Immunometabolism In Brain Aging and Neurodegeneration: Bridging Metabolic Pathways and Immune Responses.

The complex set of interactions between the immune system and metabolism, known as immunometabolism, has emerged as a critical regulator of disease outcomes in the central nervous system. Numerous studies have linked metabolic disturbances to impaired immune responses in brain aging, neurodegenerative disorders, and brain injury. In this review, we will discuss how disruptions in brain immunometabolism balance contribute to the pathophysiology of brain dysfunction.

Poststroke hyperglycemia dysregulates cap-dependent translation in neural cells.

Aims: Post stroke hyperglycemia has been shown to deter functional recovery. Earlier findings have indicated the cap-dependent translation regulator 4E-BP1 is detrimentally upregulated in hyperglycemic conditions. The present study aims to test the hypothesis that hyperglycemic ischemic reperfusion injury (I/R) affects normal protein translation poststroke.

Intra-arterial verapamil improves functional outcomes of thrombectomy in a preclinical model of extended hyperglycemic stroke.

The abrupt hyperglycemic reperfusion following thrombectomy has been shown to harm the efficacy of the intervention in stroke patients with large vessel occlusion. Studies of ours and others have shown thioredoxin-interacting protein (TXNIP) is critically involved in hyperglycemic stroke injury. We recently found verapamil ameliorates cerebrovascular toxicity of tissue plasminogen activators in hyperglycemic stroke.

Paracrine Effects of Mesenchymal Stem Cells in Ischemic Stroke: Opportunities and Challenges.

It is well acknowledged that neuroprotective effects of transplanted mesenchymal stem cells (MSCs) in ischemic stroke are attributed to their paracrine-mediated actions or bystander effects rather than to cell replacement in infarcted areas. This therapeutic plasticity is due to MSCs' ability to secrete a broad range of bioactive molecules including growth factors, trophic factors, cytokines, chemokines, and extracellular vesicles, overall known as the secretome. The secretome derivatives, such as conditioned medium (CM) or purified extracellular vesicles (EVs), exert remarkable advantages over MSC transplantation in stroke treating.

The p75 neurotrophin receptor inhibitor, LM11A-31, ameliorates acute stroke injury and modulates astrocytic proNGF.

The precursor form of nerve growth factor (proNGF) is essential to maintain NGF survival signaling. ProNGF is also among endogenous ligands for p75 neurotrophin receptor (p75ntr). Mounting evidence implies that p75ntr signaling contributes to neural damage in ischemic stroke.

Lost in Translation: Neurotrophins Biology and Function in the Neurovascular Unit.

The neurovascular unit (NVU) refers to the functional building unit of the brain and the retina, where neurons, glia, and microvasculature orchestrate to meet the demand of the retina's and brain's function. Neurotrophins (NTs) are structural families of secreted proteins and are known for exerting neurotrophic effects on neuronal differentiation, survival, neurite outgrowth, synaptic formation, and plasticity. NTs include several molecules, such as nerve growth factor, brain-derived neurotrophic factor, NT-3, NT-4, and their precursors.

Transplantation of Exercise-Induced Extracellular Vesicles as a Promising Therapeutic Approach in Ischemic Stroke.

Clinical evidence affirms physical exercise is effective in preventive and rehabilitation approaches for ischemic stroke. This sustainable efficacy is independent of cardiovascular risk factors and associates substantial reprogramming in circulating extracellular vesicles (EVs). The intricate journey of pluripotent exercise-induced EVs from parental cells to the whole-body and infiltration to cerebrovascular entity offers several mechanisms to reduce stroke incidence and injury or accelerate the subsequent recovery.

Thioredoxin interacting protein regulates age-associated neuroinflammation.

Immune system hypersensitivity is believed to contribute to mental frailty in the elderly. Solid evidence indicates NOD-like receptor pyrin domain containing-3 (NLRP3)-inflammasome activation intimately connects aging-associated chronic inflammation (inflammaging) to senile cognitive decline. Thioredoxin interacting protein (TXNIP), an inducible protein involved in oxidative stress, is essential for NLRP3 inflammasome activity.

Enhancement of angiogenesis and neurogenesis by intracerebroventricular injection of secretome from human embryonic stem cell-derived mesenchymal stem cells in ischemic stroke model.

It is well accepted that the success of mesenchymal stem cells (MSCs) therapy against experimental stroke is mainly due to cellular paracrine manners rather than to replace lost tissue per se. Given such "bystander" effects, cell-free therapeutics manifest as a promising approach in regenerative medicine. Here we aimed at evaluating the effect of conditioned medium (CM) derived from human embryonic MSCs (hESC-MSC) on the neurological deficit, neurogenesis, and angiogenesis in experimental stroke.

Verapamil as an Adjunct Therapy to Reduce tPA Toxicity in Hyperglycemic Stroke: Implication of TXNIP/NLRP3 Inflammasome.

Thrombolytic therapy has remained quite challenging in hyperglycemic patients for its association with poor prognosis and increased hemorrhagic conversions. We recently showed that tissue plasminogen activator (tPA)-induced cerebrovascular damage is associated with thioredoxin-interacting protein (TXNIP) upregulation, which has an established role in the detrimental effects of hyperglycemia. In the present work, we investigated whether verapamil, an established TXNIP inhibitor, may provide protection against hyperglycemic stroke and tPA-induced blood-brain barrier (BBB) disruption.

The conditioned medium of human embryonic stem cell-derived mesenchymal stem cells alleviates neurological deficits and improves synaptic recovery in experimental stroke.

The transplantation of mesenchymal stem cells (MSCs) is of main approaches in regenerative therapy for stroke. Due to the potential tumorigenicity and low survival rate of transplanted cells, focuses have been shifted from cell replacement to their paracrine effects. Therefore, stem cell-conditioned medium (CM) therapy has emerged as an alternative candidate.

Tissue Plasminogen Activator Promotes TXNIP-NLRP3 Inflammasome Activation after Hyperglycemic Stroke in Mice.

Hyperglycemia has been shown to counterbalance the beneficial effects of tissue plasminogen activator (tPA) and increase the risk of intracerebral hemorrhage in ischemic stroke. Thioredoxin interacting protein (TXNIP) mediates hyperglycemia-induced oxidative damage and inflammation in the brain and reduces cerebral glucose uptake/utilization. We have recently reported that TXNIP-induced NLRP3 (NOD-like receptor pyrin domain-containing-3) inflammasome activation contributes to neuronal damage after ischemic stroke.

Thioredoxin-Interacting Protein (TXNIP) Associated NLRP3 Inflammasome Activation in Human Alzheimer's Disease Brain.

Alzheimer's disease (AD) is the most common form of age-associated dementia characterized by amyloid-β plaques and neurofibrillary tangles. Recent studies have demonstrated that thioredoxin-interacting protein (TXNIP), an endogenous regulator of redox/glucose induced stress and inflammation, is now known to be upregulated in stroke, traumatic brain injury, diabetes and AD. We hypothesized that TXNIP overexpression sustains neurodegeneration through activation of the nucleotide binding and oligomerization domain-like receptor protein 3 in human AD brains.

Metabolic Syndrome, Brain Insulin Resistance, and Alzheimer's Disease: Thioredoxin Interacting Protein (TXNIP) and Inflammasome as Core Amplifiers.

Empirical evidence indicates a strong association between insulin resistance and pathological alterations related to Alzheimer's disease (AD) in different cerebral regions. While cerebral insulin resistance is not essentially parallel with systemic metabolic derangements, type 2 diabetes mellitus (T2DM) has been established as a risk factor for AD. The circulating "toxic metabolites" emerging in metabolic syndrome may engage several biochemical pathways to promote oxidative stress and neuroinflammation leading to impair insulin function in the brain or "type 3 diabetes".

Inhibition of the NLRP3-inflammasome as a potential approach for neuroprotection after stroke.

Activation of the NOD-like receptor protein (NLRP3)-inflammasome has been postulated to mediate inflammatory responses to brain damage during ischemic/reperfusion (I/R) injury. We therefore hypothesized that MCC950, a selective NLRP3-inflammasome inhibitor provides protection in mouse model of transient middle cerebral artery occlusion (tMCAO). Focal cerebral ischemia was induced by 60 min tMCAO followed by intraperitoneal administration of MCC950 (50 mg/kg) or saline at 1 h and 3 h post-occlusion.

High intensity exercise preconditioning provides differential protection against brain injury following experimental stroke.

Aims: Different modes of physical activity provide cerebrovascular protection against thromboembolic events. Based on recent reports high intensity exercise protocols appear to raise cerebral VEGF levels leading to efficient cerebral angiogenesis. The present study aims to address if moderate continuous training (MCT) and high intensity interval training (HIT) differ in preconditioning against ischemic stroke.

Thioredoxin-Interacting Protein (TXNIP) in Cerebrovascular and Neurodegenerative Diseases: Regulation and Implication.

Neurological diseases, including acute attacks (e.g., ischemic stroke) and chronic neurodegenerative diseases (e.

MCC950, the Selective Inhibitor of Nucleotide Oligomerization Domain-Like Receptor Protein-3 Inflammasome, Protects Mice against Traumatic Brain Injury.

Nucleotide oligomerization domain (NOD)-like receptor protein-3 (NLRP3) inflammasome may intimately contribute to sustaining damage after traumatic brain injury (TBI). This study aims to examine whether specific modulation of NLPR3 inflammasome by MCC950, a novel selective NLRP3 inhibitor, confers protection after experimental TBI. Unilateral cortical impact injury was induced in young adult C57BL/6 mice.

Coenzyme Q10 supplementation improves acute outcomes of stroke in rats pretreated with atorvastatin.

Objectives: Coenzyme Q10 (CoQ10, ubiquinone) stands among the safest supplements in the elderly to protect against cardiovascular disorders. Noteworthy, CoQ10 deficiency is common in many surviving stroke patients as they are mostly prescribed statins for the secondary prevention of stroke incidence lifelong. Accordingly, the current study aims to experimentally examine whether CoQ10 supplementation in animals receiving atorvastatin may affect acute stroke-induced injury.

Differential impact of treadmill training on stroke-induced neurological disorders.

Objective: Physical exercise contributes to improving stability against nerve injury caused by ischaemic stroke. Here we aimed to preliminarily investigate the effects of continuous endurance training (CET) and high-intensity interval training (HIT) on stroke-associated anxiety, locomotion, neurological assessments and P70S6 Kinase (P70S6K) activation as well. To do this, rats were trained according to HIT and CET protocols for 2 months prior to being subject to middle cerebral artery occlusion surgery.

A Search for Mitochondrial Damage in Alzheimer's Disease Using Isolated Rat Brain Mitochondria.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects regions of the brain that control cognition, memory, language, speech and awareness to one's physical surroundings. The pathological initiation and progression of AD is highly complex and its prevalence is on the rise. In his study, Alzheimer's disease was induced with single injection of amyloid-β (Aβ) peptides (30ng, by stereotaxy) in each hemisphere of the Wistar rat brain.

Nanoliposome containing cyclosporine A reduced neuroinflammation responses and improved neurological activities in cerebral ischemia/reperfusion in rat.

Cyclosporine A (CsA) is known as a neuroprotective agent against cerebral ischemia/reperfusion (I/R) in animal models. However, the significant therapeutic effects of CsA have been observed in high systemic doses or manipulating the blood-brain barrier, resulting in systemic side effects and toxicity. As the liposome nanocarriers have been developed for efficient delivery of peptide and proteins, liposomal CsA (Lipo-CsA) could improve cerebral (I/R) injuries.

Study of Sedative-Hypnotic Effects of Aloe vera L. Aqueous Extract through Behavioral Evaluations and EEG Recording in Rats.

In this study, we investigated the sedative and hypnotic effects of the aqueous extract of Aloe vera on rats. In order to evaluate the overall hypnotic effects of the Aloe vera extract, open field and loss of righting reflex tests were primarily used. The sedative and hypnotic effects of the extract were then confirmed by detection of remarkable raise in the total sleeping time through analysis of electroencephalographic (EEG) recordings of animals.