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Emerging evidence shows that disrupted gut microbiota-bile acid (BA) axis is critically involved in the development of neurodegenerative diseases. However, the alterations in spatial distribution of BAs among different brain regions that command important functions during aging and their exact roles in aging-related neurodegenerative diseases are poorly understood. Here, we analyzed the BA profiles in cerebral cortex, hippocampus, and hypothalamus of young and natural aging mice of both sexes. The results showed that aging altered brain BA profiles sex- and region- dependently, in which TßMCA was consistently elevated in aging mice of both sexes, particularly in the hippocampus and hypothalamus. Furthermore, we found that aging accumulated-TßMCA stimulated microglia inflammation in vitro and shortened the lifespan of C. elegans, as well as behavioral impairment and neuroinflammation in mice. In addition, metagenomic analysis suggested that the accumulation of brain TßMCA during aging was partially attributed to reduction in BSH-carrying bacteria. Finally, rejuvenation of gut microbiota by co-housing aged mice with young mice restored brain BA homeostasis and improved neurological dysfunctions in natural aging mice. In conclusion, our current study highlighted the potential of improving aging-related neuro-impairment by targeting gut microbiota-brain BA axis.
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Alzheimer's disease (AD) is the most common neurodegenerative disease that leads to dementia. Its pathogenesis is very complex, and inflammation is one of the main pathophysiological mechanisms of AD. Non-steroidal anti-inflammatory drugs (NSAIDs), which mainly target cyclooxygenase (COX) activity, are used to reduce the risk of AD, but several side effects limit their application. Here we assess the effect of Cyclooxygenase-2 (COX2) catalytic activity on learning ability and AD pathology using 5x Familial Alzheimer's Disease (FAD) mice with COX2 inhibition (5xFAD/COX2 KO), 5xFAD mice with cyclooxygenase inactivation of COX2 (5xFAD/COX2 Y385F), and 5xFAD mice with peroxidase (POX) inactivation of COX2 (5xFAD/COX2) H374Y), respectively. Our results indicate that learning ability of COX2 KO and mutants is improved compared to 5xFAD mice, further investigations show that Aß depositions are reduced, microglia and astrocytes homeostasis are changed in COX2 KO and mutants. Especially, there is more responsive microglia in the brain of 5xFAD/COX2 Y385F mice, and Aß depositions are more effectively cleaned at old age. Taken together, these results identify a role of COX2 Y385F in regulating microglia function and may have important implications for future treatment of AD.
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Enfermedad de Alzheimer , Enfermedades Neurodegenerativas , Ratones , Animales , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Ciclooxigenasa 2 , Ratones Transgénicos , Enfermedades Neurodegenerativas/patología , Modelos Genéticos , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Péptidos beta-Amiloides/metabolismoRESUMEN
Many species living in groups can perform prosocial behaviors via voluntarily helping others with or without benefits for themselves. To provide a better understanding of the neural basis of such prosocial behaviors, we adapted a preference lever-switching task in which mice can prevent harm to others by switching from using a lever that causes shocks to a conspecific one that does not. We found the harm avoidance behavior was mediated by self-experience and visual and social contact but not by gender or familiarity. By combining single-unit recordings and analysis of neural trajectory decoding, we demonstrated the dynamics of anterior cingulate cortex (ACC) neural activity changes synchronously with the harm avoidance performance of mice. In addition, ACC neurons projected to the mediodorsal thalamus (MDL) to modulate the harm avoidance behavior. Optogenetic activation of the ACC-MDL circuit during non-preferred lever pressing (nPLP) and inhibition of this circuit during preferred lever pressing (PLP) both resulted in the loss of harm avoidance ability. This study revealed the ACC-MDL circuit modulates prosocial behavior to avoid harm to conspecifics and may shed light on the treatment of neuropsychiatric disorders with dysfunction of prosocial behavior.
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Giro del Cíngulo , Conducta de Ayuda , Ratones , Animales , Giro del Cíngulo/fisiología , Tálamo/fisiología , Neuronas/fisiologíaRESUMEN
Inflammatory reaction in the brain activates glial cells, and over-activated glial cells secrete inflammatory mediators, which aggravates the inflammatory response in the brain and accelerates the development of Alzheimer's disease (AD) in turn. Numerous natural compounds from herbs can alleviate inflammation, and it is very promising to find anti-neuroinflammatory natural compounds. Micheliolide (MCL) is an asesquiterpene lactone. Studies have proved that MCL showed an obvious anti-inflammatory property. Nevertheless, whether MCL can treat AD has not been determined. In this research, AD model mice were fed with a diet supplemented MCL for 3 months, the cognitive ability and inflammatory state of mice were detected. We found that MCL raised the frequency of touching novel objects, cut down the escape latency, raised the number of crossing platform, inhibited the infiltration of inflammatory cells and the secretion of interleukin-1α (IL-1α), IL-12p40, IL-13, IL-17A, tumor necrosis factor-α (TNF-α), granulocyte colony stimulating factor (G-CSF), macrophage inflammatory protein-1α (MIP-1α) and monocyte chemotactic protein-1 (MCP-1) in peripheral blood samples, inhibited the hyperplasia of glial cells and the production of IL-1α, IL-4, G-CSF, granulocyte-macrophage colony stimulating factor (GM-CSF), MIP-1α and MIP-1ß, and reduced the deposition of Aß peptides in the brain of AD mice. We also concluded that MCL dropped the expression of IL-1ß, TNF-α, cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and the phosphorylation of IκB, p65 and Akt in BV-2 cells. In conclusion, MCL alleviates the intensity of systemic inflammatory reaction via inhibiting nuclear transcription factor κ gene binding (NF-κB) and phosphoinositide-3-kinase/serine/threonine kinase (PI3K/Akt) pathways in glial cells, and improves the cognitive impairment of AD mice. Therefore, MCL could be a therapeutic candidate for AD.
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Cytoplasmic dynein is an important intracellular motor protein that plays an important role in neuronal growth, axonal polarity formation, dendritic differentiation, and dendritic spine development among others. The intermediate chain of dynein, encoded by Dync1i1, plays a vital role in the dynein complex. Therefore, we assessed the behavioral and related neuronal activities in mice with dync1i1 gene knockout. Neuronal activities in primary somatosensory cortex were recorded by in vivo electrophysiology and manipulated by optogenetic and chemogenetics. Nociception of mechanical, thermal, and cold pain in Dync1i1-/- mice were impaired. The activities of parvalbumin (PV) interneurons and gamma oscillation in primary somatosensory were also impaired when exposed to mechanical nociceptive stimulation. This neuronal dysfunction was rescued by optogenetic activation of PV neurons in Dync1i1-/- mice, and mimicked by suppressing PV neurons using chemogenetics in WT mice. Impaired pain sensations in Dync1i1-/- mice were correlated with impaired gamma oscillations due to a loss of interneurons, especially the PV type. This genotype-driven approach revealed an association between impaired pain sensation and cytoplasmic dynein complex.
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Parvalbúminas , Corteza Somatosensorial , Ratones , Animales , Parvalbúminas/metabolismo , Corteza Somatosensorial/metabolismo , Dineínas Citoplasmáticas/metabolismo , Dineínas/metabolismo , Interneuronas/metabolismo , Umbral del DolorRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Kaixin San (KXS) is one of the most famous traditional Chinese formulas prescribed by Sun Simiao in 652 Christian era. It is composed of Panax ginseng C.A.Mey, Polygala tenuifolia, Poria cocos and Acorus calamus var. angustatus Besser. KXS is widely used for the treatment of emotion-thought disease, such as settling fright, quieting the spirit and nourishing the heart. However, whether KXS benefits hippocampal neurons and myocardial cells of mice impaired by paradoxical sleep deprivation (PSD) and its mechanism remains unclear. AIM OF THE STUDY: This study was aimed to investigate the effect of KXS on hippocampal neuron and cardiac ferroptosis in rapid-eye-movement (REM) sleep deprived mice and clarify its potential mechanism. MATERIALS AND METHODS: PSD was induced by a modified multi-platform method. Morris water maze (MWM) was used to detect the ability of learning and memory. Cardiac morphological changes were assessed by hematoxylin and eosin (HE) staining. Heart rate was detected by a PowerLab multichannel physiological recorder. Serum levels of atrial natriuretic peptide (ANP) and lactate dehydrogenase (LDH) were measured with biochemical kits. Transmission electron microscopy (TEM), immunofluorescent, and Western blotting analysis were used to observe the process and pathway of ferrotosis in hippocampus tissue and heart tissue of PSD mice. RESULTS: KXS administration improved the impaired learning and memory of PSD mice. It prevented the damage of mitochondria in the hippocampus and heart of PSD mice. KXS also alleviated the myocardial injury, such as morphological damage, abnormal heart rate, serum ANP, and serum LDH induced by PSD. Further study disclosed that KXS reversed the expressions of proteins involved in ferroptosis such as TFRC, SLC7A11/xCT, GPX-4, ACSL4, and FTH1 in hippocampus and heart tissues. CONCLUSIONS: KXS improved learning and memory of mice with REM sleep deprivation, which was closely associated with suppressed ferroptosis in hippocampal neurons and myocardiocytes.
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Medicamentos Herbarios Chinos , Ferroptosis , Humanos , Ratones , Animales , Privación de Sueño/metabolismo , Miocitos Cardíacos , Sueño REM , Pueblos del Este de Asia , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Medicamentos Herbarios Chinos/metabolismo , HipocampoRESUMEN
The liver is the most common site for colorectal cancer (CRC)-associated metastasis. There remain unsatisfactory medications in liver metastasis given the incomplete understanding of pathogenic mechanisms. Herein, with an orthotopic implantation model fed either regular or high-fat diets (HFD), more liver metastases were associated with an expansion of conjugated bile acids (BAs), particularly taurocholic acid (TCA) in the liver, and an increased gene expression of Na+-taurocholate cotransporting polypeptide (NTCP). Such hepatic BA change was more apparently shown in the HFD group. In the same model, TCA was proven to promote liver metastases and induce a tumor-favorable microenvironment in the liver, characterizing a high level of fibroblast activation and increased proportions of myeloid-derived immune cells. Hepatic stellate cells, a liver-residing source of fibroblasts, were dose-dependently activated by TCA, and their conditioned medium significantly enhanced the migration capability of CRC cells. Blocking hepatic BA uptake with NTCP neutralized antibody can effectively repress TCA-triggered liver metastases, with an evident suppression of tumor microenvironment niche formation. This study points to a new BA-driven mechanism of CRC-associated liver metastases, suggesting that a reduction of TCA overexposure by limiting liver uptake is a potential therapeutic option for CRC-associated liver metastasis.
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Neoplasias Colorrectales , Neoplasias Hepáticas , Simportadores , Humanos , Transportadores de Anión Orgánico Sodio-Dependiente/genética , Transportadores de Anión Orgánico Sodio-Dependiente/metabolismo , Simportadores/genética , Simportadores/metabolismo , Ácido Taurocólico/farmacología , Ácido Taurocólico/metabolismo , Microambiente TumoralRESUMEN
BACKGROUND: Valproic acid (VPA) represents one of the most efficient antiseizure medications (ASMs) for both general and focal seizures, but some patients may have inadequate control by VPA monotherapy. In this study, we aimed to verify the hypothesis that excitatory dynamic rebound induced by inhibitory power may contribute to the ineffectiveness of VPA therapy and become a predictor of post-operative inadequate control of seizures. METHODS: Awake craniotomy surgeries were performed in 16 patients with intro-operative high-density electrocorticogram (ECoG) recording. The relationship between seizure control and the excitatory rebound was further determined by diagnostic test and univariate analysis. Thereafter, kanic acid (KA)-induced epileptic mouse model was used to confirm that its behavior and neural activity would be controlled by VPA. Finally, a computational simulation model was established to verify the hypothesis. FINDINGS: Inadequate control of seizures by VPA monotherapy and post-operative status epilepticus are closely related to a significant excitatory rebound after VPA injection (rebound electrodesâ§5/64, p = 0.008), together with increased synchronization of the local field potential (LFP). In addition, the neural activity in the model mice showed a significant rebound on spike firing (53/77 units, 68.83%). The LFP increased the power spectral density in multiple wavebands after VPA injection in animal experiments (p < 0.001). Computational simulation experiments revealed that inhibitory power-induced excitatory rebound is an intrinsic feature in the neural network. INTERPRETATION: Despite the limitations, we provide evidence that inadequate control of seizures by VPA monotherapy could be associated with neural excitatory rebounds, which were predicted by intraoperative ECoG analysis. Combined with the evidence from computational models and animal experiments, our findings suggested that ineffective ASMs may be because of the excitatory rebound, which is mediated by increased inhibitory power. FUNDING: This work was supported by National Natural Science Foundation of China (62127810, 81970418), Shanghai Municipal Science and Technology Major Project (2018SHZDZX03) and ZJLab; Science and Technology Commission of Shanghai Municipality (18JC1410403, 19411969000, 19ZR1477700, 20Z11900100); MOE Frontiers Center for Brain Science; Shanghai Key Laboratory of Health Identification and Assessment (21DZ2271000); Shanghai Shenkang (SHDC2020CR3073B).
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Estado Epiléptico , Ácido Valproico , Animales , Anticonvulsivantes/farmacología , Anticonvulsivantes/uso terapéutico , China , Ratones , Convulsiones/inducido químicamente , Convulsiones/tratamiento farmacológico , Ácido Valproico/farmacologíaRESUMEN
Most basal-like breast cancers (BLBCs) are triple-negative breast cancers (TNBCs), which is associated with high malignancy, high rate of recurrence and distant metastasis, and poor prognosis among all types of breast cancer. However, there are currently no effective therapies for BLBC. Furthermore, chemoresistance limits the therapeutic options for BLBC treatment. In this study, we screen out protein activator of the interferon-induced protein kinase (PACT) as an essential gene in BLBC metastasis. We find that high PACT expression level was associated with poor prognosis among BLBC patients. In vivo and in vitro investigations indicated that PACT could regulate BLBC metastasis by interacting with SUMO-conjugating enzyme Ubc9 to stimulate the SUMOylation and thus consequently the activation of Rac1. BLBC patients receiving chemotherapy presents poorer prognosis with PACT high expression, and PACT disruption sensitizes experimental mammary tumor metastases to chemotherapy, thus providing insights to consider PACT as a potential therapeutic target to overcome acquired chemoresistance in BLBC.
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Neoplasias de la Mama , Proteínas de Unión al ARN/metabolismo , Neoplasias de la Mama Triple Negativas , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Femenino , Humanos , Sumoilación , Proteína de Unión al GTP rac1/genética , Proteína de Unión al GTP rac1/metabolismoRESUMEN
ABSTRACT: Chronic pain is highly prevalent. Individuals with cognitive disorders such as Alzheimer disease are a susceptible population in which pain is frequently difficult to diagnosis. It is still unclear whether the pathological changes in patients with Alzheimer disease will affect pain processing. Here, we leverage animal behavior, neural activity recording, optogenetics, chemogenetics, and Alzheimer disease modeling to examine the contribution of the anterior cingulate cortex (ACC) neurons to pain response. The 5× familial Alzheimer disease mice show alleviated mechanical allodynia which can be regained by the genetic activation of ACC excitatory neurons. Furthermore, the lower peak neuronal excitation, delayed response initiation, as well as the dendritic spine reduction of ACC pyramidal neurons in 5×familial Alzheimer disease mice can be mimicked by Rac1 or actin polymerization inhibitor in wild-type (WT) mice. These findings indicate that abnormal of pain sensitivity in Alzheimer disease modeling mice is closely related to the variation of neuronal activity and dendritic spine loss in ACC pyramidal neurons, suggesting the crucial role of dendritic spine density in pain processing.
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Enfermedad de Alzheimer , Dolor Crónico , Actinas , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/genética , Animales , Espinas Dendríticas , Giro del Cíngulo/fisiología , Ratones , Células PiramidalesRESUMEN
Sleep deprivation (SD) may lead to serious myocardial injury in cardiovascular diseases. Saponins extracted from the roots of Panax notoginseng, a traditional Chinese medicine beneficial to blood circulation and hemostasis, are the main bioactive components exerting cardiovascular protection in the treatment of heart disorders, such as arrhythmia, ischemia and reperfusion injury, and cardiac hypertrophy. This study aimed to explore the protective effect of stem-leaf saponins from Panax notoginseng (SLSP) on myocardial injury in SD mice. SD was induced by a modified multi-platform method. Cardiac morphological changes were assessed by hematoxylin and eosin (H&E) staining. Heart rate and ejection fraction were detected by specific instruments. Serum levels of atrial natriuretic peptide (ANP) and lactate dehydrogenase (LDH) were measured with biochemical kits. Transmission electron microscopy (TEM), immunofluorescent, and Western blotting analysis were used to observe the process and pathway of autophagy and apoptosis in heart tissue of SD mice. In vitro, rat H9c2 cells pretreated with rapamycin and the effect of SLSP were explored by acridine orange staining, transient transfection, flow cytometry, and Western blotting analysis. SLSP prevented myocardial injury, such as morphological damage, accumulation of autophagosomes in heart tissue, abnormal high heart rate, serum ANP, and serum LDH induced by SD. In addition, it reversed the expressions of proteins involved in the autophagy and apoptosis and activated PI3K/Akt/mTOR signaling pathway that is disturbed by SD. On H9c2 cells induced by rapamycin, SLSP could markedly resume the abnormal autophagy and apoptosis. Collectively, SLSP attenuated excessive autophagy and apoptosis in myocardial cells in heart tissue induced by SD, which might be acted through activating PI3K/Akt/mTOR signaling pathway.
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Sleep deprivation (SD) may cause serious neural injury in the central nervous system, leading to impairment of learning and memory. Melatonin receptor 1A (MTNR1A) plays an important role in the sleep regulation upon activation by melatonin. The present study aimed to investigate if notoginsenoside R1 (NGR1), an active compound isolated from Panax notoginseng, could alleviate neural injury, thus improve impaired learning and memory of SD mice, as well as to explore its underlying action mechanism through modulating MTNR1A. Our results showed that NGR1 administration improved the impaired learning and memory of SD mice. NGR1 prevented the morphological damage and the accumulation of autophagosomes in the hippocampus of SD mice. At the molecular level, NGR1 reversed the expressions of proteins involved in autophagy and apoptosis, such as beclin-1, LC3B, p62, Bcl-2, Bax, and cleaved-caspase 3. Furthermore, the effect of NGR1 was found to be closely related with the MTNR1A-mediated PI3K/Akt/mTOR signaling pathway. On HT-22 cells induced by autophagy inducer rapamycin, NGR1 markedly attenuated excessive autophagy and apoptosis, and the alleviative effect was abolished by the MTNR1A inhibitor. Taken together, NGR1 was shown to alleviate the impaired learning and memory of SD mice, and its function might be exerted through reduction of excessive autophagy and apoptosis of hippocampal neurons by regulating the MTNR1A-mediated PI3K/Akt/mTOR signaling pathway.
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Protein l-isoaspartyl methyltransferase (PIMT/PCMT1), an enzyme repairing isoaspartate residues in peptides and proteins that result from the spontaneous decomposition of normal l-aspartyl and l-asparaginyl residues during aging, has been revealed to be involved in neurodegenerative diseases (NDDs) and diabetes. However, the molecular mechanisms for a putative association of PIMT dysfunction with these diseases have not been clarified. Our study aimed to identify differentially expressed microRNAs (miRNAs) in the brain and kidneys of PIMT-deficient mice and uncover the epigenetic mechanism of PIMT-involved NDDs and diabetic nephropathy (DN). Differentially expressed miRNAs by sequencing underwent target prediction and enrichment analysis in the brain and kidney of PIMT knockout (KO) mice and age-matched wild-type (WT) littermates. Sequence analysis revealed 40 differentially expressed miRNAs in the PIMT KO mouse brain including 25 upregulated miRNAs and 15 downregulated miRNAs. In the PIMT KO mouse kidney, there were 80 differentially expressed miRNAs including 40 upregulated miRNAs and 40 downregulated miRNAs. Enrichment analysis and a systematic literature review of differentially expressed miRNAs indicated the involvement of PIMT deficiency in the pathogenesis in NDDs and DN. Some overlapped differentially expressed miRNAs between the brain and kidney were quantitatively assessed in the brain, kidney, and serum-derived exosomes, respectively. Despite being preliminary, these results may aid in investigating the pathological hallmarks and identify the potential therapeutic targets and biomarkers for PIMT dysfunction-related NDDs and DN.
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Nefropatías Diabéticas/genética , MicroARNs/genética , Enfermedades Neurodegenerativas/genética , Animales , China , Expresión Génica/genética , Perfilación de la Expresión Génica/métodos , Masculino , Ratones , Ratones Noqueados , MicroARNs/análisis , Proteína D-Aspartato-L-Isoaspartato Metiltransferasa/deficiencia , Proteína D-Aspartato-L-Isoaspartato Metiltransferasa/genética , Proteína D-Aspartato-L-Isoaspartato Metiltransferasa/metabolismo , Transcriptoma/genéticaRESUMEN
Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit prostaglandin (PG) formation by targeting cyclooxygenase (COX) 1 and 2. Long-term use of NSAIDs that selectively inhibit COX2 increases the risk for thrombotic events, cardiac failure, and hypertension. However, the underlying mechanisms remain unclear. In this study, COX1- and COX2-deficient rats were created via Cas9/RNA-mediated gene targeting. DNA genotyping and Western blot analysis confirmed successful generation of COX1-/-and COX2-/- rats. Adult COX1-/- rats grew normally, while more than 70% of COX2-/- rats after wean died within 2 months. Echocardiography showed markedly reduced left ventricular ejection fraction and fractional shortening in adult COX2-/- rats compared to those in wildtype (WT) controls. Histological analysis revealed accumulation of inflammatory cells and severe interstitial and perivascular fibrosis in COX2-/- cardiac tissues. Moreover, cardiac ATP and acetyl-CoA production was dramatically decreased in COX2-/- rats. Consistently, the expression of genes related to mitochondrial oxidation, such as those that encode for subunits of pyruvate dehydrogenase complex and acyl CoA dehydrogenases, were downregulated, while glycolytic hexokinase 1 (HK1) was upregulated in COX2-/- heart tissues. These observations indicate that COX2-deficient rats developed spontaneously heart failure, likely as a result of dysregulated cardiac energy metabolism.
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Antiinflamatorios no Esteroideos/farmacología , Inhibidores de la Ciclooxigenasa 2/farmacología , Ciclooxigenasa 2/metabolismo , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/metabolismo , Animales , Biomarcadores/metabolismo , Ciclooxigenasa 1/metabolismo , Ecocardiografía , Metabolismo Energético , Fibrosis , Genotipo , Insuficiencia Cardíaca/diagnóstico por imagen , Ratas , Ratas Sprague-Dawley , Volumen SistólicoRESUMEN
[This corrects the article DOI: 10.3389/fcvm.2021.694219.].
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[This corrects the article DOI: 10.3389/fphar.2021.719313.].
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OBJECTIVE: Several ß-carboline alkaloids (ßCBs), such as harmine, harmaline, harmane, and nor-harmane, are effective for Alzheimer's disease mouse models. They can be found in some plants, common foodstuffs, and blank plasma of various mammals. However, whether these compounds in mammals are exogenous or endogenous remain unclear. METHODS: The exposure levels of ßCBs and of neurotransmitters in plasma and tissues of pup rats, aging rats, mice of different physiological states, and healthy volunteers were detected by using UPLC-MS/MS. Plasma and tissue samples from 110 newborn rats up to 29 days old at 11 sampling points were collected and were analyzed to determine the concentration variation of ßCBs in the developmental phase of newborn rats. The plasma of rats aged 2 to 18 months was used to detect the variation trend of ßCBs and with some neurotransmitters. The plasma samples of normal C57BL/6 mice, APP/PS1 double transgenic mice, and scopolamine-induced memory impairment mice were collected and were analyzed to compare the difference of ßCBs in different physiological states. The exposure levels of ßCBs such as harmine, harmaline, and harmane in plasma of 550 healthy volunteers were also detected and analyzed on the basis of gender, race, and age. RESULTS: Results showed that harmine was the main compound found in rats, mice, and human, which can be detected in a newborn rat plasma (0.16 ± 0.03 ng/ml) and brain (0.33 ± 0.14 ng/g) without any exogenous consumption. The concentration of harmine in rat plasma showed a decreasing trend similar to the exposure levels of neurotransmitters such as 5-hydroxytryptamine, acetylcholine chloride, glutamic acid, tyrosine, and phenylalanine during the growth period of 18 months. The harmine exposure in rats and human indicates high dependence on the physiological and pathological status such as aging, gender, and race. CONCLUSION: The dynamic changes of harmine exposure in different animals and human, in vivo, at developmental and physiological states indicate that harmine is a naturally and widely distributed endogenous substance in different mammals and human. In addition to exogenous ingestion, spontaneous synthesis might be another important source of harmine in mammals, which should be verified by further experiment.
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Natural killer (NK) cells, a key member of innate lymphocytes, are a promising immunotherapeutic target for ischemic stroke. Astragaloside IV (ASIV) is isolated from Astragalus mongholicus Bunge (Fabaceae), a herbal medicine possessing immunomodulatory ability. This study investigated the effect of ASIV on NK cells during the acute stage of brain ischemic injury in a mouse model of middle cerebral artery occlusion (MCAO). MCAO mice treated with ASIV had better functional outcomes, smaller brain infarction and less NK cell brain infiltration. NK cell depletion echoed the protective effect of ASIV. Notably, ASIV did not enhance the protective effect of NK cell depletion against brain ischemic injury. ASIV inhibited glial cell-derived CCL2-mediated chemotaxis to prevent post-ischemic NK cell brain recruitment. Meanwhile, ASIV also abrogated NK cell-mediated cytolytic killing of neurons subjected to oxygen-glucose deprivation and suppressed NK cell-derived IFN-γ and NKG2D expression in the ischemic brain. The inhibitory effect of ASIV on NK cell brain infiltration and activation was mimicked by cryptotanshinone, a STAT3 inhibitor. There was no additive effect when ASIV and cryptotanshinone were used together. In conclusion, ASIV inhibits post-ischemic brain infiltration and activation of NK cells through STAT3 suppression, and this inhibitory effect of ASIV on NK cells plays a key role in its protection against acute ischemic brain injury. Our findings suggest that ASIV is a promising therapeutic candidate in NK cell-based immunotherapy for the treatment of acute ischemic stroke and pave the way for potential clinical trials.
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Natural killer (NK) cells, a type of cytotoxic lymphocytes, can infiltrate into ischemic brain and exacerbate neuronal cell death. Astragaloside IV (ASIV) is the major bioactive ingredient of Astragalus membranaceus, a Chinese herbal medicine, and possesses potent immunomodulatory and neuroprotective properties. This study investigated the effects of ASIV on post-ischemic brain infiltration and activation of NK cells. ASIV reduced brain infarction and alleviated functional deficits in MCAO rats, and these beneficial effects persisted for at least 7 days. Abundant NK cells infiltrated into the ischemic hemisphere on day 1 after brain ischemia, and this infiltration was suppressed by ASIV. Strikingly, ASIV reversed NK cell deficiency in the spleen and blood after brain ischemia. ASIV inhibited astrocyte-derived CCL2 upregulation and reduced CCR2+ NK cell levels in the ischemic brain. Meanwhile, ASIV attenuated NK cell activating receptor NKG2D levels and reduced interferon-γ production. ASIV restored acetylation of histone H3 and the p65 subunit of nuclear factor-κB in the ischemic brain, suggesting inhibition of histone deacetylase (HDAC). Simultaneously, ASIV prevented p65 nuclear translocation. The effects of ASIV on reducing CCL2 production, restoring acetylated p65 levels and preventing p65 nuclear translocation were mimicked by valproate, an HDAC inhibitor, in astrocytes subjected to oxygen-glucose deprivation. Our findings suggest that ASIV inhibits post-ischemic NK cell brain infiltration and activation and reverses NK cell deficiency in the periphery, which together contribute to the beneficial effects of ASIV against brain ischemia. Furthermore, ASIV's effects on suppressing NK cell brain infiltration and activation may involve HDAC inhibition.
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Saponinas , Triterpenos , Animales , Encéfalo , Histona Desacetilasas , Células Asesinas Naturales , Ratas , Saponinas/farmacología , Triterpenos/farmacologíaRESUMEN
Ketamine is a widely used intravenous anesthetic; however, basic and clinical studies have demonstrated that prolonged exposure can cause irreversible injury to the immature human brain. Yesassociated protein (YAP) is the main effector of the Hippo signaling pathway, which serves an important role in regulating tissue homeostasis and organ size during development. However, whether YAP mediates ketamineinduced apoptosis is not completely understood. Based on the functions of YAP during apoptosis resistance and cell selfrenewal regulation, the present study hypothesized that YAP serves a role during ketamineinduced apoptosis. An in vitro model was utilized to investigate the effects of ketamine on neurotoxicity and to further investigate the role of YAP in ketamineinduced apoptosis using techniques including CCK8 assay, flow cytometry and western blotting. The present study assessed the effects of YAP overexpression and knockdown on the expression of typical apoptotic markers in SHSY5Y cells. Ketamine induced apoptosis in a dosedependent manner, which was regulated by YAP. Following YAP overexpression, ketaminetreated SHSY5Y cells displayed increased activity and viability, whereas expression levels of the apoptotic markers were decreased compared with the negative control group. By contrast, ketamineinduced apoptosis was enhanced following YAP knockdown. Collectively, the results of the present study indicated that YAP may serve an important role during ketamineinduced neurotoxicity, and alterations to YAP signaling may counteract ketamineinduced apoptosis. The neuroprotective effect of YAP activation may serve as a novel pharmacological target for the treatment of ketamineinduced neurotoxicity via neurogenesis normalization.