RESUMO
Hippocampal neurons exhibit activation of both the conventional transmembrane adenylyl cyclases (tmACs) and the non-canonical soluble adenylyl cyclase (sAC) as sources of cyclic AMP (cAMP). These two cAMP sources play crucial roles in mediating signaling pathways downstream of CRHR1 in neuronal and neuroendocrine contexts. In this study, we investigate the involvement of both cAMP sources in the molecular mechanisms triggered by CRHR2α. Here we provide evidence demonstrating that UCN1 and UCN3 exert a neuritogenic effect on HT22-CRHR2α cells, which is solely dependent on the cAMP pool generated by sAC and PKA activity but independent of ERK1/2 activation. Through the characterization of the effectors implicated in neurite elongation, we found that CREB phosphorylation and c-Fos induction rely on PKA activity and ERK1/2 phosphorylation, underscoring the critical role of signaling pathway regulation. These findings strengthen the concept that localized cAMP microdomains actively participate in the regulation of these signaling processes.
Assuntos
Adenilil Ciclases , Proteínas Quinases Dependentes de AMP Cíclico , AMP Cíclico , Receptores de Hormônio Liberador da Corticotropina , Transdução de Sinais , AMP Cíclico/metabolismo , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Animais , Adenilil Ciclases/metabolismo , Camundongos , Fosforilação , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Urocortinas/metabolismo , Linhagem Celular , Neuritos/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Neurônios/metabolismoRESUMO
BACKGROUND: Neuroinflammation plays a critical role in various neurological disorders. Oxycodone has anti-inflammatory properties. The purpose of this work was to look into the effect of oxycodone in controlling lipopolysaccharide (LPS)-induced neuroinflammation in microglia. METHODS: LPS-induced HMC3 cells were subjected to oxycodone (2.5, 5, 10 and 20 µg/mL). The mRNA and protein expressions were examined by qRT-PCR and western blotting. TNF-α, IL-1ß, IL-6, and IL-8 levels were assessed by ELISA. MTT assay was adopted to measure cell viability. The interactions between CREB, miR-181c and PDCD4 were analyzed by dual-luciferase reporter assay, ChIP and/or RIP assays. RESULTS: Oxycodone treatment alleviated LPS-induced inflammation in HMC3 cells and increased p-CREB level, but reduced PDCD4 and iNOS levels in LPS-treated cells. Mechanistically, oxycodone mitigated LPS-induced neuroinflammation by upregulating miR-181c. In addition, CREB promoted miR-181c expression by directly binding to the MIR181C promoter, and miR-181c inhibited PDCD4 expression by directly binding to PDCD4 3'UTR. As expected, oxycodone alleviated LPS-induced neuroinflammation by regulating the CREB/miR-181c/PDCD4 axis. CONCLUSION: Oxycodone attenuated LPS-induced neuroinflammation in microglia by regulating the CREB/miR-181c/PDCD4 axis. These findings proved that oxycodone is a potential drug for treating neuroinflammation and elucidate the mechanisms involved.
Assuntos
Proteínas Reguladoras de Apoptose , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Lipopolissacarídeos , MicroRNAs , Microglia , Doenças Neuroinflamatórias , Oxicodona , Proteínas de Ligação a RNA , MicroRNAs/genética , MicroRNAs/metabolismo , Oxicodona/farmacologia , Oxicodona/efeitos adversos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Humanos , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas Reguladoras de Apoptose/genética , Microglia/efeitos dos fármacos , Microglia/metabolismo , Doenças Neuroinflamatórias/induzido quimicamente , Doenças Neuroinflamatórias/tratamento farmacológico , Doenças Neuroinflamatórias/genética , Anti-Inflamatórios/farmacologia , Linhagem Celular , Inflamação/induzido quimicamente , Inflamação/genética , Transdução de Sinais/efeitos dos fármacosRESUMO
OBJECTIVE: Isorhamnetin, a naturally occurring flavonoid compound, holds paramount importance as a primary constituent within several medicinal plants, exhibiting profound pharmacological significance. The aim of this study is to investigate the pain-relieving attributes of isorhamnetin in murine models through both formalin-induced pain and diabetic neuropathy scenarios. MATERIALS AND METHODS: To achieve our objective, isorhamnetin was orally administered to mice at varying dosage levels (10 to 100 mg/kg). Pain-related behaviors were assessed using the formalin test during its secondary phase. Additionally, the potential pain-alleviating effect of isorhamnetin was evaluated in a diabetic neuropathy model induced by streptozotocin. Additionally, we carried out advanced interventions using naloxone, which is a well-known antagonist of opioid receptors, yohimbine, which blocks α2-adrenergic receptors, and methysergide, which inhibits serotonergic receptors, during the formalin test. RESULTS: The oral intake of isorhamnetin showed a decrease in behaviors associated with pain that was proportional to the dose observed during the second phase of the formalin test when induced by formalin. In the diabetic neuropathy model, isorhamnetin administration effectively reversed the reduced pain threshold observed. Notably, naloxone, the opioid receptor antagonist, effectively counteracted the pain-relieving effect produced by isorhamnetin in the formalin test, whereas yohimbine and methysergide did not yield similar outcomes. Isorhamnetin also led to a reduction in elevated spinal cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) levels triggered by formalin, with this effect reversed by pre-treatment with naloxone. The compound also suppressed heightened spinal phosphorylated CREB (p-CREB) levels caused by diabetic neuropathy. CONCLUSIONS: This research determined that isorhamnetin has notable abilities to relieve pain in models of formalin-induced pain and diabetic neuropathy. The pain-relieving mechanism of isorhamnetin in the formalin-induced pain model seems to be connected to the activation of spinal opioid receptors and the adjustment of CREB protein amounts. This insight improves our knowledge of how isorhamnetin could be used therapeutically to treat pain conditions stemming from formalin-induced pain and diabetic neuropathy.
Assuntos
Analgésicos , Neuropatias Diabéticas , Formaldeído , Quercetina , Animais , Camundongos , Neuropatias Diabéticas/tratamento farmacológico , Neuropatias Diabéticas/induzido quimicamente , Quercetina/análogos & derivados , Quercetina/farmacologia , Quercetina/uso terapêutico , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Masculino , Modelos Animais de Doenças , Dor/tratamento farmacológico , Dor/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Ioimbina/farmacologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Naloxona/farmacologia , Naloxona/uso terapêutico , Estreptozocina , Medição da Dor/efeitos dos fármacos , Relação Dose-Resposta a DrogaRESUMO
BACKGROUND: Sevoflurane has been shown to stimulate neurotoxicity and lead to cognitive impairment. Berberine is known for its role in regulating nervous system diseases, including cognitive dysfunction. This study aimed to investigate the effects of berberine on cognitive dysfunction induced by sevoflurane anesthesia and its potential mechanisms. METHODS: In the in vivo study, neonatal mice were subjected to sevoflurane anesthesia to induce cognitive dysfunction. The cognitive function of the neonatal mice was evaluated using the Morris water maze test, open field test, and tail suspension test. Enzyme-linked immunosorbent assay (ELISA) was utilized to assess the levels of inflammatory factors. Immunohistochemistry (IHC) was conducted to detect ionized calcium-binding adaptor molecule 1 (IBA-1)-positive cells and cleaved caspase-3-positive cells in the hippocampus of the neonatal mice. Western blotting was used to measure the levels of cyclic adenosine monophosphate (cAMP) response element-binding protein 1 (CREB1) in hippocampal tissues and neurons. Hippocampal neurons were isolated from the hippocampus of neonatal mice. These neurons were treated with berberine or subjected to cell transfection. The cell counting kit-8 (CCK-8) assay and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay were conducted to measure cell viability and apoptosis of hippocampal neurons in vitro. RESULTS: Berberine significantly attenuated sevoflurane-induced cognitive impairment and inflammation in neonatal mice (p < 0.05 or p < 0.01). Additionally, berberine reduced sevoflurane-triggered neuronal apoptosis in the hippocampus of neonatal mice (p < 0.01). Sevoflurane markedly decreased CREB1 expression in the hippocampus of neonatal mice (p < 0.01), which was elevated by berberine treatment (p < 0.01). Mechanistically, sevoflurane significantly suppressed cell viability and promoted cell apoptosis of hippocampal neurons (p < 0.0001 or p < 0.01), which were mitigated by berberine (p < 0.05, p < 0.01, or p < 0.001). Furthermore, berberine significantly elevated CREB1 expression in sevoflurane-treated hippocampal neurons (p < 0.01). The beneficial effects of berberine on cell viability and apoptosis in sevoflurane-treated hippocampal neurons were blocked by CREB1 depletion (p < 0.001). CONCLUSION: Our results demonstrated that CREB1 was significantly decreased in the hippocampus of sevoflurane-treated neonatal mice in vivo and in sevoflurane-treated hippocampal neurons in vitro. This decrease was mitigated by berberine treatment. Moreover, berberine improved sevoflurane anesthesia-induced cognitive impairment in neonatal mice by attenuating neuronal inflammation and apoptosis in vivo. The inhibitory effects of berberine on sevoflurane-induced cell apoptosis were reversed by CREB1 downregulation. These findings indicate that berberine protects against sevoflurane anesthesia-induced cognitive impairment by reducing apoptosis of hippocampal neurons, partially through increasing CREB1 expression.
Assuntos
Animais Recém-Nascidos , Apoptose , Berberina , Disfunção Cognitiva , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Hipocampo , Neurônios , Sevoflurano , Animais , Sevoflurano/efeitos adversos , Sevoflurano/farmacologia , Sevoflurano/toxicidade , Berberina/farmacologia , Berberina/uso terapêutico , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Camundongos , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/metabolismo , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Apoptose/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Anestésicos Inalatórios/efeitos adversos , Anestésicos Inalatórios/toxicidade , MasculinoRESUMO
Adenosine receptor-mediated signaling, especially adenosine A2A receptor (A2AR) signaling, has been implicated in wound healing. However, the role of endothelial cells (ECs) in A2AR-mediated wound healing and the mechanism underlying this effect are still unclear. Here, we showed that the expression of A2AR substantially increased after wounding and was especially prominent in granulation tissue. The delaying effects of A2AR knockout (KO) on wound healing are due mainly to the effect of A2AR on endothelial cells, as shown with A2AR-KO and EC-A2AR-KO mice. Moreover, the expression of c-Ski, which is especially prominent in CD31-positive cells in granulation tissue, increased after wounding and was decreased by both EC-A2AR KO and A2AR KO. In human microvascular ECs (HMECs), A2AR activation induced EC proliferation, migration, tubule formation and c-Ski expression, whereas c-Ski depletion by RNAi abolished these effects. Mechanistically, A2AR activation promotes the expression of c-Ski through an ERK/CREB-dependent pathway. Thus, A2AR-mediated angiogenesis plays a critical role in wound healing, and c-Ski is involved mainly in the regulation of angiogenesis by A2AR via the ERK/CREB pathway. These findings identify A2AR as a therapeutic target in wound repair and other angiogenesis-dependent tissue repair processes.
Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Camundongos Knockout , Receptor A2A de Adenosina , Cicatrização , Cicatrização/fisiologia , Cicatrização/genética , Animais , Receptor A2A de Adenosina/metabolismo , Receptor A2A de Adenosina/genética , Camundongos , Humanos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Células Endoteliais/metabolismo , Neovascularização Fisiológica , Transdução de Sinais , Sistema de Sinalização das MAP Quinases/fisiologia , Proliferação de Células/genética , Movimento Celular/genética , AngiogêneseRESUMO
Sepsis is a systemic inflammatory disease that can cause multiple organ damage. Septic patients with cardiac dysfunction have a significantly higher mortality. Based on the results of bioinformatics analysis, weighted gene co-expression network analysis (WGCNA), we found that Erbin is vital in cardiomyocyte. However, the function of Erbin in sepsis-induced cardiomyopathy (SIC) has not been explicitly studied. We discussed the role of Erbin in SIC by employing the Erbin-/- mice and HL-1 cardiomyocyte. An in vitro model of inflammation in HL-1 was used to confirm stimulation with lipopolysaccharide (LPS) and a mouse model of cecal ligation and puncture (CLP) to study the molecular mechanisms under SIC. Transmission electron microscopy (TEM) was used to characterize the morphological characteristics at the ultrastructural level. The expressions of Erbin, p-RIPK1, RIPK1, p-RIPK3, RIPK3, p-MLKL, MLKL, p-PKA, PKA, p-CREB and CREB were detected by western blot. qPCR analysis was applied to detect TNF-α, IL-1ß, IL-6, RIPK1 and MLKL mRNA expression. Cell survival was detected by CCK-8 assay and the levels of c TnI concentration were detected by ELISA kit. Our study revealed that necroptosis and inflammation were activated in cardiomyocytes during sepsis and deficiency of Erbin aggravated them. Furthermore, deficiency of Erbin exacerbated systolic dysfunction including the decline of LVEF and LVFS induced by CLP. Overexpression of Erbin alleviated necroptosis and inflammation by activating PKA/CREB pathway. Our research elucidates a noval mechanism whereby Erbin participates in SIC, providing a promising therapeutic target for myocardial dysfunction during sepsis.
Assuntos
Cardiomiopatias , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Proteínas Quinases Dependentes de AMP Cíclico , Necroptose , Proteína Serina-Treonina Quinases de Interação com Receptores , Sepse , Transdução de Sinais , Animais , Sepse/complicações , Sepse/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Camundongos , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Masculino , Camundongos KnockoutRESUMO
Multiple sclerosis (MS) is a chronic condition characterized by immune cell infiltration and cytokine overproduction that led to myelin sheath inflammatory assaults, thus causing axonal destruction. The former consequently provokes motor impairment and psychological disorders. Markedly, depression is one of the most prevalent lifelong comorbidities that negatively impacts the quality of life in MS patients. Vortioxetine (VTX), a multi-modal molecule prescribed to manage depression and anxiety disorder, additionally, it displays a promising neuroprotective properties against neurodegenerative diseases such as Alzheimer's and Parkinson's. To this end, the present study investigated the potential therapeutic efficacy of VTX against experimental autoimmune encephalomyelitis (EAE) model of MS in mice. Notably, treatment with VTX significantly ameliorated EAE-induced motor disability, as evident by enhanced performance in open field, rotarod and grip strength tests, alongside a reduction in immobility time during the forced swimming test, indicating a mitigation of the depressive-like behavior; outcomes that were corroborated with histological examinations and biochemical analyses. Mechanistically, VTX enhanced serotonin levels by inhibiting both serotonin transporter (SERT) and indoleamine 2,3-dioxygenase (IDO) enzyme, thereby promoting the activation of serotonin 1A (5-HT1A) receptor. The latter triggered the stimulation of phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) cascade that entailed activation/phosphorylation of cAMP response element-binding protein (CREB). This activation increased brain derived neurotrophic factor (BDNF) and myelin basic protein (MBP) contents that mitigated demyelination in the corpus callosum. Furthermore, VTX suppressed phospho serine 536 nuclear factor kappa B (pS536 NF-κB p65) activity and reduced tumor necrosis factor-alpha (TNF-α) production. The results underscore VTX's beneficial effects on disease severity in EAE model of MS in mice by amending both inflammatory and neurodegenerative components of MS progression.
Assuntos
Fator Neurotrófico Derivado do Encéfalo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Encefalomielite Autoimune Experimental , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Serotonina , Transdução de Sinais , Vortioxetina , Animais , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/patologia , Encefalomielite Autoimune Experimental/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Camundongos , Transdução de Sinais/efeitos dos fármacos , Serotonina/metabolismo , Vortioxetina/farmacologia , Vortioxetina/uso terapêutico , Fosfatidilinositol 3-Quinases/metabolismo , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/metabolismo , Feminino , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Comportamento Animal/efeitos dos fármacosRESUMO
BACKGROUND: Ischemic stroke is a significant cause of death and disability with a limited treatment time window. The reduction of early glutamate excitotoxicity using neuroprotective agents targeting N-methyl-d-aspartic acid (NMDA) receptors have attracted recent research attention. SHPL-49, a structurally modified derivative of salidroside, was synthesized by our team. Previous studies have confirmed the neuroprotective efficacy of SHPL-49 in rats with ischemic stroke. However, the underlying mechanisms need to be clarified. METHODS: We conducted in vivo experiments using the permanent middle cerebral artery occlusion rat model to investigate the role of SHPL-49 in glutamate release at different time points and treatment durations. Glutamate transporters and receptor proteins and neural survival proteins in the brain were also examined at the same time points. In vitro, primary neurons and the coculture system of primary neurons-astrocytes were subjected to oxygen-glucose deprivation and glutamate injury. Proteomics and parallel reaction monitoring analyses were performed to identify potential therapeutic targets of SHPL-49, which were further confirmed through in vitro experiments on the inhibition and mutation of the target. RESULTS: SHPL-49 significantly reduced glutamate release caused by hypoxia-ischemia. One therapeutic pathway of SHPL-49 was promoting the expression of glutamate transporter-1 to increase glutamate reuptake and further reduce the occurrence of subsequent neurotoxicity. In addition, we explored the therapeutic targets of SHPL-49 and its regulatory effects on glutamate receptors for the first time. SHPL-49 enhanced neuroprotection by activating the NMDA subunit NR2A, which upregulated the cyclic-AMP response binding protein (CREB) neural survival pathway and Akt phosphorylation. Since calcium/calmodulin-dependent kinase IIα (CaMKIIα) is necessary for synaptic transmission of NMDA receptors, we explored the interaction between CaMKIIα and SHPL-49, which protected CaMKIIα from hypoxia-ischemia-induced autophosphorylation damage. CONCLUSION: Overall, SHPL-49 enhanced neuronal survival and attenuated acute ischemic stroke by promoting the NR2A-CAMKâ ¡α-Akt/CREB pathway. Our study provides the first evidence demonstrating that the neuroprotective effect of SHPL-49 is achieved by promoting the NR2A subunit to extend the treatment time window, making it a promising drug for ischemic stroke.
Assuntos
Glucosídeos , Ácido Glutâmico , AVC Isquêmico , Neurônios , Fármacos Neuroprotetores , Fenóis , Animais , Masculino , Ratos , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Modelos Animais de Doenças , Transportador 2 de Aminoácido Excitatório , Glucosídeos/farmacologia , Infarto da Artéria Cerebral Média/tratamento farmacológico , AVC Isquêmico/tratamento farmacológico , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fenóis/farmacologia , Fenóis/química , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
Menopausal depression, often associated with hormonal fluctuations such as decreased estrogen levels, imposes significant mental health burdens. Despite the antidepressant biological properties of standardized rice bran supplement (RBS), its impact on menopausal depression and underlying mechanisms remains largely unexplored. In this study, we investigated the antidepressant effects of RBS in a mouse model of estrogen deficiency-induced depression. Ovariectomized (OVX) mice received oral doses of RBS (250 and 1000 mg/kg) and 17ß estradiol over a 20-week period. RBS administration resulted in decreased immobility time in the tail suspension and forced swim tests, along with increased locomotor activity in the open field test. Furthermore, RBS enhanced nitric oxide production and neuronal nitric oxide synthase (nNOS) expression in the hippocampi of OVX mice. Additionally, RBS administration phosphorylated extracellular signal-regulated kinase (ERK), cAMP response element-binding protein (CREB), and tropomyosin receptor kinase B and increased the protein expression of brain-derived neurotrophic factor (BDNF) in the hippocampus. These findings suggest that RBS alleviated depressive behaviors in OVX mice by augmenting hippocampal nNOS expression and activating the ERK-CREB-BDNF signaling pathway. Therefore, based on these results, we propose that RBS is a promising agent to treat menopausal depression, a challenging condition.
Assuntos
Antidepressivos , Fator Neurotrófico Derivado do Encéfalo , Depressão , Suplementos Nutricionais , Hipocampo , Óxido Nítrico Sintase Tipo I , Oryza , Ovariectomia , Animais , Oryza/química , Feminino , Camundongos , Depressão/tratamento farmacológico , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Antidepressivos/farmacologia , Antidepressivos/administração & dosagem , Antidepressivos/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Suplementos Nutricionais/análise , Óxido Nítrico Sintase Tipo I/metabolismo , Óxido Nítrico Sintase Tipo I/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Comportamento Animal/efeitos dos fármacos , Humanos , Menopausa/efeitos dos fármacos , Modelos Animais de Doenças , Óxido Nítrico/metabolismo , Receptor trkB/metabolismo , Transdução de Sinais/efeitos dos fármacos , Camundongos Endogâmicos C57BL , MAP Quinases Reguladas por Sinal Extracelular/metabolismoRESUMO
BACKGROUND: Transient receptor potential vanilloid type 4 (TRPV4) is a versatile ion channel with diverse roles in immune cells, including macrophages. While its function in inflammation remains debated, we investigated its role in regulating IL-10 production and its impact on macrophage reprogramming during inflammation. METHODS: We investigated the connection between TRPV4 activation and CREB-mediated IL-10 production during inflammation. Notably, this signaling pathway was found to reprogram macrophages and enhance their ability to resist inflammatory damage. The experiments were conducted on primary macrophages and were further corroborated by animal studies. RESULTS: In response to TRPV4 activation during inflammation, we observed a significant increase in intracellular Ca2+ levels, which triggered the activation of the transcription factor CREB, subsequently upregulating IL-10 production. This IL-10 played a pivotal role in reprogramming macrophages to withstand inflammatory damage. Using a mouse model of acute lung injury (ALI), we confirmed that TRPV4 activation during ALI led to IL-10 secretion, but this increase did not significantly contribute to inflammation resolution. Moreover, we found that TRPV4 prevented the accumulation of dysfunctional mitochondria in macrophages through the CREB-IL-10 axis during inflammation. Suppression of CREB or TRPV4 inhibition exacerbated mitochondrial dysfunction, while treatment with recombinant IL-10 mitigated these effects. Additionally, IL-10 induced mitophagy and cleared dysfunctional mitochondria in LPS-exposed cells. CONCLUSION: Our study highlights the essential role of TRPV4 in regulating IL-10 production and mitochondrial health in macrophages during inflammation. These findings contribute to understand the role of TRPV4 in immune responses and suggest potential therapeutic targets for modulating inflammation-induced cellular dysfunction.
Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Inflamação , Interleucina-10 , Macrófagos , Camundongos Endogâmicos C57BL , Canais de Cátion TRPV , Animais , Canais de Cátion TRPV/metabolismo , Interleucina-10/metabolismo , Macrófagos/metabolismo , Macrófagos/imunologia , Camundongos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Inflamação/metabolismo , Masculino , Cálcio/metabolismo , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Células Cultivadas , Lipopolissacarídeos/farmacologiaRESUMO
Diabetic neuropathic pain (DNP) is a diabetic complication that causes severe pain and deeply impacts the quality of the sufferer's daily life. Currently, contemporary clinical treatments for DNP generally exhibit a deficiency in effectiveness. Electroacupuncture (EA) is recognized as a highly effective and safe treatment for DNP with few side effects. Regrettably, the processes via which EA alleviates DNP are still poorly characterized. Transient receptor potential vanilloid 1 (TRPV1) and phosphorylated calcium/calmodulin-dependent protein kinase II (p-CaMKII) are overexpressed on spinal cord dorsal horn (SCDH) in DNP rats, and co-localization is observed between them. Capsazepine, a TRPV1 antagonist, effectively reduced nociceptive hypersensitivity and downregulated the overexpression of phosphorylated CaMKIIα in rats with DNP. Conversely, the CaMKII inhibitor KN-93 did not have any impact on TRPV1. EA alleviated heightened sensitivity to pain caused by nociceptive stimuli and downregulated the level of TRPV1, p-CaMKIIα, and phosphorylated cyclic adenosine monophosphate response element-binding protein (p-CREB) in DNP rats. Intrathecal injection of capsaicin, on the other hand, reversed the above effects of EA. These findings indicated that the CaMKII/CREB pathway on SCDH is located downstream of TRPV1 and is affected by TRPV1. EA alleviates DNP through the TRPV1-mediated CaMKII/CREB pathway.
Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Neuropatias Diabéticas , Eletroacupuntura , Ratos Sprague-Dawley , Canais de Cátion TRPV , Animais , Canais de Cátion TRPV/metabolismo , Canais de Cátion TRPV/antagonistas & inibidores , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/antagonistas & inibidores , Eletroacupuntura/métodos , Ratos , Masculino , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Neuropatias Diabéticas/terapia , Neuropatias Diabéticas/metabolismo , Capsaicina/farmacologia , Capsaicina/análogos & derivados , Transdução de Sinais , Corno Dorsal da Medula Espinal/metabolismo , Benzenossulfonamidas , BenzilaminasRESUMO
Cutaneous melanoma (cM) is a prevalent invasive cancer resulting from the malignant transformation of melanocytes. At present, the primary treatment for melanoma is surgical resection, which is not appropriate for patients with metastasis. Therefore, it is necessary to identify effective therapeutic targets for the early diagnosis and treatment of metastatic melanoma. Acyl-CoA thioesterase 7 (ACOT7) has been reported to be involved in the progression of multiple cancer, while its role in melanoma has not been extensively researched. Through gain-of-function and loss-of-function experiments, ACOT7 was identified as a tumor promoter that facilitates the progression of melanoma cells. Cell proliferation was promoted by overexpressing ACOT7 in M14 cells, and was suppressed by silencing ACOT7 in MeWo cells. Knockdown of ACOT7 induced cell cycle arrest by increasing the expressions of cyclin dependent kinase inhibitor 1B (P27) and cyclin dependent kinase inhibitor 1â¯A (P21), while simultaneously reducing proliferating cell nuclear antigen (PCNA) expression. Upregulation of ACOT7 promoted the cell cycle of melanoma cells. Additionally, apoptosis was induced by the absence of ACOT7 through activating caspase-3 and poly (ADP-ribose) polymerase (PARP). The metastatic and invasive capacity of melanoma cells was significantly enhanced by the overexpression of ACOT7 and inhibited by the downregulation of ACOT7. Moreover, the cAMP responsive element binding protein 1 (CREB1) positively regulates ACOT7 expression by binding to its promoter region. A decrease of cell proliferation, migration and invasion, as well as an increase of cell apoptosis induced by silencing CREB1 were obviously reversed by ACOT7. In summary, ACOT7 transcriptionally activated by CREB1 elevates the progression of cM.
Assuntos
Proliferação de Células , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Melanoma , Neoplasias Cutâneas , Humanos , Melanoma/metabolismo , Melanoma/patologia , Melanoma/genética , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Tioléster Hidrolases/metabolismo , Tioléster Hidrolases/genética , Apoptose , Progressão da Doença , Melanoma Maligno Cutâneo , Regulação Neoplásica da Expressão Gênica , Animais , Movimento Celular/genética , CamundongosRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Ischemic stroke is an acute central nervous system disease that poses a threat to human health. It induces a series of severe pathological mechanisms, ultimately leading to neuronal cell death in the brain due to local ischemia and hypoxia. Buyang Huanwu decoction (BYHWD), as a representative formula for treating ischemic stroke, has shown good therapeutic effects in stroke patients. AIM OF THE STUDY: This study aimed to explore the mechanism of BYHWD in promoting neural remodeling after ischemic stroke from the perspective of neuronal synaptic plasticity, based on the cAMP/PKA/CREB signaling pathway. MATERIALS AND METHODS: A modified suture technique was employed to establish a rat model of MCAO. The rats were divided into sham, model, and BYHWD (20 g/kg) groups. After the corresponding intervention, rat brains from each group were collected. TMT quantitative proteomics technology was employed for the research. Following proteomics studies, we investigated the mechanism of BYHWD in the intervention of ischemic stroke through animal experiments and cell experiments. The experimental animals were divided into sham, model, and BYHWD (5 g/kg, 10 g/kg, and 20 g/kg) groups. Infarct volume and severity of brain injury were measured by TTC staining. HE staining was utilized to evaluate alterations in tissue morphology. The Golgi staining was used to observe changes in cell body, dendrites, and dendritic spines. Transmission electron microscopy was used to observe the ultrastructure of synapses in the cortex and hippocampus. TUNEL staining was conducted to identify apoptotic neurons. Meanwhile, a stable and reliable (OGD/R) SH-SY5Y cell model was established. The effect of BYHWD-containing serum on SH-SY5Y cell viability was measured by CCK-8 kit. The apoptosis situation of SH-SY5Y cells was determined by Annexin V-FITC/PI. Immunofluorescence was employed to measure the fluorescence intensity of synaptic-related factors Syt1, Psd95, and Syn1. Synaptic plasticity pathways were assessed by using RT-qPCR and Western blot to determine the expression levels of cAMP, Psd95, Prkacb, Creb1/p-Creb1, BDNF, Shank2, Syn1, Syt1, Bcl-2, Bcl-2/Bax mRNA and proteins. RESULTS: After treatment with BYHWD, notable alterations were detected in the signaling pathways linked to synaptic plasticity and the cAMP signaling pathway-related targets among the intervention targets. This trend of change was also reflected in other bioinformatics analyses, indicating the important role of synaptic plasticity changes before and after modeling and drug intervention. The results of vivo and vitro experiments showed that BYHWD improved local pathological changes, and reduced cerebral infarct volume, and neurological function scores in MCAO rats. It increased dendritic spine density, improved synaptic structural plasticity, and had a certain neuroprotective effect. BYHWD increased the postsynaptic membrane thickness, synaptic interface curvature, and synaptic quantity. 10% BYHWD-containing serum was determined as the optimal concentration for treatment. 10% BYHWD-containing serum significantly reduced the overall apoptotic rate of (OGD/R) SH-SY5Y cells. Immunofluorescence experiments demonstrated that 10% BYHWD-containing serum could improve synaptic plasticity and increase the relative expression levels of synaptic-related proteins Syt1, Psd95, and Syn1. BYHWD and decoction-containing serum upregulated the mRNA and protein expression levels in (OGD/R) SH-SY5Y cells and MCAO rats, suggesting its ability to improve damaged neuronal synaptic plasticity and enhance transmission efficiency, which might be achieved through the regulation of the cAMP/PKA/CREB pathway. CONCLUSIONS: This study may provide a basis for clinical medication by elucidating the underlying experimental evidence for the promotion of neural plasticity after ischemic stroke by BYHWD.
Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , AMP Cíclico , Medicamentos de Ervas Chinesas , AVC Isquêmico , Plasticidade Neuronal , Ratos Sprague-Dawley , Transdução de Sinais , Animais , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Plasticidade Neuronal/efeitos dos fármacos , AVC Isquêmico/tratamento farmacológico , Masculino , AMP Cíclico/metabolismo , Ratos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Modelos Animais de Doenças , Fármacos Neuroprotetores/farmacologia , Infarto da Artéria Cerebral Média/tratamento farmacológicoRESUMO
Lead (Pb2+) is one of the most common toxic metals present in the environment, and lead exposure causes serious health issues in humans. Lead is widely used because of its physio-chemical characteristics, which include softness, corrosion resistance, ductility, and low conductivity. Lead affects almost all human organs, specifically the central nervous system. Lead neurotoxicity is connected to various neural pathways, including brain-derived neurotrophic factor (BDNF) protein level alterations, cyclic adenosine 3',5'-monophosphate (cAMP) response element binding protein (CREB) pathway changes, and N-methyl-D-aspartate receptors (NMDARs) changes. Lead primarily affects protein kinase C (PKC) through the replacement of calcium (Ca2+) ions in the CREB pathway. In this review, we have discussed the effect of lead on the CREB pathway and its implications on the nervous system, highlighting its effects on learning, synaptic plasticity, memory, and cognitive deficits. This review provides an understanding of the lead-induced alterations in the CREB pathway, which can lead to the future prospect of its use as a diagnostic marker as well as a therapeutic target for neurodegenerative disorders.
Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Chumbo , Doenças Neurodegenerativas , Humanos , Chumbo/toxicidade , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/induzido quimicamente , Animais , Transdução de Sinais/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacosRESUMO
Glycogen storage, conversion and utilization in astrocytes play an important role in brain energy metabolism. The conversion of glycogen to lactate through glycolysis occurs through the coordinated activities of various enzymes and inhibition of this process can impair different brain processes including formation of long-lasting memories. To replenish depleted glycogen stores, astrocytes undergo glycogen synthesis, a cellular process that has been shown to require transcription and translation during specific stimulation paradigms. However, the detail nuclear signaling mechanisms and transcriptional regulation during glycogen synthesis in astrocytes remains to be explored. In this report, we study the molecular mechanisms of vasoactive intestinal peptide (VIP)-induced glycogen synthesis in astrocytes. VIP is a potent neuropeptide that triggers glycogenolysis followed by glycogen synthesis in astrocytes. We show evidence that VIP-induced glycogen synthesis requires CREB-mediated transcription that is calcium dependent and requires conventional Protein Kinase C but not Protein Kinase A. In parallel to CREB activation, we demonstrate that VIP also triggers nuclear accumulation of the CREB coactivator CRTC2 in astrocytic nuclei. Transcriptome profiles of VIP-induced astrocytes identified robust CREB transcription, including a subset of genes linked to glucose and glycogen metabolism. Finally, we demonstrate that VIP-induced glycogen synthesis shares similar as well as distinct molecular signatures with glucose-induced glycogen synthesis, including the requirement of CREB-mediated transcription. Overall, our data demonstrates the importance of CREB-mediated transcription in astrocytes during stimulus-driven glycogenesis.
Assuntos
Astrócitos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Glicogênio , Peptídeo Intestinal Vasoativo , Astrócitos/metabolismo , Glicogênio/metabolismo , Glicogênio/biossíntese , Animais , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Peptídeo Intestinal Vasoativo/metabolismo , Transcrição Gênica , Células Cultivadas , Proteína Quinase C/metabolismo , Regulação da Expressão Gênica , Camundongos , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Núcleo Celular/metabolismoRESUMO
BACKGROUND: Gender is a significant risk factor for late-onset Alzheimer's disease (AD), often attributed to the decline of estrogen. The plant estrogen secoisolariciresinol diglucoside (SDG) has demonstrated anti-inflammatory and neuroprotective effects. However, the protective effects and mechanisms of SDG in female AD remain unclear. METHODS: Ten-month-old female APPswe/PSEN1dE9 (APP/PS1) transgenic mice were treated with SDG to assess its potential ameliorative effects on cognitive impairments in a female AD model through a series of behavioral and biochemical experiments. Serum levels of gut microbial metabolites enterodiol (END) and enterolactone (ENL) were quantified using HPLC-MS. Correlation analysis and broad-spectrum antibiotic cocktail (ABx) treatment were employed to demonstrate the involvement of END and ENL in SDG's cognitive improvement effects in female APP/PS1 mice. Additionally, an acute neuroinflammation model was constructed in three-month-old C57BL/6J mice treated with lipopolysaccharide (LPS) and subjected to i.c.v. injection of G15, an inhibitor of G protein-coupled estrogen receptor (GPER), to investigate the mediating role of the estrogen receptor GPER in the cognitive benefits conferred by SDG. RESULTS: SDG administration resulted in significant improvements in spatial, recognition, and working memory in female APP/PS1 mice. Neuroprotective effects were observed, including enhanced expression of CREB/BDNF and PSD-95, reduced ß-amyloid (Aß) deposition, and decreased levels of TNF-α, IL-6, and IL-10. SDG also altered gut microbiota composition, increasing serum levels of END and ENL. Correlation analysis indicated significant associations between END, ENL, cognitive performance, hippocampal Aß-related protein mRNA expression, and cortical neuroinflammatory cytokine levels. The removal of gut microbiota inhibited END and ENL production and eliminated the neuroprotective effects of SDG. Furthermore, GPER was found to mediate the inhibitory effects of SDG on neuroinflammatory responses. CONCLUSION: These findings suggest that SDG promotes the production of gut microbial metabolites END and ENL, which inhibit cerebral ß-amyloid deposition, activate GPER to enhance CREB/BDNF signaling pathways, and suppress neuroinflammatory responses. Consequently, SDG exerts neuroprotective effects and ameliorates cognitive impairments associated with AD in female mice.
Assuntos
Doença de Alzheimer , Fator Neurotrófico Derivado do Encéfalo , Butileno Glicóis , Disfunção Cognitiva , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Microbioma Gastrointestinal , Glucosídeos , Camundongos Transgênicos , Doenças Neuroinflamatórias , Receptores de Estrogênio , Receptores Acoplados a Proteínas G , Animais , Feminino , Doença de Alzheimer/metabolismo , Doença de Alzheimer/tratamento farmacológico , Glucosídeos/farmacologia , Glucosídeos/uso terapêutico , Camundongos , Microbioma Gastrointestinal/efeitos dos fármacos , Butileno Glicóis/farmacologia , Butileno Glicóis/uso terapêutico , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Doenças Neuroinflamatórias/metabolismo , Doenças Neuroinflamatórias/tratamento farmacológico , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Receptores de Estrogênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Modelos Animais de DoençasRESUMO
BACKGROUND: Despite endothelial dysfunction being an initial step in the development of hypertension and associated cardiovascular/renal injuries, effective therapeutic strategies to prevent endothelial dysfunction are still lacking. GPR183 (G protein-coupled receptor 183), a recently identified G protein-coupled receptor for oxysterols and hydroxylated metabolites of cholesterol, has pleiotropic roles in lipid metabolism and immune responses. However, the role of GPR183 in the regulation of endothelial function remains unknown. METHODS: Endothelial-specific GPR183 knockout mice were generated and used to examine the role of GPR183 in endothelial senescence by establishing 2 independent hypertension models: desoxycorticosterone acetate/salt-induced and Ang II (angiotensin II)-induced hypertensive mice. Echocardiography, transmission electron microscopy, blood pressure measurement, vasorelaxation response experiments, flow cytometry analysis, and chromatin immunoprecipitation analysis were performed in this study. RESULTS: Endothelial GPR183 was significantly induced in hypertensive mice, which was further confirmed in renal biopsies from subjects with hypertensive nephropathy. Endothelial-specific deficiency of GPR183 markedly alleviated cardiovascular and renal injuries in hypertensive mice. Moreover, we found that GPR183 regulated endothelial senescence in both hypertensive mice and aged mice. Mechanistically, GPR183 disrupted circadian signaling by inhibiting PER1 (period circadian regulator 1) expression, thereby facilitating endothelial senescence and dysfunction through the cAMP (cyclic adenosine monophosphate)/PKA (protein kinase A)/CREB (cAMP-response element binding protein) signaling pathway. Importantly, pharmacological inhibition of the oxysterol-GPR183 axis by NIBR189 or clotrimazole ameliorated endothelial senescence and cardiovascular/renal injuries in hypertensive mice. CONCLUSIONS: This study discovers a previously unrecognized role of GPR183 in promoting endothelial senescence. Pharmacological targeting of GPR183 may be an innovative therapeutic strategy for hypertension and its associated complications.
Assuntos
Senescência Celular , Hipertensão , Oxisteróis , Receptores Acoplados a Proteínas G , Animais , Humanos , Masculino , Camundongos , Células Cultivadas , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Acetato de Desoxicorticosterona , Células Endoteliais/metabolismo , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oxisteróis/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Transdução de SinaisRESUMO
Lard is highly appreciated for its flavor. However, it has not been elucidated how to consume lard while at the same time eliminating its adverse effects on postpartum cognitive function. Female mice were divided into three groups (n = 10): soybean oil (SO), lard oil (LO), and a mixture of soybean oil and lard at a ratio of 1:1 (LS). No significant difference was observed between the SO and LS groups in behavioral testing of the maternal mice, but the LO group was significantly worse compared with these two groups. Moreover, the SO and LS supplementation increased docosahexaenoic acid (DHA) and total n-3 polyunsaturated fatty acid (PUFA) levels in the brain and short-chain fatty acid (SCFA)-producing bacteria in feces, thereby mitigating neuroinflammation and lowering the p-ERK(1/2)/ERK(1/2), p-CREB/CREB, and BDNF levels in the brain compared to the LO group. Collectively, the LS group inhibited postpartum cognitive impairment by regulating the brain fatty acid composition, neuroinflammation, gut microbiota, and the SCFA/ERK(1/2)/CREB/BDNF signaling pathway compared to lard.
Assuntos
Fator Neurotrófico Derivado do Encéfalo , Encéfalo , Disfunção Cognitiva , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Ácidos Graxos Voláteis , Período Pós-Parto , Óleo de Soja , Animais , Feminino , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Camundongos , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Ácidos Graxos Voláteis/metabolismo , Óleo de Soja/farmacologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Ácidos Graxos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacosRESUMO
Depression is a widespread disease, with high mortality and recurrence rates. Recent studies have shown that elevated cytokine levels are implicated in the molecular mechanisms of depression. Oxidative stress contributes to the stimulation of cytokine production. Growing evidence suggests that ginsenoside Re (Gs-Re) exerts a neuroprotective effect on the hippocampus by suppressing oxidative stress and inflammation. However, the effect and mechanism of Gs-Re in the treatment of depression remain understudied. This study aimed to evaluate the neuroprotective and antidepressant-like effects of Gs-Re and the possible underlying mechanisms. In this article, the antidepressant-like effect of the Gs-Re was studied both in vitro (H2O2-induced oxidative stress in HT-22 cells) and in vivo (reserpine-induced depressive model mice). Our results indicated that, at the cellular level, Gs-Re effectively enhanced cell survival following H2O2 stimulation, inhibited the mass production of oxidative stress markers (MDA and ROS), and prevented the occurrence of apoptosis. Moreover, Gs-Re significantly reduced the levels of proinflammatory cytokines IL-1ß, IL-6, and TNF-α and restored the abnormal mitochondrial membrane potential. Subsequently, Gs-Re treatment reversed reserpine-induced neuroinflammation and depressive-like behaviors in vivo and inhibited microglia overactivation. Furthermore, the alterations in the BDNF/TrkB/ERK/CREB signaling pathway induced by H2O2 or reserpine in HT-22 cells or in the mouse hippocampus were significantly reversed by Gs-Re. K252a blocked the improvement of Gs-Re on depression-like behavior and eliminated the inhibition of oxidative stress and neuroinflammation in vivo. This study suggested that Gs-Re produces neuroprotective and depressive effects by inhibiting oxidative stress and inflammation and activating the BDNF/TrkB/ERK/CREB pathway.
Assuntos
Antidepressivos , Fator Neurotrófico Derivado do Encéfalo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Depressão , Ginsenosídeos , Estresse Oxidativo , Transdução de Sinais , Animais , Estresse Oxidativo/efeitos dos fármacos , Ginsenosídeos/farmacologia , Ginsenosídeos/administração & dosagem , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Camundongos , Depressão/tratamento farmacológico , Depressão/metabolismo , Masculino , Transdução de Sinais/efeitos dos fármacos , Antidepressivos/farmacologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Camundongos Endogâmicos C57BL , Receptor trkB/metabolismoRESUMO
Rice protein peptide (RPP) has been reported to alleviate the symptoms of dextran sulfate sodium (DSS)-induced colitis, but its potential protective effect and fundamental neurobiological mechanisms against DSS-induced inflammatory bowel disease (IBD), coupled with depression and cognitive impairment, remain unclear. In this study, RPP treatment in DSS-induced mice inhibited decreases in body weight and colon length and improved intestinal barrier function and behavioral performance. RPP treatment enhanced phenylalanine and tyrosine metabolism in the brains of mice, and it upregulated metabolites such as l-dopa, phenylethylamine, and 3,4-dihydroxyphenylacetate. Additionally, RPP treatment enhanced the brain-derived neurotrophic factor (BDNF) by upregulating the BDNF/TrkB/CREB signaling pathway. Spearman's correlation analysis revealed that the phenylalanine and tyrosine contents in the brain were significantly negatively correlated with the BDNF/TrkB/CREB signaling pathway and behavioral performance. In conclusion, this study suggested that RPP may serve as a unique nutritional strategy for preventing IBD and its associated cognitive impairment and depression symptoms.