HMGB1 mediates synaptic loss and cognitive impairment in an animal model of sepsis-associated encephalopathy

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

Опубликована: Март 11, 2023

Microglial activation-mediated neuroinflammation is one of the essential pathogenic mechanisms sepsis-associated encephalopathy (SAE). Mounting evidence suggests that high mobility group box-1 protein (HMGB1) plays a pivotal role in and SAE, yet mechanism by which HMGB1 induces cognitive impairment SAE remains unclear. Therefore, this study aimed to investigate underlying SAE.An model was established cecal ligation puncture (CLP); animals sham underwent cecum exposure alone without perforation. Mice inflachromene (ICM) were continuously injected with ICM intraperitoneally at daily dose 10 mg/kg for 9 days starting 1 h before CLP operation. The open field, novel object recognition, Y maze tests performed on 14-18 after surgery assess locomotor activity function. secretion, state microglia, neuronal measured immunofluorescence. Golgi staining detect changes morphology dendritic spine density. In vitro electrophysiology long-term potentiation (LTP) CA1 hippocampus. vivo neural oscillation hippocampus.CLP-induced accompanied increased secretion microglial activation. phagocytic capacity microglia enhanced, resulting aberrant pruning excitatory synapses loss reduced activity, impaired LTP, decreased theta Inhibiting treatment reversed these changes.HMGB1 activation, synaptic pruning, neuron dysfunction an animal leading impairment. These results suggest might be target treatment.

Язык: Английский

---

Fisetin ameliorates cognitive impairment by activating mitophagy and suppressing neuroinflammation in rats with sepsis‐associated encephalopathy

CNS Neuroscience & Therapeutics, Год журнала: 2021, Номер 28(2), С. 247 - 258

Опубликована: Ноя. 27, 2021

Fisetin, the effective ingredient of traditional Chinese medicine named Cotinus coggygria, is recommended to be active therapeutic in many disorders. However, its role sepsis-associated encephalopathy (SAE) remains unclarified.Cecal ligation and puncture (CLP) operation was performed establish a rat model SAE. Rats were grouped according surgery fisetin administration. Cognitive impairment assessed by Morris water maze test. Disruption blood-brain barrier (BBB) integrity detected Evan's blue staining. The mitophagy, reactive oxygen species (ROS) generation, NLRP3 inflammasome activation, pro-inflammatory cytokines levels measured through western blot double immunofluorescence labeling. A transmission electron microscope applied for observation mitochondrial autophagosomes.Rats CLP group presented increased expression IL-1R1, pNF-κB, TNF-α, iNOS microglial cells, indicating severe inflammation central nervous system (CNS). Nevertheless, there no increase BBB permeability. Meanwhile, activated cerebral microvascular endothelial cells (CMECs), with an elevation caspase-1 IL-1β secretion into CNS. In addition, we found significantly improved cognitive dysfunction rats Neuroprotective effects might associated inhibition neuroinflammation, represented decreased microglia. Furthermore, induced scavenged ROS, blocked activation CMECs, as evidenced reduced release CNS.Collectively, fisetin-blocked via promoting mitophagy CMECs may suppress CNS, reduce contribute amelioration impairment.

Язык: Английский

---

Beneficial effects of natural flavonoids on neuroinflammation

Frontiers in Immunology, Год журнала: 2022, Номер 13

Опубликована: Окт. 24, 2022

Neuroinflammation is the fundamental immune response against multiple factors in central nervous system and characterized by production of inflammatory mediators, activated microglia astrocytes, recruitment innate adaptive cells to sites, that contributes pathological process related brain diseases, such as Alzheimer’s disease, Parkinson’s depression, stroke. Flavonoids, a species important natural compounds, have been widely revealed alleviate neuroinflammation inhibiting pro-inflammatory elevating secretion anti-inflammatory factors, modulating polarization astrocyte, mainly via suppressing activation NLRP3 inflammasome, well NF-κB, MAPK, JAK/STAT pathways, promoting Nrf2, AMPK, BDNF/CREB, Wnt/β-Catenin, PI3k/Akt signals SIRT1-mediated HMGB1 deacetylation. This review will provide latest comprehensive knowledge on therapeutic benefits mechanisms flavonoids neuroinflammation, might be developed into food supplements or lead compounds for neuroinflammation-associated disorders.

Язык: Английский

---

Endothelial dysfunction: Pathophysiology and therapeutic targets for sepsis-induced multiple organ dysfunction syndrome

Biomedicine & Pharmacotherapy, Год журнала: 2024, Номер 178, С. 117180 - 117180

Опубликована: Июль 27, 2024

Sepsis and septic shock are critical medical conditions characterized by a systemic inflammatory response to infection, significantly contributing global mortality rates. The progression multiple organ dysfunction syndrome (MODS) represents the most severe complication of sepsis markedly increases clinical mortality. Central pathophysiology sepsis, endothelial cells play crucial role in regulating microcirculation maintaining barrier integrity across various organs tissues. Recent studies have underscored pivotal function development sepsis-induced MODS. This review aims provide comprehensive overview MODS, with specific focus on dysfunction. It also compiles compelling evidence regarding potential small molecules that could attenuate subsequent multi-organ damage modulating function. Thus, this serves as an essential resource for practitioners involved diagnosing, managing, providing intensive care associated injuries, emphasizing importance targeting enhance outcomes patients.

Язык: Английский

---

Targeting novel regulated cell death：Ferroptosis, pyroptosis, and autophagy in sepsis-associated encephalopathy

Biomedicine & Pharmacotherapy, Год журнала: 2024, Номер 174, С. 116453 - 116453

Опубликована: Март 20, 2024

Sepsis-associated encephalopathy (SAE), a common neurological complication of sepsis, is heterogenous complex clinical syndrome caused by the dysfunctional response host to infection. This leads excess mortality and morbidity worldwide. Despite relevance with high incidence, there lack understanding for its both acute/chronic pathogenesis therapeutic management. A better molecular mechanisms behind SAE may provide tools enhance efficacy. Mounting evidence indicates that some types non-apoptotic regulated cell death (RCD), such as ferroptosis, pyroptosis, autophagy, contribute SAE. Targeting these RCD meaningful targets future treatments against review summarizes core mechanism which We focus on emerging compounds can inhibit delineate their beneficial pharmacological effects Within this we suggest inhibition serve potential strategy

Язык: Английский

---

Mechanism and role of mitophagy in the development of severe infection

Cell Death Discovery, Год журнала: 2024, Номер 10(1)

Опубликована: Фев. 19, 2024

Abstract Mitochondria produce adenosine triphosphate and potentially contribute to proinflammatory responses cell death. Mitophagy, as a conservative phenomenon, scavenges waste mitochondria their components in the cell. Recent studies suggest that severe infections develop alongside mitochondrial dysfunction mitophagy abnormalities. Restoring protects against excessive inflammation multiple organ failure sepsis. Here, we review normal process, its interaction with invading microorganisms immune system, summarize mechanism of during infection. We highlight critical role preventing

Язык: Английский

---

Targeting selective autophagy and beyond: From underlying mechanisms to potential therapies

Journal of Advanced Research, Год журнала: 2024, Номер 65, С. 297 - 327

Опубликована: Май 14, 2024

Autophagy is an evolutionarily conserved turnover process for intracellular substances in eukaryotes, relying on lysosomal (in animals) or vacuolar yeast and plants) mechanisms. In the past two decades, emerging evidence suggests that, under specific conditions, autophagy can target particular macromolecules organelles degradation, a termed selective autophagy. Recently, accumulating studies have demonstrated that abnormality of closely associated with occurrence progression many human diseases, including neurodegenerative cancers, metabolic cardiovascular diseases. This review aims at systematically comprehensively introducing its role various while unravelling molecular mechanisms By providing theoretical basis development related small-molecule drugs as well treating this seeks to contribute understanding therapeutic potential. review, we introduce dissect major categories been discovered. We also focus recent advances underlying both classical non-classical Moreover, current situation targeting different types further summarized, valuable insights into discovery more candidate future. On other hand, reveal clinically relevant implementations are potentially autophagy, such predictive approaches treatments tailored individual patients.

Язык: Английский

---

Mechanism of Salvia miltiorrhiza Bunge extract to alleviate Chronic Sleep Deprivation-Induced cognitive dysfunction in rats

Phytomedicine, Год журнала: 2024, Номер 130, С. 155725 - 155725

Опубликована: Май 12, 2024

Bidirectional communication between the gut microbiota and brain may play an essential role in cognitive dysfunction associated with chronic sleep deprivation(CSD). Salvia miltiorrhiza Bunge (Danshen, DS), a famous Chinese medicine functional tea, is extensively used to protect learning memory capacities, although mechanism of action remains unknown.

Язык: Английский

---

Decreased excitatory and increased inhibitory transmission in the hippocampal CA1 drive neuroinflammation-induced cognitive impairments in mice

Brain Behavior and Immunity, Год журнала: 2025, Номер 128, С. 416 - 428

Опубликована: Апрель 24, 2025

Язык: Английский

---

Multi-Target Effects of ß-Caryophyllene and Carnosic Acid at the Crossroads of Mitochondrial Dysfunction and Neurodegeneration: From Oxidative Stress to Microglia-Mediated Neuroinflammation

Antioxidants, Год журнала: 2022, Номер 11(6), С. 1199 - 1199

Опубликована: Июнь 18, 2022

Inflammation and oxidative stress are interlinked interdependent processes involved in many chronic diseases, including neurodegeneration, diabetes, cardiovascular cancer. Therefore, targeting inflammatory pathways may represent a potential therapeutic strategy. Emerging evidence indicates that phytochemicals extracted from edible plants have the to ameliorate disease phenotypes. In this scenario, ß-caryophyllene (BCP), bicyclic sesquiterpene, carnosic acid (CA), an ortho-diphenolic diterpene, were demonstrated exhibit anti-inflammatory, antioxidant activities, as well neuroprotective mitoprotective effects different vitro vivo models. BCP essentially promotes its by acting selective agonist allosteric modulator of cannabinoid type-2 receptor (CB2R). CA is pro-electrophilic compound that, response oxidation, converted electrophilic form. This can interact activate Keap1/Nrf2/ARE transcription pathway, triggering synthesis endogenous “phase 2” enzymes. However, given nature chemical structure, also exhibits direct effects. readily cross BBB accumulate brain regions, giving rise preventing mitochondrial dysfunction inhibiting activated microglia, substantially through activation pro-survival signalling pathways, regulation apoptosis autophagy, molecular mechanisms related quality control. Findings vitro/in experimental models Parkinson’s Alzheimer’s reported beneficial both compounds, suggesting their use treatments be promising strategy management neurodegenerative diseases aimed at maintaining homeostasis ameliorating glia-mediated neuroinflammation.

Язык: Английский

---