced glutathione (GSH) levels in both hepatic and brain tissues. Histopathological analysis confirmed these findings, demonstrating that EAFM attenuated TAA-induced hepatocellular necrosis, inflammation, and hippocampal neurodegeneration. The results indicate that F. micrantha confers robust hepatoprotective and neuroprotective effects against HE, primarily mediated through its antioxidant activity and restoration of neurochemical balance, positioning it as a promising therapeutic candidate.

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.