Novel synergistic mechanism of 11-keto-β-boswellic acid and Z-Guggulsterone on ischemic stroke revealed by single-cell transcriptomics

Pharmacological Research, Год журнала: 2023, Номер 193, С. 106803 - 106803

Опубликована: Май 23, 2023

Although strides have been made, the challenge of preventing and treating ischemic stroke continues to persist globally. For thousands years, natural substances Frankincense Myrrh employed in Chinese Indian medicine address cerebrovascular diseases, with key components 11-keto-β-boswellic acid (KBA) Z-Guggulsterone (Z-GS) being active agents. In this study, synergistic effect underlying mechanism KBA Z-GS on were examined using single-cell transcriptomics. Fourteen cell types identified KBA-Z-GS-treated penumbra, microglia astrocytes account for largest proportion. They further re-clustered into six seven subtypes, respectively. GSVA analysis reflected distinct roles each subtype. Pseudo-time trajectory indicated that Slc1a2 Timp1 core fate transition genes regulated by KBA-Z-GS. addition, KBA-Z-GS synergistically inflammatory reactions cellular metabolism ferroptosis astrocytes. Most notably, we established an innovative drug-gene regulation pattern, divided four categories based pattern. Finally, Spp1 was demonstrated as hub target Taken together, study reveals cerebral ischemia, may be that. Precise drug development targeting offer a potential therapeutic approach stroke.

Язык: Английский

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Blood glutamate scavenging as a novel glutamate-based therapeutic approach for post-traumatic brain injury anxiety and social impairment

Translational Psychiatry, Год журнала: 2023, Номер 13(1)

Опубликована: Фев. 4, 2023

Traumatic brain injury (TBI) is a serious condition that associated with an increased risk of severe, long-term psychiatric consequences. Drugs target the glutamatergic system have proven successful in treating both TBI and many its sequelae. Blood glutamate scavengers (BGS) cause decrease blood levels, leading to reduction glutamate's concentration gradient from decreased levels glutamate. This study evaluated BGS pyruvate as treatment for TBI-related neuropsychiatric conditions rat model. 213 rats were divided into four groups 2 × design: Sham or treated control treatment. Magnetic resonance imaging, neurological status, assessed following injury. Four weeks after start treatment, all underwent behavioral tests assess anxious behavior social impairment (aggressive hierarchical behavior). Rats responded positively several tasks, lowering reducing anxiety depression, well modulating changes behavior. Glutamate scavenging may be effective therapeutic option post-TBI by elevations levels.

Язык: Английский

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The Integrity of the Blood–Brain Barrier as a Critical Factor for Regulating Glutamate Levels in Traumatic Brain Injury

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(6), С. 5897 - 5897

Опубликована: Март 20, 2023

A healthy blood-brain barrier (BBB) shields the brain from high concentrations of blood glutamate, which can cause neurotoxicity and neurodegeneration. It is believed that traumatic injury (TBI) causes long-term BBB disruption, subsequently increasing glutamate in blood, addition to increased resulting neuronal injury. Here, we investigate relationship between levels context permeability. Rats exposed disruption through an osmotic model or TBI treated with intravenous saline were compared control rats intact saline. After administration, cerebrospinal fluid tissue analyzed. The results showed a strong correlation groups disruption. We conclude protects permeability vital component regulating brain. These findings bring new approach treating consequences other diseases where central mechanism their development.

Язык: Английский

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The Relationship between Post-Traumatic Stress Disorder Due to Brain Injury and Glutamate Intake: A Systematic Review

Nutrients, Год журнала: 2024, Номер 16(6), С. 901 - 901

Опубликована: Март 21, 2024

There is a growing body of evidence that suggests connection between traumatic brain injury (TBI) and subsequent post-traumatic stress disorder (PTSD). While the exact mechanism unknown, we hypothesize chronic glutamate neurotoxicity may play role. The consumption dietary modifiable factor influencing levels in blood and, therefore, brain. In this systematic review, explored relationship development post-TBI PTSD. Of 1748 articles identified, 44 met inclusion criteria for analysis review. We observed individuals from countries with diets traditionally high had greater odds developing PTSD after TBI (odds ratio = 15.2, 95% confidence interval 11.69 to 19.76, p < 0.01). These findings support hypothesis chronically elevated concentrations caused by intake invoke neurodegeneration processes could ultimately result Further studies will clarify whether lowering via diet would be an effective strategy preventing or treating

Язык: Английский

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Evidence Implicating Blood-Brain Barrier Impairment in the Pathogenesis of Acquired Epilepsy following Acute Organophosphate Intoxication

Journal of Pharmacology and Experimental Therapeutics, Год журнала: 2023, Номер 388(2), С. 301 - 312

Опубликована: Окт. 12, 2023

Organophosphate (OP) poisoning can trigger cholinergic crisis, a life-threatening toxidrome that includes seizures and status epilepticus. These acute toxic responses are associated with persistent neuroinflammation spontaneous recurrent (SRS), also known as acquired epilepsy. Blood-brain barrier (BBB) impairment has recently been proposed pathogenic mechanism linking OP intoxication to chronic adverse neurologic outcomes. In this review, we briefly describe the cellular molecular components of BBB, review evidence altered BBB integrity following intoxication, discuss potential mechanisms by which may promote dysfunction. We highlight complex interplay between dysfunction suggests positive feedforward interaction. Lastly, examine research from diverse models disease states suggest loss contribute epileptogenic processes. Collectively, literature identifies convergent justifies further mechanistic into how causes its role in pathogenesis SRS potentially other long-term sequelae. Such is critical for evaluating stabilization neuroprotective strategy mitigating OP-induced epilepsy possibly seizure disorders etiologies. SIGNIFICANCE STATEMENT: Clinical preclinical studies support link blood-brain epileptogenesis; however, causal relationship difficult prove. Mechanistic delineate relationships provide novel insights resulting organophosphate non-OP neurological conditions such cognitive impairment.

Язык: Английский

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Diet’s Impact on Post-Traumatic Brain Injury Depression: Exploring Neurodegeneration, Chronic Blood–Brain Barrier Destruction, and Glutamate Neurotoxicity Mechanisms

Nutrients, Год журнала: 2023, Номер 15(21), С. 4681 - 4681

Опубликована: Ноя. 4, 2023

Traumatic brain injury (TBI) has a profound impact on cognitive and mental functioning, leading to lifelong impairment significantly diminishing the quality of life for affected individuals. A healthy blood-brain barrier (BBB) plays crucial role in guarding against elevated levels blood glutamate, making its permeability vital aspect glutamate regulation within brain. Studies have shown efficacy reducing excess as treatment post-TBI depression, anxiety, aggression. The purpose this article is evaluate involvement dietary development depression after TBI. We performed literature search examine effects diets abundant which are common Asian populations, when compared low prevalent Europe America. specifically explored these context chronic BBB damage TBI, may initiate neurodegeneration subsequently an through mechanism neurotoxicity. glutamate-rich diet leads increased contrasted with glutamate-poor diet. Within disruption, translate heightened concentrations, thereby intensifying due

Язык: Английский

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Role of regulatory non-coding RNAs in traumatic brain injury

Neurochemistry International, Год журнала: 2023, Номер 172, С. 105643 - 105643

Опубликована: Ноя. 24, 2023

Язык: Английский

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Chemically Functionalized Single-Walled Carbon Nanotubes Prevent the Reduction in Plasmalemmal Glutamate Transporter EAAT1 Expression in, and Increase the Release of Selected Cytokines from, Stretch-Injured Astrocytes in Vitro

Cells, Год журнала: 2024, Номер 13(3), С. 225 - 225

Опубликована: Янв. 25, 2024

We tested the effects of water-soluble single-walled carbon nanotubes, chemically functionalized with polyethylene glycol (SWCNT-PEG), on primary mouse astrocytes exposed to a severe in vitro simulated traumatic brain injury (TBI). The application SWCNT-PEG culture media injured did not affect cell damage levels, when compared those obtained from injured, functionalization agent (PEG)-treated cells. Furthermore, change levels oxidatively damaged proteins astrocytes. However, this nanomaterial prevented reduction plasmalemmal glutamate transporter EAAT1 expression caused by injury, rendering level par that control, uninjured PEG-treated astrocytes; parallel, there was no significant GFAP. Additionally, increased release selected cytokines are generally considered be involved recovery processes following injuries. As loss EAATs has been implicated as culprit suffering human patients TBI, could have valuable at site, preventing astrocytic and consequently allowing for much-needed uptake extracellular space, accumulation which leads unwanted excitotoxicity. Additional potential therapeutic benefits reaped fact stimulated astrocytes, would promote after thus counteract excess proinflammatory present TBI.

Язык: Английский

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The Role of Glutamate and Blood–Brain Barrier Disruption as a Mechanistic Link between Epilepsy and Depression

Cells, Год журнала: 2024, Номер 13(14), С. 1228 - 1228

Опубликована: Июль 21, 2024

Epilepsy is associated with substantial neuropsychiatric impairments that persist long after the onset of condition, significantly impacting quality life. The goal this review was to uncover how pathological consequences epilepsy, such as excessive glutamate release and a disrupted blood-brain barrier (BBB), contribute emergence disorders. We hypothesize epilepsy induces dysfunctional BBB through hyperexcitation, which then further amplifies post-ictal levels and, thus, triggers neurodegenerative processes. This identifies determinants concentration in brain explores potential therapeutic interventions restore integrity. Our focus on restoration guided by premise it may improve regulation, consequently mitigating neurotoxicity contributes symptoms.

Язык: Английский

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Untargeted Metabolomics Reveals Metabolic Link Between Histone H3K27 Demethylase UTX and Neurodevelopment

Journal of Cellular and Molecular Medicine, Год журнала: 2025, Номер 29(1)

Опубликована: Янв. 1, 2025

Ubiquitously transcribed tetratricopeptide repeat on chromosome X (UTX) is a chromatin modifier responsible for regulating the demethylation of histone H3 lysine 27 trimethylation (H3K27me3), which crucial human neurodevelopment. To date, impact UTX neurodevelopment remains elusive. Therefore, this study aimed to investigate potential molecular mechanisms underlying effects through untargeted metabolomics based ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). We found that knockout in neurones leads cell death and apoptosis hippocampus cortex, as well induces impaired learning memory functions mice. Moreover, deletion contributed significant metabolic perturbations brain tissues. A total 223 differential metabolites were identified between wild-type (WT) cKO Pathway analysis indicated pathways mainly affected by alanine, aspartate, glutamate metabolism, resulting alterations L-alanine, L-aspartate, D-aspartate, N-acetylaspartylglutamate, L-glutamate, argininosuccinic acid. These data emphasised may exert key effect mechanism be related regulation metabolism pathways, especially characteristic involved pathway.

Язык: Английский

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