Blood-Brain Barrier Dysfunction in CNS Disorders and Putative Therapeutic Targets: An Overview

Pharmaceutics, Год журнала: 2021, Номер 13(11), С. 1779 - 1779

Опубликована: Окт. 26, 2021

The blood-brain barrier (BBB) is a fundamental component of the central nervous system (CNS). Its functional and structural integrity vital to maintain homeostasis brain microenvironment by controlling passage substances regulating trafficking immune cells between blood brain. BBB primarily composed highly specialized microvascular endothelial cells. These cells' special features physiological properties are acquired maintained through concerted effort hemodynamic cellular cues from surrounding environment. This complex multicellular system, comprising cells, astrocytes, pericytes, neurons, known as neurovascular unit (NVU). strictly controls transport nutrients metabolites into parenchyma tightly regulated while limiting access potentially harmful via efflux transcytosis metabolic mechanisms. Not surprisingly, disruption has been associated with onset and/or progression major neurological disorders. Although association disease clear, its nature not always evident, specifically regard whether an impaired function results pathological condition or damage primary pathogenic factor prodromal disease. In either case, repairing could be viable option for treating reducing effects CNS this review, we describe structure in both healthy altered/diseased conditions. Additionally, provide overview potential therapeutic targets that leveraged restore concomitant treatment these

Язык: Английский

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Central role of microglia in sepsis-associated encephalopathy: From mechanism to therapy

Frontiers in Immunology, Год журнала: 2022, Номер 13

Опубликована: Июль 26, 2022

Sepsis-associated encephalopathy (SAE) is a cognitive impairment associated with sepsis that occurs in the absence of direct infection central nervous system or structural brain damage. Microglia are thought to be macrophages system, devouring bits neuronal cells and dead brain. They activated various ways, microglia-mediated neuroinflammation characteristic diseases, including SAE. Here, we systematically described pathogenesis SAE demonstrated microglia closely related occurrence development Furthermore, comprehensively discussed function phenotype summarized their activation mechanism role pathogenesis. Finally, this review summarizes recent studies on treating by blocking microglial toxic factors produced after activation. We suggest targeting may putative treatment for

Язык: Английский

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Pathophysiology of Sepsis and Genesis of Septic Shock: The Critical Role of Mesenchymal Stem Cells (MSCs)

International Journal of Molecular Sciences, Год журнала: 2022, Номер 23(16), С. 9274 - 9274

Опубликована: Авг. 17, 2022

The treatment of sepsis and septic shock remains a major public health issue due to the associated morbidity mortality. Despite an improvement in understanding physiological pathological mechanisms underlying its genesis growing number studies exploring even higher range targeted therapies, no significant clinical progress has emerged past decade. In this context, mesenchymal stem cells (MSCs) appear more as attractive approach for cell therapy both experimental models. Pre-clinical data suggest cornerstone role these their secretome control host immune response. Host-derived factors released from infected (i.e., alarmins, HMGB1, ATP, DNA) well pathogen-associated molecular patterns (e.g., LPS, peptidoglycans) can activate MSCs located parenchyma around vessels upregulate expression cytokines/chemokines growth that influence, respectively, recruitment mobilization. However, way which exert beneficial effects terms survival inflammation states unclear. This review presents interactions identified between mediators immunity tissue repair sepsis. We also propose paradigms related plausible roles process shock. Finally, we offer presentation open innovative avenues research involving prognostic, diagnostic, therapeutic point view

Язык: Английский

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Puerarin protects against sepsis-associated encephalopathy by inhibiting NLRP3/Caspase-1/GSDMD pyroptosis pathway and reducing blood-brain barrier damage

European Journal of Pharmacology, Год журнала: 2023, Номер 945, С. 175616 - 175616

Опубликована: Фев. 28, 2023

Puerarin (Pue), an isoflavone compound extracted from Pueraria, has been shown to inhibit inflammation and reduce cerebral edema. The neuroprotective effect of puerarin attracted much attention in recent years. Sepsis-associated encephalopathy (SAE) is a serious complication sepsis that causes damage the nervous system. This study aimed investigate on SAE elucidate potential underlying mechanisms. A rat model was established by cecal ligation puncture, injected intraperitoneally immediately after operation. found improve survival rate neurobehavioral score rats, alleviate symptoms, level brain injury markers NSE S100β, pathological changes tissue. also factors related classical pathway pyroptosis, such as NLRP3, Caspase-1, GSDMD, ASC, IL-1β, IL-18. reduced water content penetration Evan's Blue dye expression MMP-9. In vitro experiments, we further confirmed inhibitory neuronal pyroptosis establishing HT22 cells. Our findings suggest may inhibiting NLRP3/Caspase-1/GSDMD-mediated reducing blood-brain barrier damage, thus playing role protection. provide novel therapeutic strategy for SAE.

Язык: Английский

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Molecular mechanism of METTL3 regulating hippocampal neuronal injury induced by sepsis-associated encephalopathy

Archives of Physiology and Biochemistry, Год журнала: 2025, Номер unknown, С. 1 - 11

Опубликована: Март 2, 2025

Objective: This study explores the mechanism of methyltransferase like 3 (METTL3) on sepsis-associated encephalopathy (SAE)-induced hippocampal neuronal injury.

Язык: Английский

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Recent progress on nanotechnologies for enhancing blood‐brain barrier permeability

Smart Molecules, Год журнала: 2025, Номер unknown

Опубликована: Март 20, 2025

Abstract The blood‐brain barrier (BBB) is a substantial impediment to effectively delivering central nervous system (CNS) therapies. In this review, we provide comprehensive dissection of the BBB's elaborate structure and function discuss inherent limitations conventional drug delivery mechanisms due its impermeability. We summarized creative deployment nanocarriers, astute modification small molecules bolster their CNS penetration capabilities as well burgeoning potential magnetic nanoparticles optical techniques that are positioned enable more precise targeted across BBB current clinical application some nanomedicines. addition, emphasize indispensable role artificial intelligence in designing novel materials paramount significance interdisciplinary research surmounting challenges associated with penetration. Our review meticulously integrates these insights accentuate impact nanotechnological innovations disease management. It presents promising trajectory for evolution patient care neurological disorders suggests scientific strides could lead efficacious treatments improved outcomes those afflicted such conditions.

Язык: Английский

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Malvidin alleviates mitochondrial dysfunction and ROS accumulation through activating AMPK-α/UCP2 axis, thereby resisting inflammation and apoptosis in SAE mice

Frontiers in Pharmacology, Год журнала: 2023, Номер 13

Опубликована: Янв. 9, 2023

This study aimed to explore the protective roles of malvidin in life-threatened sepsis-associated encephalopathy (SAE) and illustrate underlying mechanism. SAE mice models were developed treated with for subsequently effects evaluation. Malvidin restored neurobehavioral retardation, declined serum S100β NSE levels, sustained cerebrum morphological structure, improved blood-brain barrier integrity elevated tight junction proteins, decreased evans blue leakage, finally protect from brain injury. Mechanistically, prevented mitochondrial dysfunction enhanced JC-1 aggregates ATP ROS accumulation lipid peroxidation increased antioxidant enzymes. UCP2 protein levels found be after LPS stimulation BV-2 cells, recovered its a dependent manner. In vivo inhibition genipin or vitro interference siRNA both disrupted membrane potential, intensified DCF signals, being key target malvidin. Moreover, dorsomorphin block assays verified that upregulated expression through phosphorylating AMPK models. Also, alleviated progression ROS-dependent NLRP3 inflammasome activation mediated pro-inflammatory cytokines secretion pathway apoptosis weakened body formation tunel positive Bax, cytochrome C, caspase-3 Bcl-2 levels. Overall, this illustrated targeted AMPK-α/UCP2 axis restore LPS-induced alleviate accumulation, which further inhibits way, ultimately protected mice, providing reference development prophylactic approach.

Язык: Английский

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Mast cell activation mediates blood–brain barrier impairment and cognitive dysfunction in septic mice in a histamine-dependent pathway

Frontiers in Immunology, Год журнала: 2023, Номер 14

Опубликована: Фев. 1, 2023

Sepsis-associated encephalopathy (SAE) is a diffuse cerebral dysfunction resulting from systemic inflammatory response to infection; however, its pathophysiology remains unclear. Sepsis-induced neuroinflammation and blood-brain barrier (BBB) disruption are crucial factors in brain function disturbance SAE. Mast cells (MCs) activation plays an important role several models; SAE has not been comprehensively investigated.We first established model by cecal ligation puncture (CLP) surgery checked the of MCs. MCs was using immumohistochemical staining Toluidine Blue staining. We administrated cromolyn (10mg/ml), MC stabilizer, rescue septic mice. Brain cytokines levels were measured biochemical assays. BBB assessed measuring key tight-junction (TJ) proteins. Cognitive mice analyzed Y maze open field test. Transwell cultures microvascular endothelial (BMVECs) co-cultured with used assess interaction BMVECs MCs.Results showed that overactivated hippocampus CLP-induced Cromolyn intracerebroventricular (i.c.v) injection substantially inhibited responses, ameliorated impairment, improved survival rate alleviated cognitive In vitro experiments, we revealed increased sensitivity against lipopolysaccharide (LPS) challenge. Furthermore, found histamine/histamine 1 receptor (H1R) mediated between BMVECs, amplifies LPS-induced responses modulating TLR2/4-MAPK signaling pathway.MCs could mediate impairment histamine-dependent pathway.

Язык: Английский

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TRIM45 aggravates microglia pyroptosis via Atg5/NLRP3 axis in septic encephalopathy

Journal of Neuroinflammation, Год журнала: 2023, Номер 20(1)

Опубликована: Ноя. 30, 2023

Neuroinflammation mediated by microglial pyroptosis is an important pathogenic mechanism of septic encephalopathy (SAE). It has been reported that TRIM45 associated with tumours and inflammatory diseases. However, the role in SAE relationship between are unknown. In this study, we found played regulating molecular mechanism.SAE was induced intraperitoneal injection LPS WT AAV-shTRIM45 mice. BV2 cells were treated LPS/ATP vitro. Cognitive function assessed Morris water maze. Nissl staining used to evaluate histological structural lesions. ELISA dectect neuroinflammation. qPCR detect mRNA levels cytokines, NLRP3, autophagy genes. Western blotting immunofluorescence analysis analyse expression proteins. Changes reactive oxygen species (ROS) observed flow cytometry. mitochondrial membrane potential detected JC-1 staining. Peripheral blood mononuclear extracted from density gradient centrifugation then for qPCR, western detection. To further explore mechanism, overexpression plasmids Atg5 as well siRNA-TRIM45 siRNA-Atg5 downstream pathway NLRP3. The protein peripheral sepsis patients examined.Knocking down protected against neuronal damage cognitive impairment knockdown inhibited secretion cytokines vivo vitro, which NLRP3/Gsdmd-N activation. Overexpression could activate NLRP3 Further examination showed regulated activation altering autophagic flux. also affected changes ROS potential. Thus, knocking reduce pyroptosis, proinflammatory improve function. addition, level increased. There a positive linear correlation APACHE II score TRIM45, SOFA TRIM45. Compared group GCS > 9, increased ≤ 8.TRIM45 plays key neuroinflammation caused LPS, may involve TRIM45-mediated exacerbation via Atg5/NLRP3 axis.

Язык: Английский

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From immune dysregulation to organ dysfunction: understanding the enigma of Sepsis

Frontiers in Microbiology, Год журнала: 2024, Номер 15

Опубликована: Авг. 26, 2024

Sepsis is a syndrome precipitated by immune dysregulation in response to infection, and represents pivotal factor global mortality attributed diseases. The recent consensus delineates sepsis as perilous state of organ dysfunction arising from the host’s maladaptive reaction infection. It masks complexity breadth mechanisms involved sepsis, which characterized simultaneous hyperinflammation immunosuppression. highly correlated with response, mainly mediated various cells their interactions. This can lead plethora complications, encompassing systemic inflammatory metabolic disturbances, infectious shock, MODS, DIC. Furthermore, more research studies have been conducted on past few years. pathological characteristics improved or treated targeting signaling pathways like NF-B, JAK–STAT, PI3K-Akt, p38-MAPK. Combined drug therapy better than single for sepsis. article will review latest progress pathogenesis treatment

Язык: Английский

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