RESUMEN
Ventricular remodeling after myocardial infarction(VRAMI) is a pathological phenomenon triggered by the abrupt occlusion of coronary arteries, leading to myocardial ischemia and hypoxia. This intricate process encompasses alterations in the dimensions, composition, and elasticity of the ventricular tissue and reflects pathophysiological reactions and self-repair after cardiomyocytes are damaged. The characteristic pathological manifestation of VRAMI is the presence of myocardial fibrosis(MF), wherein fibrotic cardiac tissue undergoes a loss of contractile and relaxation capacity, ultimately culminating in heart failure(HF) and significantly impacting the patient's prognosis. Endothelial-mesenchymal transition(EndMT) is a biological process in which endothelial cells, in response to diverse pathological stimuli such as ischemia and hypoxia in the embryonic development period, undergo morphological alterations and functional impairment, progressively acquiring mesenchymal cell properties and ultimately differentiating into mesenchymal cells. The ongoing advancement of the EndMT process will result in an excessive buildup of collagen, thereby inducing structural harm to the myocardium and exacerbating the processes of VRAMI and MF. Recent investigations have demonstrated the pivotal involvement of EndMT in the pathological advancement of VRAMI. Consequently, a targeted intervention aimed at effectively impeding VRAMI, safeguarding cardiac function, and potentially serving as a novel therapeutic target for the prevention and treatment of VRAMI. This article provides a comprehensive review of recent Chinese and international literature, focusing on the role and pathophysiological mechanisms of EndMT in VRAMI. Additionally, it discusses the research progress of innovative targeted interventions using both traditional Chinese and Western medicine, so as to offer new insights and a theoretical foundation for the clinical treatment of the disease.
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Infarto del Miocardio , Remodelación Ventricular , Humanos , Infarto del Miocardio/fisiopatología , Animales , Medicamentos Herbarios Chinos , Células Endoteliales , Transición Epitelial-Mesenquimal , Medicina Tradicional China , Transición Endotelial-MesenquimatosaRESUMEN
This study aims to investigate the effect of Naotaifang(NTF) on the proteins associated with microglial polarization and glial scar in the rat model of cerebral ischemia reperfusion injury(CIRI). The CIRI model was established by middle cerebral artery occlusion/reperfusion. The 48 successfully modeled rats were randomized into model 7 d, model 14 d, NTF 7 d, and NTF 14 d groups(n=12). In addition, 12 SD rats were selected as the sham group. The NTF group was administrated with NTF suspension at 27 g·kg~(-1)·d~(-1) by gavage, and the sham, model 7 d, and model 14 d groups were administrated with the same volume of normal saline every day by gavage for 7 and 14 days, respectively. After the intervention, Longa score was evaluated. The infarct volume was measured by 2,3,5-triphenyl-2H-tetrazolium chloride(TTC) staining. Morris water maze and open field tests were carried out to evaluate the spatial learning, memory, cognitive function, and anxiety degree of rats. Hematoxylin-eosin(HE) staining was employed to observe the morphological structure and damage of the brain tissue. The immunofluorescence assay was employed to measure the expression of glial fibrillary acidic protein(GFAP) and glial scar. Western blot was employed to determine the protein levels of GFAP, neurocan, phosphacan, CD206, arginase-1(Arg-1), interleukin(IL)-1ß, IL-6, and IL-4. Compared with the sham, model 7 d and model 14 d groups showed cerebral infarction of different degrees, severe pathological injury of cerebral cortex and hippocampus, neurological impairment, reduced spatial learning and memory, cognitive dysfunction, severe anxiety, astrocyte hyperplasia, thickening penumbra glial scar, and up-regulated protein levels of IL-1ß, IL-6, GFAP, neurocan, phosphacan, CD206, and Arg-1(P<0.01). Compared with the model group, NTF 7 d and NTF 14 d groups improved spatial learning, memory, and cognitive function, reduced anxiety, improved nerve function, reduced cerebral infarction volume, reduced astrocyte hyperplasia, thinned penumbra glial scar, down-regulated the protein levels of GFAP, neurocan, phosphacan, IL-6, and IL-1ß, and up-regulated the protein levels of IL-4, CD206, and Arg-1(P<0.05 or P<0.01). NTF exerts a neuroprotective effect on CIRI by inducing the M2 polarization of microglia, inhibiting inflammatory response, and reducing the formation of glial scar.
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Isquemia Encefálica , Medicamentos Herbarios Chinos , Daño por Reperfusión , Ratas , Animales , Microglía/metabolismo , Gliosis/patología , Ratas Sprague-Dawley , Hiperplasia , Interleucina-4 , Interleucina-6 , Neurocano , Proteínas Tirosina Fosfatasas Clase 5 Similares a Receptores , Infarto de la Arteria Cerebral Media , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/metabolismo , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/metabolismoRESUMEN
Sand mining, which has tripled in the last two decades, is an emerging concern for global biodiversity. However, the paucity of sand mining data worldwide prevents understanding the extent of sand mining impacts and how it affects wildlife populations and ecosystems, which is critical for timely mitigation and conservation actions. Integrating remote sensing and field surveys over 14 years, we investigated mining impacts on the critically endangered Yangtze finless porpoise (Neophocaena asiaeorientalis asiaeorientalis) in Dongting Lake, China. We found that sand mining presented a consistent, widespread disturbance in Dongting Lake. Porpoises strongly avoided mining sites, especially those of higher mining intensity. The extensive sand mining significantly contracted the porpoise's range and restricted their habitat use in the lake. Water traffic for sand transportation further blocked the species's river-lake movements, affecting the population connectivity. In addition, mining-induced loss of near-shore habitats, a critical foraging and nursery ground for the porpoise, occurred in nearly 70% of the water channels of our study region. Our findings provide the first empirical evidence of the impacts of unregulated sand extractions on species distribution. Our spatio-temporally explicit approach and findings support regulation and conservation, yielding broader implications for sustainable sand mining worldwide.
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Marsopas , Arena , Animales , Ecosistema , Cetáceos , Marsopas/fisiología , Lagos , China , MineríaRESUMEN
Mitochondrial damage is a critical contributor to stroke-induced injury, and mitochondrial quality control (MQC) is the cornerstone of restoring mitochondrial homeostasis and plays an indispensable role in alleviating pathological process of stroke. Mitochondria quality control promotes neuronal survival via various adaptive responses for preserving mitochondria structure, morphology, quantity and function. The processes of mitochondrial fission and fusion allow for damaged mitochondria to be segregated and facilitate the equilibration of mitochondrial components such as DNA, proteins and metabolites. The process of mitophagy is responsible for the degradation and recycling of damaged mitochondria. This review aims to offer a synopsis of the molecular mechanisms involved in MQC for recapitulating our current understanding of the complex role that MQC plays in the progression of stroke. Speculating on the prospect that targeted manipulation of MQC mechanisms may be exploited for the rationale design of novel therapeutic interventions in the ischaemic stroke and haemorrhagic stroke. In the review, we highlight the potential of MQC as therapeutic targets for stroke treatment and provide valuable insights for clinical strategies.
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Isquemia Encefálica , Accidente Cerebrovascular , Isquemia Encefálica/patología , Humanos , Mitocondrias/metabolismo , Dinámicas Mitocondriales , Mitofagia , Accidente Cerebrovascular/patologíaRESUMEN
Cerebral ischemia-reperfusion injury(CIRI) is an important factor hindering the recovery of ischemic stroke patients after blood flow recanalization. Mitochondria, serving as the "energy chamber" of cells, have multiple important physiological functions, such as supplying energy, metabolizing reactive oxygen species, storing calcium, and mediating programmed cell death. During CIRI, oxidative stress, calcium overload, inflammatory response, and other factors can easily lead to neuronal mitochondrial dyshomeostasis, which is the key pathological link leading to secondary injury. As reported, the mitochondrial quality control(MQC) system, mainly including mitochondrial biosynthesis, kinetics, autophagy, and derived vesicles, is an important endogenous mechanism to maintain mitochondrial homeostasis and plays an important protective role in the damage of mitochondrial structure and function caused by CIRI. This paper reviewed the mechanism of MQC and the research progress on MQC-targeting therapy of CIRI in recent 10 years to provide theoretical references for exploring new strategies for the prevention and treatment of ischemic stroke with traditional Chinese medicine.
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Isquemia Encefálica , Accidente Cerebrovascular Isquémico , Daño por Reperfusión , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/metabolismo , Isquemia Encefálica/prevención & control , Calcio/metabolismo , Humanos , Mitocondrias/patología , Especies Reactivas de Oxígeno/metabolismo , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/metabolismo , Daño por Reperfusión/prevención & controlRESUMEN
Cerebral ischemia-reperfusion injury(CIRI) is a complex cascade process and seriously hinders the recovery of patients with acute ischemic stroke, which has become an urgent public health issue to be addressed. Silent information regulators(SIRTs) are a family of nicotinamide adenine dinucleotide(NAD~+)-dependent deacetylases, capable of deacylating the histone and non-histone lysine groups. Accumulating evidence has demonstrated that SIRTs are able to regulate the pathological processes such as oxidative stress, inflammatory response, mitochondrial dysfunction, and programmed cell death of CIRI through post-translational deacetylation, and exert the neuroprotection function. In this study, we reviewed the papers about the role and regulatory mechanisms of SIRTs in the pathological process of CIRI published in the past decade. Further, we summarized the research advance in the prevention and treatment of CIRI with Chinese medicine targeting SIRTs and the related signaling pathways. This review will provide new targets and theoretical support for the clinical application of Chinese medicine in treating CIRI during the occurrence of ischemic stroke.
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Isquemia Encefálica , Accidente Cerebrovascular Isquémico , Daño por Reperfusión , Sirtuinas , Humanos , Isquemia Encefálica/enzimología , Isquemia Encefálica/terapia , Accidente Cerebrovascular Isquémico/enzimología , Accidente Cerebrovascular Isquémico/terapia , Medicina Tradicional China , Estrés Oxidativo , Daño por Reperfusión/enzimología , Daño por Reperfusión/metabolismo , Daño por Reperfusión/terapia , Sirtuinas/metabolismoRESUMEN
Ischemic stroke is one of the main causes of death and long-term disability worldwide, which seriously affects the quality of life of patients and brings a heavy economic burden to families and society. Epidemiological studies have shown that stroke has become the second leading cause of death and major disabling disease in the world, with the characteristics of high morbidity, high recurrence, and high mortality. Epigenetic mechanism is the molecular process where gene expression and function in each cell are dynamically regulated and interconnected and a biological mechanism that changes genetic performance without changing the DNA sequence, including DNA methylation, histone modifications, and non-coding RNA. However, the research on epigenetics is currently focused on other diseases such as tumors. Recent studies have found that epigenetics has received extensive attention in the past few decades as a key factor involved in the pathophysiological process of ischemic stroke. The present study introduced the mediation of epigenetics in the induction of stroke, summarized the potential drug targets for these mechanisms in the treatment of stroke, and further explored the significance of traditional Chinese medicine(TCM) against cerebral ischemia injury based on TCM classification of stroke.
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Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Metilación de ADN , Epigénesis Genética , Humanos , Accidente Cerebrovascular Isquémico/genética , Calidad de Vida , ARN no Traducido/genética , ARN no Traducido/metabolismo , Accidente Cerebrovascular/genéticaRESUMEN
When ischemia or hemorrhagic stroke occurs, astrocytes are activated by a variety of endogenous regulatory factors to become reactive astrocytes. Subsequently, reactive astrocytes proliferate, differentiate, and migrate around the lesion to form glial scar with the participation of microglia, neuron-glial antigen 2(NG2) glial cells, and extracellular matrix. The role of glial scars at different stages of stroke injury is different. At the middle and late stages of the injury, the secreted chondroitin sulfate proteoglycan and chondroitin sulfate are the main blockers of axon regeneration and nerve function recovery. Targeted regulation of glial scars is an important pathway for neurological rehabilitation after stroke. Chinese medicine has been verified to be effective in stroke rehabilitation in clinical practice, possibly because it has the functions of promoting blood resupply, anti-inflammation, anti-oxidative stress, inhibiting cell proliferation and differentiation, and benign intervention in glial scars. This study reviewed the pathological process and signaling mechanisms of glial scarring after stroke, as well as the intervention of traditional Chinese medicine upon glial scar, aiming to provide theoretical reference and research evidence for developing Chinese medicine against stroke in view of targeting glial scarring.
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Gliosis , Accidente Cerebrovascular , Astrocitos , Axones/patología , Cicatriz/tratamiento farmacológico , Cicatriz/etiología , Cicatriz/patología , Gliosis/patología , Humanos , Medicina Tradicional China , Regeneración Nerviosa , Accidente Cerebrovascular/tratamiento farmacológicoRESUMEN
Hearing is considered the primary sensory modality of cetaceans and enables their vital life functions. Information on the hearing sensitivity variability within a species obtained in a biologically relevant wild context is fundamental to evaluating potential noise impact and population-relevant management. Here, non-invasive auditory evoked-potential methods were adopted to describe the audiograms (11.2-152 kHz) of a group of four wild Yangtze finless porpoises (Neophocaena asiaeorientalis asiaeorientalis) during a capture-and-release health assessment project in Poyang Lake, China. All audiograms presented a U shape, generally similar to those of other delphinids and phocoenids. The lowest auditory threshold (51-55 dB re 1 µPa) was identified at a test frequency of 76 kHz, which was higher than that observed in aquarium porpoises (54 kHz). The good hearing range (within 20 dB of the best hearing sensitivity) was from approximately 20 to 145 kHz, and the low- and high-frequency hearing cut-offs (threshold > 120 dB re l µPa) were 5.6 and 170 kHz, respectively. Compared with aquarium porpoises, wild porpoises have significantly better hearing sensitivity at 32 and 76 kHz and worse sensitivity at 54, 108 and 140 kHz. The audiograms of this group can provide a basis for better understanding the potential impact of anthropogenic noise.
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Audición/fisiología , Ruido/efectos adversos , Marsopas/fisiología , Animales , Umbral Auditivo , Potenciales Evocados AuditivosRESUMEN
Cerebral ischemia injury, the leading cause of morbidity and mortality worldwide, initiates sequential molecular and cellular pathologies that underlie ischemic encephalopathy (IE), such as ischemic stroke, Alzheimer disease (AD), Parkinson's disease (PD), epilepsy, etc. Targeted therapeutic treatments are urgently needed to tackle the pathological processes implicated in these neurological diseases. Recently, accumulating studies demonstrate that microRNA-124 (miR-124), the most abundant miRNA in brain tissue, is aberrant in peripheral blood and brain vascular endothelial cells following cerebral ischemia. Importantly, miR-124 regulates a variety of pathophysiological processes that are involved in the pathogenesis of age-related IE. However, the role of miR-124 has not been systematically illustrated. Paradoxically, miR-124 exerts beneficial effects in the age-related IE via regulating autophagy, neuroinflammation, oxidative stress, neuronal excitability, neurodifferentiation, Aß deposition, and hyperphosphorylation of tau protein, while it may play a dual role via regulating apoptosis and exerts detrimental effects on synaptic plasticity and axonal growth. In the present review, we thus focus on the paradoxical roles of miR-124 in age-related IE, as well as the underlying mechanisms. A great understanding of the effects of miR-124 on the hypoxic-ischemic brain will open new avenues for therapeutic approaches to protect against cerebral ischemia injury.
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Apoptosis , Muerte Celular Autofágica , Lesiones Encefálicas/metabolismo , Isquemia Encefálica/metabolismo , MicroARNs/metabolismo , Estrés Oxidativo , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Animales , Lesiones Encefálicas/patología , Isquemia Encefálica/patología , Humanos , Accidente Cerebrovascular/metabolismo , Accidente Cerebrovascular/patologíaRESUMEN
Polyamines (putrescine, spermidine, and spermine) are essential polycations that play important roles in various physiological and pathophysiological processes in mammalian cells. The study was to investigate their role in cardioprotection against ischemia/reperfusion (I/R) injury and the underlying mechanism. Isolated hearts from male Sprague-Dawley rats were Langendorff-perfused and cardiac I/R was achieved by 30 min of global ischemia followed by 120 min of reperfusion. Different concentrations of polyamines (0.1, 1, 10, and 15 µmol/L of putrescine, spermidine, and spermine), cyclosporin A (0.2 µmol/L), or atractyloside (20 µmol/L) were given 10 min before the onset of reperfusion. The hemodynamics were monitored; the lactate dehydrogenase (LDH) levels in the coronary effluent were measured spectrophotometrically; infarct size was determined by the 2,3,5-triphenyltetrazolium chloride staining method; and mitochondrial permeability transition pore (MPTP) opening was determined spectrophotometrically by the Ca2+-induced swelling of isolated cardiac mitochondria. The results showed that compared to I/R alone, 0.1 and 1 µmol/L polyamines treatment improved heart function, reduced LDH release, decreased infarct size, and these effects were inhibited by atractyloside (MPTP activator). In isolated mitochondria from normal rats, 0.1 and 1 µmol/L polyamines treatment inhibited MPTP opening. However, 10 and 15 µmol/L polyamines treatment had the opposite effects, and these effects were inhibited by cyclosporin A (MPTP inhibitor). Our findings showed that polyamines may have either protective or damaging effects on hearts suffering from I/R by inhibiting or activating MPTP opening.
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Proteínas de Transporte de Membrana Mitocondrial/fisiología , Daño por Reperfusión Miocárdica/fisiopatología , Poliaminas/metabolismo , Animales , Ciclosporina/farmacología , Masculino , Mitocondrias Cardíacas/fisiología , Poro de Transición de la Permeabilidad Mitocondrial , Ratas , Ratas Sprague-DawleyRESUMEN
In schistosomiasis, egg deposition in the liver contributes to the formation of hepatic granuloma and fibrosis, which are the most serious clinical pathological features. It has been proposed that activation of the nuclear factor kappa B (NF-κB) signaling pathways is closely associated with the development of hepatic granuloma and fibrosis. Genistein has been shown to inhibit the activity of NF-κB signaling pathways, which might be a potential agent to protect against Schistosoma japonicum egg-induced liver granuloma and fibrosis. In this study, liver granuloma and fibrosis were induced by infecting BALB/c mice with 18 ± 3 cercariae of S. japonicum. At the beginning of egg granuloma formation (early phase genistein treatment from 4 to 6 weeks after infection) or after the formation of liver fibrosis (late phase genistein treatment from 6 to 10 weeks after infection), the infected mice were injected with genistein (25, 50 mg/kg). The results revealed that genistein treatment significantly decreased the extent of hepatic granuloma and fibrosis in infected mice. The activity of NF-κB signaling declined sharply after the treatment with genistein, as evidenced by the inhibition of NF-κB-p65, phospho-NF-κB-p65, and phospo-IκB-α expressions, as well as the expression of IκB-α and the messenger RNA (mRNA) expression of inflammatory cytokines (MCP1, TNFα, IL1ß, IL4, IL10) mediated by NF-κB signaling pathways in the early phase of the infection. Moreover, western blot and immunohistochemistry assays demonstrated that the contents of α-smooth muscle actin (α-SMA) and transforming growth factor-ß were dramatically reduced in liver tissue under the treatment of genistein in the late phase of the infection. At the same time, the mRNA expression of MCP1, TNFα, and IL10 was inhibited markedly. These results provided evidence that genistein reduces S. japonicum egg-induced liver granuloma and fibrosis, at least partly due to decreased NF-κB signaling, and subsequently decreased MCP1, TNFα, and IL10 expressions. This implies that genistein can be a potential natural agent against schistosomiasis.
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Antiprotozoarios/uso terapéutico , Genisteína/uso terapéutico , Granuloma/tratamiento farmacológico , Quinasa I-kappa B/antagonistas & inhibidores , Cirrosis Hepática/tratamiento farmacológico , Schistosoma japonicum/efectos de los fármacos , Esquistosomiasis Japónica/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Factor de Transcripción ReIA/antagonistas & inhibidores , Animales , Cercarias/metabolismo , Quimiocina CCL2/biosíntesis , Quimiocina CCL2/genética , Activación Enzimática , Granuloma/parasitología , Granuloma/patología , Interleucina-10/biosíntesis , Interleucina-10/genética , Hígado/parasitología , Hígado/patología , Cirrosis Hepática/parasitología , Cirrosis Hepática/patología , Masculino , Ratones , Ratones Endogámicos BALB C , ARN Mensajero/metabolismo , Schistosoma japonicum/genética , Esquistosomiasis Japónica/parasitología , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
Controlled photoluminescence tuning is important for the optimization and modification of phosphor materials. Herein we report an isostructural solid solution of (CaMg)x(NaSc)1-xSi2O6 (0 < x < 1) in which cation nanosegregation leads to the presence of two dilute Eu(2+) centers. The distinct nanodomains of isostructural (CaMg)Si2O6 and (NaSc)Si2O6 contain a proportional number of Eu(2+) ions with unique, independent spectroscopic signatures. Density functional theory calculations provided a theoretical understanding of the nanosegregation and indicated that the homogeneous solid solution is energetically unstable. It is shown that nanosegregation allows predictive control of color rendering and therefore provides a new method of phosphor development.
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Social behaviors are poorly known for the critically endangered Yangtze finless porpoise (YFP, Neophocaena asiaeorientalis asiaeorientalis). Here, group composition and dispersal patterns of the YFP population living in the Poyang Lake were studied by parentage-based pedigree analyses using 21 microsatellite loci and a 597 bp segment of the mitochondrial DNA control region. In this study, 21 potential mother-offspring pairs and six potential father-offspring pairs (including two potential parents-offspring pairs) were determined, among which 12 natural mother-offspring groups and a maternal group of three generations were found. No genetically-determined fathers were found associated with their offspring. This study also found that maternally related porpoises at the reproductive state tend to group together. This suggest maternal relationship and reproductive state may be factors for grouping in the YFP population. In natural mother-offspring groups, male offspring were all younger than two years old, which suggest male offspring may leave their mothers at approximately two years of age, or at least they were not in tight association with their mothers as they may have been under two years old. However, female offspring can stay longer with their mothers and can reproduce in the natal group.
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Marsopas/crecimiento & desarrollo , Marsopas/fisiología , Animales , Conservación de los Recursos Naturales , ADN Mitocondrial/genética , Especies en Peligro de Extinción , Femenino , Lagos , Masculino , Repeticiones de Microsatélite/genética , Filogenia , Marsopas/clasificación , Marsopas/genéticaRESUMEN
OBJECTIVES: Astragaloside IV (AST IV) and ligustrazine (Lig), the main ingredients of Astragali Radix and Chuanxiong Rhizoma respectively, have demonstrated significant benefits in treatment of cerebral ischemia -reperfusion injury (CIRI); however, the mechanisms underlying its benificial effects remain unclear. SUMO-1ylation and deSUMO-2/3ylation of dynamin-related protein 1 (Drp1) results in mitochondrial homeostasis imbalance following CIRI, which subsequently aggravates cell damage. This study investigates the mechanisms by which AST IV combined with Lig protects against CIRI, focusing on the involvement of SUMOylation in mitochondrial dynamics. METHODS: Rats were administrated AST IV and Lig for 7 days, and middle cerebral artery occlusion was established to mimic CIRI. Neural function, cerebral infarction volume, cerebral blood flow, cognitive function, cortical pathological lesions, and mitochondrial morphology were measured. SH-SY5Y cells were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) injury. Mitochondrial membrane potential and lactic dehydrogenase (LDH), reactive oxygen species (ROS), and adenosine triphosphate (ATP) levels were assessed with commercial kits. Moreover, co-immunoprecipitation (Co-IP) was used to detect the binding of SUMO1 and SUMO2/3 to Drp1. The protein expressions of Drp1, Fis1, MFF, OPA1, Mfn1, Mfn2, SUMO1, SUMO2/3, SENP1, SENP2, SENP3, SENP5, and SENP6 were measured using western blot. RESULTS: In rats with CIRI, AST IV and Lig improved neurological and cognitive functions, restored CBF, reduced brain infarct volume, and alleviated cortical neuron and mitochondrial damage. Moreover, in SH-SY5Y cells, the combination of AST IV and Lig enhanced cellular viability, decreased release of LDH and ROS, increased ATP content, and improved mitochondrial membrane potential. Furthermore, AST IV combined with Lig reduced the binding of Drp1 with SUMO1, increased the binding of Drp1 with SUMO2/3, suppressed the expressions of Drp1, Fis1, MFF, and SENP3, and increased the expressions of OPA1, Mfn1, Mfn2, SENP1, SENP2, and SENP5. SUMO1 overexpression promoted mitochondrial fission and inhibited mitochondrial fusion, whereas SUMO2/3 overexpression suppressed mitochondrial fission. AST IV combined with Lig could reverse the effects of SUMO1 overexpression while enhancing those of SUMO2/3 overexpression. CONCLUSIONS: This study posits that the combination of AST IV and Lig has the potential to reduce the SUMO-1ylation of Drp1, augment the SUMO-2/3ylation of Drp1, and thereby exert a protective effect against CIRI.
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Dinámicas Mitocondriales , Neuroblastoma , Pirazinas , Saponinas , Triterpenos , Humanos , Animales , Ratas , Especies Reactivas de Oxígeno , Adenosina Trifosfato , Dinaminas , Cisteína EndopeptidasasRESUMEN
Ischemic stroke, a devastating disease associated with high mortality and disability worldwide, has emerged as an urgent public health issue. A-kinase anchoring proteins (AKAPs) are a group of signal-organizing molecules that compartmentalize and anchor a wide range of receptors and effector proteins and have a major role in stabilizing mitochondrial function and promoting neurodevelopmental development in the central nervous system (CNS). Growing evidence suggests that dysregulation of AKAPs expression and activity is closely associated with oxidative stress, ion disorder, mitochondrial dysfunction, and blood-brain barrier (BBB) impairment in ischemic stroke. However, the underlying mechanisms remain inadequately understood. This review provides a comprehensive overview of the composition and structure of A-kinase anchoring protein (AKAP) family members, emphasizing their physiological functions in the CNS. We explored in depth the molecular and cellular mechanisms of AKAP complexes in the pathological progression and risk factors of ischemic stroke, including hypertension, hyperglycemia, lipid metabolism disorders, and atrial fibrillation. Herein, we highlight the potential of AKAP complexes as a pharmacological target against ischemic stroke in the hope of inspiring translational research and innovative clinical approaches.
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Proteínas de Anclaje a la Quinasa A , Accidente Cerebrovascular Isquémico , Humanos , Proteínas de Anclaje a la Quinasa A/metabolismo , Accidente Cerebrovascular Isquémico/metabolismo , Animales , Barrera Hematoencefálica/metabolismo , Isquemia Encefálica/metabolismoRESUMEN
Ischemic stroke is a leading cause of disability and death worldwide. However, the clinical efficacy of recanalization therapy as a preferred option is significantly hindered by reperfusion injury. The transformation between different phenotypes of gliocytes is closely associated with cerebral ischemia/ reperfusion injury (CI/RI). Moreover, gliocyte polarization induces metabolic reprogramming, which refers to the shift in gliocyte phenotype and the overall transformation of the metabolic network to compensate for energy demand and building block requirements during CI/RI caused by hypoxia, energy deficiency, and oxidative stress. Within microglia, the pro-inflammatory phenotype exhibits upregulated glycolysis, pentose phosphate pathway, fatty acid synthesis, and glutamine synthesis, whereas the anti-inflammatory phenotype demonstrates enhanced mitochondrial oxidative phosphorylation and fatty acid oxidation. Reactive astrocytes display increased glycolysis but impaired glycogenolysis and reduced glutamate uptake after CI/RI. There is mounting evidence suggesting that manipulation of energy metabolism homeostasis can induce microglial cells and astrocytes to switch from neurotoxic to neuroprotective phenotypes. A comprehensive understanding of underlying mechanisms and manipulation strategies targeting metabolic pathways could potentially enable gliocytes to be reprogrammed toward beneficial functions while opening new therapeutic avenues for CI/RI treatment. This review provides an overview of current insights into metabolic reprogramming mechanisms in microglia and astrocytes within the pathophysiological context of CI/RI, along with potential pharmacological targets. Herein, we emphasize the potential of metabolic reprogramming of gliocytes as a therapeutic target for CI/RI and aim to offer a novel perspective in the treatment of CI/RI.
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Isquemia Encefálica , Daño por Reperfusión , Humanos , Animales , Daño por Reperfusión/metabolismo , Isquemia Encefálica/metabolismo , Isquemia Encefálica/terapia , Metabolismo Energético/fisiología , Astrocitos/metabolismo , Neuroglía/metabolismo , Microglía/metabolismo , Reprogramación MetabólicaRESUMEN
BACKGROUND: Cerebral ischemia/reperfusion injury (CIRI) is a sequence of pathophysiological processes after blood recanalization in the patients with ischemic stroke, and has become the hinder for the rehabilitation. Naotaifang formula (NTF) has exhibited the clinical effectiveness for this disease. However, its action effects and molecular mechanisms against CIRI are not fully elucidated. PURPOSE: The research was to clarify the crosstalk between ferroptosis and necroptosis in CIRI, and uncover the mechanism underlying the neuroprotection of NTF. METHODS: This study established MCAO/R rat models with various reperfusion times. Western blot, transmission electron microscope, laser speckle imaging, immunofluorescence, immunohistochemistry and pathological staining were conducted to detect and analyze the obtained results. Subsequently, various NTF doses were used to intervene in MCAO/R rats, and biology experiments, such as western blot, Evans blue, immunofluorescence and immunohistochemistry, were used to analyze the efficacy of NTF doses. The effect of NTF was further clarified through in vitro experiments. Eventually, HT22 cells that suffered OGD/R were subjected to pre-treatment with plasmids overexpressing HSP90, MLKL, and GPX4 to indicate the interaction among ferroptosis and necroptosis. RESULTS: There was a gradual increase in the Zea Longa score and cerebral infarction volume following CIRI with prolonged reperfusion. Furthermore, the expression of factors associated with pro-ferroptosis and pro-necroptosis was upregulated in the cortex and hippocampus. NTF alleviated ferroptosis and necroptosis in a dose-dependent manner, downregulated HSP90 levels, reduced blood-brain barrier permeability, and thus protected nerve cells from CIRI. The results in vitro research aligned with those of the in vivo research. HSP90 and MLKL overexpression promoted necroptosis and ferroptosis while activating the GCN2-ATF4 pathway. GPX4 overexpression had no effect on necroptosis or the associated signaling pathway. The administration of NTF alone, as well as its combination with the overexpression of HSP90, MLKL, or GPX4 plasmids, decreased the expression levels of factors associated with pro-ferroptosis and pro-necroptosis and reduced the protein levels of the HSP90-GCN2-ATF4 pathway. Moreover, the regulatory effects of the NTF alone group on GSH, ferrous iron, and GCN2 were more significant compared with those of the HSP90 overexpression combination group. CONCLUSION: Ferroptosis and necroptosis were gradually aggravated following CIRI with prolonged reperfusion. MLKL overexpression may promote ferroptosis and necroptosis, while GPX4 overexpression may have little effect on necroptosis. HSP90 overexpression accelerated both forms of cell death via the HSP90-GCN2-ATF4 pathway. NTF alleviated ferroptosis and necroptosis to attenuate CIRI by regulating the HSP90-GCN2-ATF4 pathway. Our research provided evidence for the potential of drug development by targeting HSP90, MLKL, and GPX4 to protect against ischemic stroke.
Asunto(s)
Factor de Transcripción Activador 4 , Ferroptosis , Proteínas HSP90 de Choque Térmico , Necroptosis , Fármacos Neuroprotectores , Daño por Reperfusión , Animales , Masculino , Ratones , Ratas , Factor de Transcripción Activador 4/metabolismo , Isquemia Encefálica/tratamiento farmacológico , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos/farmacología , Ferroptosis/efectos de los fármacos , Proteínas HSP90 de Choque Térmico/metabolismo , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Necroptosis/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Ratas Sprague-Dawley , Daño por Reperfusión/tratamiento farmacológico , Transducción de Señal/efectos de los fármacosRESUMEN
Cerebral ischemia/reperfusion injury (CIRI) is a major contributor to poor prognosis of ischemic stroke. Flavonoids are a broad family of plant polyphenols which are abundant in traditional Chinese medicine (TCM) and have beneficial effects on several diseases including ischemic stroke. Accumulating studies have indicated that flavonoids derived from herbal TCM are effective in alleviating CIRI after ischemic stroke in vitro or in vivo, and exhibit favourable therapeutical potential. Herein, we systematically review the classification, metabolic absorption, neuroprotective efficacy, and mechanisms of TCM flavonoids against CIRI. The literature suggest that flavonoids exert potential medicinal functions including suppressing excitotoxicity, Ca2+ overloading, oxidative stress, inflammation, thrombin's cellular toxicity, different types of programmed cell deaths, and protecting the blood-brain barrier, as well as promoting neurogenesis in the recovery stage following ischemic stroke. Furthermore, we identified certain matters that should be taken into account in future research, as well as proposed difficulties and opportunities in transforming TCM-derived flavonoids into medications or functional foods for the treatment or prevention of CIRI. Overall, in this review we aim to provide novel ideas for the identification of new prospective medication candidates for the therapeutic strategy against ischemic stroke.