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Entomopathogenic fungi (EPF) infect insects by landing on and penetrating cuticles. Emerging evidence has shown that, prior to the invasion of insects, fungal cells have to battle and overcome diverse challenges, including the host behavioral defenses, colonization resistance mediated by ectomicrobiotas, host recognition, and generation of enough penetration pressure. The ascomycete EPF such as Metarhizium and Beauveria can thus produce adhesive proteins and/or the exopolysaccharide mucilage to tightly glue fungal cells on cuticles. Producing antimicrobial peptides and chemical compounds can enable EPF to outcompete cuticular defensive microbes. The use of divergent membrane receptors, accumulation, and quick degradation of lipid droplets in conidial cells can help EPF recognize proper hosts and build up cellular turgor to breach cuticles for systematic invasion. Further investigations are still required to unveil the multifaceted and intricate relationships between EPF and insect hosts.
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Ascomicetos , Beauveria , Metarhizium , Animales , Insectos/microbiología , Esporas FúngicasRESUMEN
The tactics used by animal pathogens to combat host immunity are largely unclear. Here, we report the depiction of the virulence-required effector Tge1 deployed by the entomopathogen Metarhizium robertsii to suppress Drosophila antifungal immunity. Tge1 can target both GNBP3 and GNBP-like 3 (GL3), and the latter can bind to ß-glucans like GNBP3, whereas the glucan binding by both receptors can be attenuated by Tge1. As opposed to the surveillance GNBP3, GL3 is inducible in Drosophila depending on the Toll pathway via a positive feedback loop mechanism. Losses of GNBP3 and GL3 genes result in the deregulations of protease cascade, Spätzle maturation, and antimicrobial gene expressions in Drosophila upon fungal challenges. Fly survival assays confirm that GL3 plays a more essential role than GNBP3 in combating fungal infections. In addition to evidencing the gene-for-gene interactions between fungi and insects, our data advance insights into Drosophila antifungal immunity.
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Proteínas de Drosophila , Parásitos , beta-Glucanos , Animales , Drosophila/metabolismo , Antifúngicos/farmacología , beta-Glucanos/farmacología , beta-Glucanos/metabolismo , Parásitos/metabolismo , Proteínas de Drosophila/metabolismo , Proteínas Portadoras/metabolismoRESUMEN
Entomopathogenic fungi (EPF) distribute in different fungal phyla with variable host ranges and play essential role in regulating insect populations by infecting hosts via cuticle penetration. The representative ascomycete EPF of Metarhizium and Beauveria species have been widely used in mechanistic investigations of fungus-insect interactions and as ecofriendly mycoinsecticides. Here, we review the function of diverse genes, pathways, and secondary metabolites associated with EPF stepwise infections. In particular, emerging evidence has shown that EPF have to outcompete insect ectomicrobiotas prior to penetrating cuticles, and subvert or evade host antifungal immunity by using effector-like proteins and chemicals like plant pathogens. Future prospects are discussed for a better understanding of fungal pathobiology, which will provide novel insights into microbe-animal interactions.
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Beauveria , Metarhizium , Micosis , Animales , Insectos/microbiología , Metarhizium/genética , Metarhizium/metabolismo , Beauveria/genética , Especificidad del Huésped , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismoRESUMEN
In addition to innate immunity in a physiological context, insects have evolved behavioral defenses against parasite attacks. Here, we report that Drosophila can sense the CFEM (common in fungal extracellular membrane) protein Mcdc9, which acts as a negative virulence factor of the entomopathogenic fungus Metarhizium robertsii. The individual deletions of 18 CFEM genes in Metarhizium followed by fly infection identified three null mutants that could kill the flies more quickly than the wild-type strain, among which Mcdc9 can coat fungal spores and interact with the fly chemosensory protein CheA75a. The deletion of Mcdc9 in the fungus or the knockdown of CheA75a in flies had a similar effect, in which a greater number of fungal spores were left on flies than on the respective controls after topical infection. Thus, similar to the accelerated death of the wild-type flies treated with ΔMcdc9, the CheA75aRNAi flies succumbed more quickly than the control insects topically challenged with the wild-type strain. The CheA75a gene is highly transcribed in fly legs and wings, and positive electrophysiological responses were evidenced in tarsal sensilla after stimulation with the Mcdc9 protein. The results imply that this CFEM protein could be sensed as a contact elicitor inducing the hygienic behavior of flies against fungal parasitic infection, which reveals a previously unsuspected mechanism of fungus-insect interactions.
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Metarhizium , Parásitos , Enfermedades Parasitarias , Animales , Parásitos/metabolismo , Proteínas de la Membrana/genética , Insectos , Esporas Fúngicas/genética , Esporas Fúngicas/metabolismo , Proteínas Fúngicas/metabolismo , Drosophila/metabolismo , Metarhizium/genéticaRESUMEN
BACKGROUND: There are about 7000 rare diseases worldwide, of which only 5% of the diseases can be treated with medicines, showing that it's important to improve patient access to orphan drugs. Recently, China has actively worked to set up a national system for rare diseases to improve the diagnosis and treatment capabilities and ensure the accessibility of drugs. However, the benefits of the system have yet not to be measured. This study aimed to provide an overview of orphan drug access based on the Compendium of China's First List of Rare Diseases and National Network to Collaborate on Diagnosis and Treatment of Rare Diseases, expecting to map a blueprint for orphan drug access in China. METHODS: Framework of China's national system for rare diseases was summarized. We surveyed the availability and affordability of 79 approved orphan drugs based on the Compendium of China's First List of Rare Diseases in 30 leading provincial institutions from 2017 to 2020. The availability was measured annually at 3 levels (market, hospital and drug), and affordability was reflected by comparing costs of daily defined dose with per capita income of urban and rural residents, with the National Basic Medical Insurance considered. RESULTS: The market availability of orphan drugs in China showed an upward trend. As of 2020, the median hospital-level availability was 41.1% (increased by 1.5 times), highly available drugs increased by 16.5%. There were 64/74 orphan drugs that were affordable to rural/urban residents with the National Basic Medical Insurance considered (an increase of 14.1%), and the urban-rural gap of affordability ratio was narrowed (down by 6.0%). Comprehensive analysis showed the proportions of drugs with better availability and affordability in urban and rural areas by 2020 were 39.4% and 32.3%, respectively, which had increased but were still at a low level. CONCLUSIONS: China's national system for rare diseases has made great progress in orphan drug access, indicating that it's been functioning under the joint reformation of medical treatment, medical insurance and medicines supply. The list of rare diseases will be updated and collaboration in networks will be enhanced to further improve the system.
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Producción de Medicamentos sin Interés Comercial , Enfermedades Raras , China , Humanos , Enfermedades Raras/tratamiento farmacológico , Enfermedades Raras/epidemiologíaRESUMEN
Background: GJ-4 is extracted from Gardenia jasminoides J. Ellis (Fructus Gardenia) with crocin composition and has been demonstrated to improve memory deficits in several dementia models in our previous studies. Objective: This study aimed to evaluate the effects of GJ-4 on hyperlipidemic vascular dementia (VD) and explore the underlying mechanisms. Design: In the current study, we employed a chronic hyperlipidemic VD rat model by permanent bilateral common carotid arteries occlusion (2-VO) based on high-fat diet (HFD), which is an ideal model to mimic the clinical pathogenesis of human VD. Results: Our results showed that GJ-4 could significantly reduce serum lipids level and improve cerebral blood flow in hyperlipidemic VD rats. Additionally, treatment with GJ-4 remarkedly ameliorated memory impairment and alleviated neuronal injury. Mechanistic investigation revealed that the neuroprotective effects of GJ-4 might be attributed to the inhibition of microglia-mediated neuro-inflammation via regulating the M1/M2 polarization. Our data further illustrated that GJ-4 could regulate the phenotype of microglia through activating the peroxisome proliferator-activated receptor-γ (PPAR-γ) and subsequently inhibited nuclear factor-κB (NF-κB) nuclear translocation and increased CCAAT/enhancer-binding protein ß (C/EBPß) expression. Conclusion: Our results implied that GJ-4 might be a promising drug to improve VD through the regulation of microglial M1/M2 polarization and the subsequent inhibition of neuro-inflammation.
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Mitotane is the only drug approved to treat adrenocortical carcinoma (ACC), and a relationship of pharmacokinetic/pharmacodynamic has been characterized. However, limited evidence concerning affecting factors in large interindividual variability of the pharmacokinetics of mitotane is available. To address this question, a retrospective analysis was performed on ACC Chinese patients treated with mitotane for more than 3 months. Mitotane plasma trough concentrations were detected at the steady state, and CYP2B6, CYP3A4, and pregnane X receptor (PXR) polymorphisms were genotyped. After examining homogeneous pharmacologic data, we restricted the analyses to 36 patients that received mitotane for a median (interquartile range, IQR) of 9 months (5.00-22.50) with a median dose of 2 g/day (2.00-2.50). As a result, drug exposure was significantly influenced by the cumulative dose of mitotane, and CYP2B6 516GG and CYP2B6 26570CC were at high risk to be below the therapeutic range of mitotane. No association was found between mitotane concentrations with CYP3A4 or PXR polymorphism. Our data firstly indicated that the cumulative dose of mitotane and polymorphisms of CYP2B6 516 and CYP2B6 26570 might significantly affect mitotane plasma trough concentrations in Chinese ACC patients.
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Neuroinflammation plays an important role in neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer's disease. HACE1 (HECT domain and Ankyrin repeat Containing E3 ubiquitin-protein ligase 1) is a tumor suppressor. Recent evidence suggests that HACE1 may be involved in oxidative stress responses. Due to the critical role of ROS in neuroinflammation, we speculated that HACE1 might participate in neuroinflammation and related neurodegenerative diseases, such as PD. In this study, we investigated the role of HACE1 in neuroinflammation of PD models. We showed that HACE1 knockdown exacerbated LPS-induced neuroinflammation in BV2 microglial cells in vitro through suppressing ubiquitination and degradation of activated Rac1, an NADPH oxidase subunit. Furthermore, we showed that HACE1 exerted vital neuronal protection through increasing Rac1 activity and stability in LPS-treated SH-SY5Y cells, as HACE1 knockdown leading to lower tolerance to LPS challenge. In MPTP-induced acute PD mouse model, HACE1 knockdown exacerbated motor deficits by activating Rac1. Finally, mutant α-synuclein (A53T)-overexpressing mice, a chronic PD mouse model, exhibited age-dependent reduction of HACE1 levels in the midbrain and striatum, implicating that HACE1 participated in PD pathological progression. This study for the first time demonstrates that HACE1 is a negative regulator of neuroinflammation and involved in the PD pathogenesis by regulating Rac1 activity. The data support HACE1 as a potential target for PD and other neurodegenerative diseases.
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Trastornos Parkinsonianos/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Proteína de Unión al GTP rac1/metabolismo , Animales , Western Blotting , Línea Celular Tumoral , Técnica del Anticuerpo Fluorescente , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Enfermedades Neuroinflamatorias/metabolismo , Prueba de Desempeño de Rotación con Aceleración Constante , UbiquitinaciónRESUMEN
BACKGROUND: Accumulating evidence demonstrates that traditional Chinese medicines that act on multiple targets could effectively treat various multi-etiological diseases, including cerebrovascular diseases, Alzheimer's disease (AD), Parkinson's disease (PD) and so on. Previous studies have shown that crocin richments (GJ-4), Gardenia jasminoides J.Ellis extract, provide neuroprotective effects on cognitive impairments in AD mouse models. However, the mechanism how GJ-4 improves cognition remains still unclear. PURPOSE: The aim of this study was to uncover the protective effects and underlying mechanism of GJ-4 on PrP-hAßPPswe/PS1ΔE9 (APP/PS1) transgenic mice. METHODS: APP/PS1 mice were given GJ-4 (10, 20, and 50 mg/kg), donepezil (5 mg/kg) and memantine (5 mg/kg) orally at eight months of age for 12 consecutive weeks. Morris water maze and novel object recognition were conducted to assess the cognitive ability of mice. The release of inflammatory cytokines was determined by RT-PCR assay, and the pathological features of neurons and microglia were assayed by immunohistochemistry and immunofluorescence assay. The expression of Aß-related proteins and signaling pathways were determined by Western blot. RESULTS: The behavioral results revealed that GJ-4 ameliorated the cognitive deficits of APP/PS1 mice measured by Morris water maze and novel object recognition tests. Mechanism studies indicated that GJ-4 significantly decreased ß-amyloid (Aß) level through reducing Aß production and promoting Aß degradation. It has been reported that Aß plaques trigger the hyper-phosphorylation of tau protein in APP/PS1 mice. Consistent with previous studies, hyper-phosphorylation of tau was also occurred in APP/PS1 mice in the present study, and GJ-4 inhibited Tau phosphorylation at different sites. Overwhelming evidence indicates that neuroinflammation stimulated by Aß and hyperphosphorylated tau is involved in the pathological progression of AD. We found that GJ-4 suppressed neuroinflammatory responses in the brain through regulating phosphatidylinositide 3-kinase/AKT (PI3K/AKT) signaling pathway activation, and subsequent expression of inflammatory proteins and release of inflammatory cytokines. CONCLUSION: Altogether, GJ-4 ameliorated cognition of APP/PS1 transgenic mice through multiple targets, including Aß, tau and neuroinflammation. This study provides a solid research basis for further development of GJ-4 as a potential candidate for the treatment of AD.
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Disfunción Cognitiva , Medicamentos Herbarios Chinos , Gardenia , Animales , Cognición , Disfunción Cognitiva/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Ratones , Ratones Transgénicos , Fosfatidilinositol 3-QuinasasRESUMEN
Parkinson's disease (PD) is the second most common neurodegenerative disease, but none of the current treatments for PD can halt the progress of the disease due to the limited understanding of the pathogenesis. In PD development, the communication between the brain and the gastrointestinal system influenced by gut microbiota is known as microbiota-gut-brain axis. However, the explicit mechanisms of microbiota dysbiosis in PD development have not been well elucidated yet. FLZ, a novel squamosamide derivative, has been proved to be effective in many PD models and is undergoing the phase I clinical trial to treat PD in China. Moreover, our previous pharmacokinetic study revealed that gut microbiota could regulate the absorption of FLZ in vivo. The aims of our study were to assess the protective effects of FLZ treatment on PD and to further explore the underlying microbiota-related mechanisms of PD by using FLZ as a tool. In the current study, chronic oral administration of rotenone was utilized to induce a mouse model to mimic the pathological process of PD. Here we revealed that FLZ treatment alleviated gastrointestinal dysfunctions, motor symptoms, and dopaminergic neuron death in rotenone-challenged mice. 16S rRNA sequencing found that PD-related microbiota alterations induced by rotenone were reversed by FLZ treatment. Remarkably, FLZ administration attenuated intestinal inflammation and gut barrier destruction, which subsequently inhibited systemic inflammation. Eventually, FLZ treatment restored blood-brain barrier structure and suppressed neuroinflammation by inhibiting the activation of astrocytes and microglia in the substantia nigra (SN). Further mechanistic research demonstrated that FLZ treatment suppressed the TLR4/MyD88/NF-κB pathway both in the SN and colon. Collectively, FLZ treatment ameliorates microbiota dysbiosis to protect the PD model via inhibiting TLR4 pathway, which contributes to one of the underlying mechanisms beneath its neuroprotective effects. Our research also supports the importance of microbiota-gut-brain axis in PD pathogenesis, suggesting its potential role as a novel therapeutic target for PD treatment.
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Microglial activation-induced neuroinflammation is critical in the pathogenesis of neurodegenerative diseases. Activated microglia are regulated mainly by innate pattern recognition receptors (PRRs) on their surface, of which macrophage receptor with collagenous structure (Marco) is a well-characterized scavenger receptor constitutively expressed on specific subsets of macrophages, including microglia. Increasing evidence has shown that Marco is involved in the pathogenesis of a range of inflammatory processes. However, research on the role of Marco in regulating neuroinflammation has reported conflicting results. In the present study, we examined the role Marco played in triggering neuroinflammation and its underlying mechanisms. The results demonstrated that silencing the Marco gene resulted in a significantly reduced neuroinflammatory response and vice versa. α-Syn stimulation in Marco overexpressing cells induced a pronounced inflammatory response, suggesting that Marco alone could trigger an inflammatory response. We also found that TLR2 significantly promoted Marco-mediated neuroinflammation, indicating TLR2 was an important co-receptor of Marco. Knocking down the TLR2 gene in microglia and mouse substantia nigra resulted in decreased expression of Marco. Subsequent mechanistic studies showed that deleting the SRCR domain of Marco resulted in disruption of the inflammatory response and the interaction between TLR2 and Marco. This suggested that TLR2 binds directly to the SRCR domain of Marco and regulates Marco-mediated neuroinflammation. In summary, this investigation revealed that TLR2 could potentiate Marco-mediated neuroinflammation by interacting with the SRCR domain of Marco, providing a new target for inhibiting neuroinflammation in neurodegenerative diseases.
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Enfermedades Neuroinflamatorias/metabolismo , Receptores Inmunológicos/metabolismo , Receptor Toll-Like 2/metabolismo , Animales , Línea Celular , Técnicas de Silenciamiento del Gen , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Microglía , Óxido Nítrico/metabolismo , Polisacáridos/farmacología , Unión Proteica , Dominios Proteicos , Mapeo de Interacción de Proteínas , Interferencia de ARN , Receptores Inmunológicos/antagonistas & inhibidores , Receptores Inmunológicos/química , Proteínas Recombinantes/metabolismo , Receptor Toll-Like 2/antagonistas & inhibidores , Receptor Toll-Like 2/genética , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismo , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Necrosis Tumoral alfa/genética , alfa-Sinucleína/farmacologíaRESUMEN
The gut microbiota plays an important role in regulating the pharmacokinetics and pharmacodynamics of many drugs. FLZ, a novel squamosamide derivative, has been shown to have neuroprotective effects on experimental Parkinson's disease (PD) models. FLZ is under phase â clinical trial now, while the underlying mechanisms contributing to the absorption of FLZ are still not fully elucidated. Due to the main metabolite of FLZ was abundant in feces but rare in urine and bile of mice, we focused on the gut microbiota to address how FLZ was metabolized and absorbed. In vitro studies revealed that FLZ could be exclusively metabolized to its major metabolite M1 by the lanosterol 14 alpha-demethylase (CYP51) in the gut microbiota, but was almost not metabolized by any other metabolism-related organs, such as liver, kidney, and small intestine. M1 was quickly absorbed into the blood and then remethylated to FLZ by catechol O-methyltransferase (COMT). Notably, dysbacteriosis reduced the therapeutic efficacy of FLZ on the PD mouse model by inhibiting its absorption. The results show that the gut microbiota mediate the absorption of FLZ through a FLZ-M1-FLZ circulation. Our research elucidates the vital role of the gut microbiota in the absorption of FLZ and provides a theoretical basis for clinical pharmacokinetic studies and clinical application of FLZ in the treatment of PD.
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Mitochondrial dysfunction is involved in the pathogenesis of Parkinson's disease (PD). Mitochondrial morphology is dynamic and precisely regulated by mitochondrial fission and fusion machinery. Aberrant mitochondrial fragmentation, which can result in cell death, is controlled by the mitochondrial fission protein, dynamin-related protein 1 (Drp1). Our previous results demonstrated that FLZ could correct mitochondrial dysfunction, but the effect of FLZ on mitochondrial dynamics remain uncharacterized. In this study, we investigated the effect of FLZ and the role of Drp1 on 1-methyl-4-phenylpyridinium (MPP+)-induced mitochondrial fission in neurons. We observed that FLZ blocked Drp1, inhibited Drp1 enzyme activity, and reduced excessive mitochondrial fission in cultured neurons. Furthermore, by inhibiting mitochondrial fission and ROS production, FLZ improved mitochondrial integrity and membrane potential, resulting in neuroprotection. FLZ curtailed the reduction of synaptic branches of primary cultured dopaminergic neurons caused by MPP+ exposure, reduced abnormal fission, restored normal mitochondrial distribution in neurons, and exhibited protective effects on dopaminergic neurons. The in vitro research results were validated using an MPTP-induced PD mouse model. The in vivo results revealed that FLZ significantly reduced the mitochondrial translocation of Drp1 in the midbrain of PD mice, which, in turn, reduced the mitochondrial fragmentation in mouse substantia nigra neurons. FLZ also protected dopaminergic neurons in PD mice and increased the dopamine content in the striatum, which improved the motor coordination ability of the mice. These findings elucidate this newly discovered mechanism through which FLZ produces neuroprotection in PD.
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Fungal G-protein coupled receptors (GPCRs) play essential roles in sensing environmental cues including host signals. The study of GPCR in mediating fungus-insect interactions is still limited. Here we report the evolution of GPCR genes encoded in the entomopathogenic Metarhizium species and found the expansion of Pth11-like GPCRs in the generalist species with a wide host range. By deletion of ten candidate genes MrGpr1-MrGpr10 selected from the six obtained subfamilies in the generalist M. robertsii, we found that each of them played a varied level of roles in mediating appressorium formation. In particular, deletion of MrGpr8 resulted in the failure of appressorium formation on different substrates and the loss of virulence during topical infection of insects but not during injection assays when compared with the wild-type (WT) strain. Further analysis revealed that disruption of MrGpr8 substantially impaired the nucleus translocation of the mitogen-activated protein kinase (MAPK) Mero-Fus3 but not the MAPK Mero-Slt2 during appressorium formation. We also found that the defect of AMrGpr8 could not be rescued with the addition of cyclic AMP for appressorium formation. Relative to the WT, differential expression of the selected genes have also been detected in AMrGpr8. The results of this study may benefit the understanding of fungus-interactions mediated by GPCRs.
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Regulación Fúngica de la Expresión Génica , Insectos , Metarhizium/genética , Metarhizium/patogenicidad , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Virulencia/genética , Animales , Eliminación de GenRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Gardenia jasminoides J. Ellis (Fructus Gardenia) is a traditional Chinese medicine with diverse pharmacological functions, such as anti-inflammation, anti-depression, as well as improvement of cognition and ischemia brain injury. GJ-4 is a natural extract from Gardenia jasminoides J. Ellis (Fructus Gardenia) and has been proved to improve memory impairment in Alzheimer's disease (AD) mouse model in our previous studies. AIM OF THE STUDY: This study aimed to evaluate the therapeutic effects of GJ-4 on vascular dementia (VD) and explore the potential mechanisms. MATERIAL AND METHODS: In our experiment, a focal cerebral ischemia and reperfusion rat model was successfully developed by the middle cerebral artery occlusion and reperfusion (MCAO/R). GJ-4 (10 mg/kg, 25 mg/kg, 50 mg/kg) and nimodipine (10 mg/kg) were orally administered to rats once a day for consecutive 12 days. Learning and memory behavioral performance was assayed by step-down test and Morris water maze test. The neurological scoring test was performed to evaluate the neurological function of rats. 2,3,5-Triphenyltetrazolium chloride (TTC) staining and Nissl staining were respectively employed to determine the infarct condition and neuronal injury of the brain. Iba1 immunohistochemistry was used to show the activation of microglia. Moreover, the synaptic damage and inflammatory level were detected by Western blot. RESULTS: GJ-4 could significantly improve memory impairment, cerebral infraction, as well as neurological deficits of VD rats induced by MCAO/R. Further research indicated VD-induced neuronal injury was alleviated by GJ-4. In addition, GJ-4 could protect synapse of VD rats by upregulating synaptophysin (SYP) expression, post synaptic density 95 protein (PSD95) expression, and downregulating N-Methyl-D-Aspartate receptor 1 (NMDAR1) expression. Subsequent investigation of the underlying mechanisms identified that GJ-4 could suppress neuroinflammatory responses, supported by inhibited activation of microglia and reduced expression of inflammatory proteins, which ultimately exerted neuroprotective effects on VD. Further mechanistic study indicated that janus kinase 2 (JAK2)/signal transducer and activator of transcription 1 (STAT1) pathway was inhibited by GJ-4 treatment. CONCLUSION: These results suggested that GJ-4 might serve as a potential drug to improve VD. In addition, our study indicated that inhibition of neuroinflammation might be a promising target to treat VD.
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Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Demencia Vascular/prevención & control , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Janus Quinasa 2/metabolismo , Trastornos de la Memoria/prevención & control , Memoria/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Nootrópicos/farmacología , Extractos Vegetales/farmacología , Daño por Reperfusión/prevención & control , Factor de Transcripción STAT1/metabolismo , Animales , Encéfalo/enzimología , Encéfalo/patología , Encéfalo/fisiopatología , Demencia Vascular/enzimología , Demencia Vascular/etiología , Demencia Vascular/psicología , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos/farmacología , Gardenia , Infarto de la Arteria Cerebral Media/complicaciones , Infarto de la Arteria Cerebral Media/enzimología , Infarto de la Arteria Cerebral Media/fisiopatología , Mediadores de Inflamación/metabolismo , Masculino , Trastornos de la Memoria/enzimología , Trastornos de la Memoria/etiología , Trastornos de la Memoria/psicología , Microglía/efectos de los fármacos , Microglía/metabolismo , Microglía/patología , Ratas Sprague-Dawley , Daño por Reperfusión/enzimología , Daño por Reperfusión/etiología , Daño por Reperfusión/fisiopatología , Transducción de Señal , Sinapsis/efectos de los fármacos , Sinapsis/metabolismo , Sinapsis/patologíaRESUMEN
Chronic neuroinflammation is of great importance in the pathogenesis of Parkinson's disease (PD). During the process of neuroinflammation, overactivated microglia release many proinflammatory factors, which eventually induce neurodegeneration. Inhibition of excessive microglial activation is regarded as a promising strategy for PD treatment. Src is a non-receptor tyrosine kinase that is closely related to tumors. Recently, some reports indicated that Src is a central mediator in multiple signaling pathways including neuroinflammation. The aim of our study was to demonstrate the role of Src in microglial regulation and neuroinflammation. The lipopolysaccharide (LPS)-stimulated BV2 microglia model and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model were applied in this study. The results showed that inhibition of Src could significantly relieve microgliosis and decrease levels of inflammatory factors. Besides, inhibition of Src function reduced the loss of dopaminergic neurons and improved the motor behavior of the MPTP-treated mice. Thus, this study not only verified the critical role of Src tyrosine kinase in neuroinflammation but also further proved that interfering neuroinflammation is beneficial for PD treatment. More importantly, this study shed a light on the hypothesis that Src tyrosine kinase might be a potential therapeutic target for PD and other neuroinflammation-related diseases.
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Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease characterized by the autoimmune attack of oligodendrocytes, leading to demyelination and progressive functional deficits. CXC chemokine receptor 2 (CXCR2) is recently reported to orchestrate the migration, proliferation and differentiation of oligodendrocyte precursor cells (OPCs), which implies its possible involvement in the demyelinating process. Here, we used a CXCR2 antagonist, compound 2, as a tool to investigate the role of CXCR2 in demyelination and the underlying mechanism. The primary cultured oligodendrocytes and cuprizone (CPZ)-intoxicated mice were applied in the present study. The results showed that compound 2 significantly promoted OPC proliferation and differentiation. In the demyelinated lesions of CPZ-intoxicated mice, vigorous OPC proliferation and myelin repair was observed after compound 2 treatment. Subsequent investigation of the underlying mechanisms identified that upon inhibition of CXCR2, compound 2 treatment upregulated Ki67, transcription factor 2 (Olig2) and Caspr expression, activated PI3K/AKT/mTOR signaling, ultimately promoted OPCs differentiation and enhanced remyelination. In conclusion, our results demonstrated that CXCR2 antagonism efficiently promoted OPC differentiation and enhanced remyelination in CPZ-intoxicated mice, supporting CXCR2 as a promising therapeutic target for the treatment of chronic demyelinating diseases such as MS.
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Esclerosis Múltiple/patología , Células Precursoras de Oligodendrocitos/efectos de los fármacos , Receptores de Interleucina-8B/antagonistas & inhibidores , Remielinización/efectos de los fármacos , Animales , Diferenciación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Ratones , Ratones Endogámicos C57BL , Células Precursoras de Oligodendrocitos/metabolismo , Transducción de Señal/efectos de los fármacos , Células MadreRESUMEN
The neuroprotective agent 3-hydroxymorphinan (3-HM) is a well-documented and highly safe therapeutic intervention for the inflammatory-related effects of Parkinson's disease (PD). However, the bioavailability of 3-HM is very low due to the rapid first-pass metabolism of the phenolic moiety. In the present study, we sought to improve the metabolic stability and overall pharmacokinetic profile of 3-HM. Based on an iterative design process that a suitably arranged heterocycle with an NH group would serve as the metabolically stable isostere of the phenolic group, we designed and synthesized two analogues of 3-HM. Benzimidazolone compound 8 (imidazolone-morphinan) was comparable in activity to 3-HM against lipopolysaccharide (LPS)-induced inflammatory responses in microglial BV2 cells and in vivo animal experiments (MPTP-induced PD mouse model). Moreover, the in vitro study showed that imidazolone-morphinan was non-toxic to microglia, indicating its high safety. Considering the favourable and unique preclinical profiles, compound 8 was nominated as a candidate for further clinical development.