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BACKGROUND: Iron deposition and ferroptosis are involved in ischemic stroke injury, but the choice of drugs for treatment is limited. PURPOSE: To investigate the potential neuroprotective effects of Rosmarinic acid (RosA) encapsulated within nanoliposomes (RosA-LIP) on ischemic stroke. METHODS: Wild-type (WT) and TfR1EC cKO (specific knockout of the TfR1 gene in BMECs) mice used to establish a dMCAO model, with simultaneous administration of RosA-LIP (20 mg/kg/d, i.p.) or RosA (20 mg/kg/d, i.p.). RESULTS: The successful synthesis of RosA-LIP resulted in enhanced stability and precise delivery in both the serum and brain. The administration of RosA-LIP effectively mitigated ischemia-induced behavioral abnormalities and pathological damage. RosA-LIP inhibited ferroptosis by ameliorating mitochondrial abnormalities, increasing GPX4 levels, and decreasing ACSL4/LPCAT3/Lox-dependent lipid peroxidation. RosA-LIP effectively improved bloodâbrain barrier (BBB) permeability, increased tight junctions (TJs) protein expression and reduced iron levels in ischemic tissue and brain microvascular endothelial cells (BMECs) by modulating FPN1 and TfR1 levels. Furthermore, RosA-LIP suppressed TfR1 to attenuate ACSL4/LPCAT3/Lox-mediated ferroptosis in TfR1EC cKO mice subjected to dMCAO. CONCLUSION: RosA-LIP effectively increased the brain level of RosA and protected against ferroptosis through the regulation of TfR1 in BMECs.
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Barrera Hematoencefálica , Cinamatos , Depsidos , Células Endoteliales , Ferroptosis , Liposomas , Receptores de Transferrina , Ácido Rosmarínico , Animales , Depsidos/farmacología , Cinamatos/farmacología , Ferroptosis/efectos de los fármacos , Receptores de Transferrina/metabolismo , Ratones , Células Endoteliales/efectos de los fármacos , Barrera Hematoencefálica/efectos de los fármacos , Masculino , Ratones Noqueados , Fármacos Neuroprotectores/farmacología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Isquemia Encefálica/tratamiento farmacológico , Modelos Animales de Enfermedad , Peroxidación de Lípido/efectos de los fármacos , Ratones Endogámicos C57BL , Accidente Cerebrovascular Isquémico/tratamiento farmacológicoRESUMEN
The significance of iron in myocardial mitochondria function cannot be underestimated, because deviations in iron levels within cardiomyocytes may have profound detrimental effects on cardiac function. In this study, we investigated the effects of ferroportin 1 (FPN1) on cardiac iron levels and pathological alterations in mice subjected to chronic intermittent hypoxia (CIH). The cTNT-FPN1 plasmid was administered via tail vein injection to induce the mouse with FPN1 overexpression in the cardiomyocytes. CIH was established by exposing the mice to cycles of 21%-5% FiO2 for 3 min, 8 h per day. Subsequently, the introduction of hepcidin resulted in a reduction in FPN1 expression, and H9C2 cells were used to establish an IH model to further elucidate the role of FPN1. First, FPN1 overexpression ameliorated CIH-induced cardiac dysfunction, myocardial hypertrophy, mitochondrial damage and apoptosis. Second, FPN1 overexpression attenuated ROS levels during CIH. In addition, FPN1 overexpression mitigated CIH-induced cardiac iron accumulation. Moreover, the administration of hepcidin resulted in a reduction in FPN1 levels, further accelerating the CIH-induced levels of ROS, LIP and apoptosis in H9C2 cells. These findings indicate that the overexpression of FPN1 in cardiomyocytes inhibits CIH-induced cardiac iron accumulation, subsequently reducing ROS levels and mitigating mitochondrial damage. Conversely, the administration of hepcidin suppressed FPN1 expression and worsened cardiomyocyte iron toxicity injury.
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Apoptosis , Cardiomegalia , Proteínas de Transporte de Catión , Hipoxia , Hierro , Miocitos Cardíacos , Especies Reactivas de Oxígeno , Animales , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Cardiomegalia/metabolismo , Cardiomegalia/genética , Cardiomegalia/patología , Cardiomegalia/etiología , Proteínas de Transporte de Catión/metabolismo , Proteínas de Transporte de Catión/genética , Hipoxia/metabolismo , Hipoxia/complicaciones , Ratones , Especies Reactivas de Oxígeno/metabolismo , Hierro/metabolismo , Masculino , Hepcidinas/metabolismo , Hepcidinas/genética , Línea Celular , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , RatasRESUMEN
The objective of this study is to examine the potential protective effect of rosmarinic acid (RosA) encapsulated within nanoliposomes (RosA-LIP) on hepatic damage induced by iron overload. The characteristics, stability, and release of RosA-LIP in vitro were identified. The mice were randomly assigned to five groups: Control, Model, Model+DFO (DFO), Model+RosA (RosA), and Model+RosA-LIP (RosA-LIP). The iron overload model was induced by administering iron dextran (i.p.). The DFO, RosA, and RosA-LIP groups received iron dextran and were subsequently treated with DFO, RosA, and RosA-LIP for 14 days. We developed a novel formulation of RosA-LIP that exhibited stability and controlled release properties. Firstly, RosA-LIP improved liver function and ameliorated pathological changes in a mouse model of iron overload. Secondly, RosA-LIP demonstrated the ability to enhance the activities of T-SOD, GSH-Px, and CAT, while reducing the levels of MDA and 4-HNE, thereby effectively mitigating oxidative stress damage induced by iron overload. Thirdly, RosA-LIP reduced hepatic iron levels by downregulating FTL, FTH, and TfR1 levels. Additionally, RosA-LIP exerted a suppressive effect on hepcidin expression through the BMP6-SMAD1/5/8 signaling pathway. Furthermore, RosA-LIP upregulated FPN1 expression in both the liver and duodenum, thereby alleviating iron accumulation in these organs in mice with iron overload. Notably, RosA exhibited a comparable iron chelation effect, and RosA-LIP demonstrated superior efficacy in mitigating liver damage induced by excessive iron overload. RosA-LIP exhibited favorable sustained release properties, targeted delivery, and efficient protection against iron overload-induced liver damage. A schematic representation of the proposed protective mechanism of rosmarinic acid liposome during iron overload. Once RosA-LIP is transported into cells, RosA is released. On the one hand, RosA attenuates the BMP6-SMAD1/5/8-SMAD4 signaling pathway activation, leading to inhibiting hepcidin transcription. Then, the declined hepcidin contacted the inhibitory effect of FPN1 in hepatocytes and duodenum, increasing iron mobilization. On the other hand, RosA inhibits TfR1 and ferritin expression, which decreases excessive iron and oxidative damage.
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The present study aimed to investigate the impact of hydrogen (H2) on chronic intermittent hypoxia (CIH)-induced cardiac hypertrophy in mice by modulating iron metabolism. C57BL/6N mice were randomly allocated into four groups: control (Con), CIH, CIH + H2, and H2. The mice were exposed to CIH (21-5% FiO2, 3 min/cycle, 8 h/d), and received inhalation of a hydrogen-oxygen mixture (2 h/d) for 5 weeks. Cardiac and mitochondrial function, levels of reactive oxygen species (ROS), and iron levels were evaluated. The H9C2 cell line was subjected to intermittent hypoxia (IH) and treated with H2. Firstly, we found H2 had a notable impact on cardiac hypertrophy, ameliorated pathological alterations and mitochondrial morphology induced by CIH (p < 0.05). Secondly, H2 exhibited a suppressive effect on oxidative injury by decreasing levels of inducible nitric oxide synthase (i-NOS) (p < 0.05) and 4-hydroxynonenal (4-HNE) (p < 0.01). Thirdly, H2 demonstrated a significant reduction in iron levels within myocardial cells through the upregulation of ferroportin 1 (FPN1) proteins (p < 0.01) and the downregulation of transferrin receptor 1 (TfR1), divalent metal transporter 1 with iron-responsive element (DMT1(+ire)), and ferritin light chain (FTL) mRNA or proteins (p < 0.05). Simultaneously, H2 exhibited the ability to decrease the levels of Fe2+ and ROS in H9C2 cells exposed to IH (p < 0.05). Moreover, H2 mediated the expression of hepcidin, hypoxia-inducible factor-1α (HIF-1α) (p < 0.01), and iron regulatory proteins (IRPs), which might be involved in the regulation of iron-related transporter proteins. These results suggested that H2 may be beneficial in preventing cardiac hypertrophy, a condition associated with reduced iron toxicity.
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BACKGROUND: Chronic atrophic gastritis (CAG) is a chronic inflammatory disease and premalignant lesion of gastric cancer. As an antimicrobial peptide, hepcidin can maintain iron metabolic balance and is susceptible to inflammation. OBJECTIVES: The objective of this study was to clarify whether hepcidin is involved in abnormal iron metabolism and ferroptosis during CAG pathogenesis. METHODS: Non-atrophic gastritis (NAG) and chronic atrophic gastritis (CAG) patient pathology slides were collected, and related protein expression was detected by immunohistochemical staining. The CAG rat model was established using MNNG combined with an irregular diet. RESULTS: CAG patients and rats exhibited iron deposition in gastric tissue. CAG-induced ferroptosis in the stomach was characterized by decreased GPX4 and FTH levels and increased 4-HNE levels. Hepcidin, which is mainly located in parietal cells, was elevated in CAG gastric tissue. The high gastric level of hepcidin inhibited iron absorption in the duodenum by decreasing the protein expression of DMT1 and FPN1. In addition, the IL-6/STAT3 signaling pathway induced hepcidin production in gastric tissue. CONCLUSION: Our results showed that the high level of gastric hepcidin induced ferroptosis in the stomach but also inhibited iron absorption in the intestines. Inhibiting hepcidin might be a new strategy for the prevention of CAG in the future.
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Background: Chronic intermittent hypoxia (CIH) could cause neuronal damage, accelerating the progression of dementia. However, safe and effective therapeutic drugs and delivery are needed for successful CIH therapy. Purpose: To investigate the neuroprotective effect of Huperzine A (HuA) packaged with nanoliposomes (HuA-LIP) on neuronal damage induced by CIH. Methods: The stability and release of HuA-LIP in vitro were identified. Mice were randomly divided into the Control, CIH, HuA-LIP, and HuA groups. The mice in the HuA and HuA-LIP groups received HuA (0.1 mg/kg, i.p.), and HuA-LIP was administered during CIH exposure for 21 days. HuA-LIP contains the equivalent content of HuA. Results: We prepared a novel formulation of HuA-LIP that had good stability and controlled release. First, HuA-LIP significantly ameliorated cognitive dysfunction and neuronal damage in CIH mice. Second, HuA-LIP elevated T-SOD and GSH-Px abilities and decreased MDA content to resist oxidative stress damage induced by CIH. Furthermore, HuA-LIP reduced brain iron levels by downregulating TfR1, hepcidin, and FTL expression. In addition, HuA-LIP activated the PKAα/Erk/CREB/BDNF signaling pathway and elevated MAP2, PSD95, and synaptophysin to improve synaptic plasticity. Most importantly, compared with HuA, HuA-LIP showed a superior performance against neuronal damage induced by CIH. Conclusion: HuA-LIP has a good sustained-release effect and targeting ability and efficiently protects against neural injury caused by CIH.
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Alcaloides , Liposomas , Ratones , Animales , Liposomas/farmacología , Hipoxia/metabolismo , Hipocampo , Alcaloides/farmacología , Estrés OxidativoRESUMEN
Objective: To investigate the effects of Banxia Houpo decoction on the renal NLRP3/Caspase-1/IL-1ß signaling pathway in chronic intermittent hypoxia mice. Methods: C57BL/6 mice were randomly divided into 3 groups, normal control group (Control), chronic intermittent hypoxia group (CIH), and Banxia Houpo decoction treatment group (BHD), with 10 mice in each group. Mice in the CIH group and BHD group were placed in a hypoxic chamber. The oxygen volume fraction in the cabin was decreased from 21% to 9% in 90 s, and then oxygen was filled in 90 s to gradually increase the oxygen volume fraction in the cabin to 21%, while the mice in the control group were placed in the cabin and filled with normal air, processing 8 hours per day for 21 days. The mice in BHD group were treated with Banxia Houpu decoction by gavage before entering the cabin every day, and the control group and CIH group were given an equal volume of normal saline. After modeling, the changes of renal function indexes in each group were detected; HE and Masson staining were used to observe the pathological conditions of the kidney; Western blot and immunohistochemical staining were used to detect the protein expression levels of the nucleotide-binding oligomerization domain-like receptor protein 3(NLRP3), aspartate-specific cysteine protein 1(Caspase-1) and interleukine-1beta(IL-1ß). Results: Compared with control group, the contents of serum renal functional indexes UA, BUN and SCr in CIH group were increased significantly (P<0.01), and after BHD treatment, they all were decreased significantly compared with CIH group (P<0.01). Compared with control group, the results of HE staining showed that in the CIH group, glomerular endothelial cells were degenerated and necrotic, and vacuoles of different sizes appeared in renal tubular epithelial cells, and a small amount of renal tubular epithelial cells fell off and died. The pathological condition of the BHD group was improved compared with CIH group, the glomerular morphology gradually returned to normal, and a small amount of renal tubular epithelial cells fell off and died. Compared with control group, Masson staining results showed that there was obvious fibrosis around the glomeruli in the CIH group, the fibrosis was significantly reduced in the BHD group. The expression levels of NLRP3, Caspase-1, IL-1ß and IL-18 were increased significantly compared with control group (P<0.05 or P<0.01), and immunohistochemical staining showed that NLRP3 was mainly expressed in renal tubular epithelial cells and interstitial macrophages, caspase-1 and IL-1ß were mainly found in the cytoplasm of renal tubular epithelial cells. After BHD treatment, the expression levels of each protein were decreased compared with CIH group (P<0.05). Conclusion: Banxia Houpu decoction can reduce the kidney damage by inhibiting the expression of related molecules in the NLRP3/Casapse-1/IL-1ß signaling pathway.
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Enfermedades Renales , Proteína con Dominio Pirina 3 de la Familia NLR , Ratones , Animales , Caspasa 1/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Células Endoteliales/patología , Ratones Endogámicos C57BL , Riñón/lesiones , Hipoxia/patología , Fibrosis , OxígenoRESUMEN
Oxidative stress and deficient bioenergetics are key players in the pathological process of cerebral ischemia reperfusion injury (I/R). As a mitochondrial iron storage protein, mitochondrial ferritin (FtMt) plays a pivotal role in protecting neuronal cells from oxidative damage under stress conditions. However, the effects of FtMt in mitochondrial function and activation of apoptosis under cerebral I/R are barely understood. In the present study, we found that FtMt deficiency exacerbates neuronal apoptosis via classical mitochondria-depedent pathway and the endoplasmic reticulum (ER) stress pathway in brains exposed to I/R. Conversely, FtMt overexpression significantly inhibited oxygen and glucose deprivation and reperfusion (OGD/R)-induced apoptosis and the activation of ER stress response. Meanwhile, FtMt overexpression rescued OGD/R-induced mitochondrial iron overload, mitochondrial dysfunction, the generation of reactive oxygen species (ROS) and increased neuronal GSH content. Using the Seahorse and O2K cellular respiration analyser, we demonstrated that FtMt remarkably improved the ATP content and the spare respiratory capacity under I/R conditions. Importantly, we found that glucose consumption was augmented in FtMt overexpressing cells after OGD/R insult; overexpression of FtMt facilitated the activation of glucose 6-phosphate dehydrogenase and the production of NADPH in cells after OGD/R, indicating that the pentose-phosphate pathway is enhanced in FtMt overexpressing cells, thus strengthening the antioxidant capacity of neuronal cells. In summary, our results reveal that FtMt protects against I/R-induced apoptosis through enhancing mitochondrial bioenergetics and regulating glucose metabolism via the pentose-phosphate pathway, thus preventing ROS overproduction, and preserving energy metabolism.
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Adriamycin (ADR) has been utilized to treat cancer for several decades. However, ADR-induced renal injury is one of the most common side effects accompanying ADR therapy. In the present study, we revealed that astragaloside IV (ASIV) was beneficial for renal injury caused by Adriamycin. We demonstrated that ASIV significantly ameliorated kidney injury, improved renal dysfunction, reduced oxidative stress, alleviated iron accumulation, and inhibited the induction of ferroptosis by ADR. ASIV also rescued the intracellular levels of nuclear factor-erythroid-2-related factor 2 (Nrf2) and promoted nuclear translocation of Nrf2. These protective effects of ASIV on renal injury might be attained through the ASIV-induced activation of the Pi3K/Akt signaling pathway. In vitro, the treatment of the HK-2 cells with fer-1 or deferoxamine mesylate obviously improved cell viability during Adriamycin administration. On the other hand, the protective role of ASIV can be abrogated by RSL3 to some extent. Moreover, ASIV lowered the expression of transferrin receptor 1 and divalent metal transporter 1 while enhancing the expression of ferropotin 1 and glutathione peroxidase 4 in ADR administrated cells, the effects of which were akin to those of deferoxamine mesylate. Furthermore, ASIV increased the phosphorylation of Pi3K, Akt, and the expression of Nrf2 and glutathione peroxidase 4 compared to HK-2 cells stimulated by ADR. However, Pi3K inhibitor LY294002 abrogated these activations. In conclusion, ferroptosis may involve in ADR-induced nephrotoxicity, and ASIV might protect nephrocytes against ADR-induced ferroptosis, perhaps via activations of the Pi3K/Akt and Nrf2 signaling pathways.
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Liver pathological changes are as high as 21%-78% in diabetic patients, and treatment options are lacking. Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor that is widely used in the clinic and is approved to treat obesity and diabetes. However, the specific protection mechanism needs to be clarified. In the present study, db/db mice were used to simulate Type 2 diabetes mellitus (T2DM), and they were intraperitoneally injected daily with liraglutide (200 µg/kg/d) for 5 weeks. Hepatic function, pathologic changes, oxidative stress, iron levels, and ferroptosis were evaluated. First, liraglutide decreased serum AST and ALT levels, and suppressed liver fibrosis in db/db mice. Second, liraglutide inhibited the ROS production by upregulating SOD, GSH-PX, and GSH activity as well as by downregulating MDA, 4-HNE, and NOX4 expression in db/db mice. Furthermore, liraglutide attenuated iron deposition by decreasing TfR1 expression and increasing FPN1 expression. At the same time, liraglutide decreased ferroptosis by elevating the expression of SLC7A11 and the Nrf2/HO-1/GPX4 signaling pathway in the livers of db/db mice. In addition, liraglutide decreased the high level of labile iron pools (LIPs) and intracellular lipid ROS induced by high glucose in vitro. Therefore, we speculated that liraglutide played a crucial role in reducing iron accumulation, oxidative damage and ferroptosis in db/db mice.
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Diabetes Mellitus Tipo 2 , Ferroptosis , Animales , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Hierro , Liraglutida/farmacología , Hígado/metabolismo , Ratones , Especies Reactivas de Oxígeno/metabolismoRESUMEN
CONTEXT: Obstructive sleep apnoea (OSA) causes chronic intermittent hypoxia (CIH), which results in mitochondrial dysfunction and generates reactive oxygen species (ROS) in the heart. Excessive free iron could accelerate oxidative damage, which may be involved in this process. Banxia-Houpu decoction (BHD) was reported to improve the apnoea hypopnoea index in OSA patients, but the specific mechanism was still unclear. OBJECTIVE: To investigate whether BHD could reduce CIH-induced heart damage by regulating iron metabolism and mitochondrial function. MATERIALS AND METHODS: C57BL/6N mice were randomly divided into control, CIH and BHD groups. Mice were exposed to CIH (21 - 5% O2, 20 times/h, 8 h/d) and administered BHD (3.51, 7.01 and 14.02 g/kg, intragastrically) for 21 d. Cardiac and mitochondrial function, iron levels, apoptosis and mitophagy were determined. RESULTS: BHD (7.01 g/kg) significantly improved cardiac dysfunction, pathological change and mitochondrial structure induced by CIH. BHD increased the Bcl-2/Bax ratio (1.4-fold) and inhibited caspase 3 cleavage in CIH mice (0.45-fold). BHD activated mitophagy by upregulating Parkin (1.94-fold) and PINK1 (1.26-fold), inhibiting the PI3K-AKT-mTOR pathway. BHD suppressed ROS generation by decreasing NOX2 (0.59-fold) and 4-HNE (0.83-fold). BHD reduced the total iron in myocardial cells (0.72-fold) and mitochondrial iron by downregulating Mfrn2 (0.81-fold) and MtFt (0.78-fold) proteins, and upregulating ABCB8 protein (1.33-fold). Rosmarinic acid, the main component of Perilla Leaf in BHD, was able to react with Fe2+ and Fe3+ in vitro. DISCUSSION AND CONCLUSIONS: These findings encourage the use of BHD to resist cardiovascular injury and provide the theoretical basis for clinical treatment in OSA patients.
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Medicamentos Herbarios Chinos/farmacología , Lesiones Cardíacas/prevención & control , Hipoxia/tratamiento farmacológico , Hierro/metabolismo , Animales , Apoptosis/efectos de los fármacos , Cinamatos/farmacología , Depsidos/farmacología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Medicamentos Herbarios Chinos/administración & dosificación , Lesiones Cardíacas/etiología , Hipoxia/complicaciones , Masculino , Ratones , Ratones Endogámicos C57BL , Mitocondrias/efectos de los fármacos , Mitocondrias/patología , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Apnea Obstructiva del Sueño/complicaciones , Ácido RosmarínicoRESUMEN
Obstructive sleep apnea (OSA) patients exhibit different degrees of cognitive impairment, which is related to the activation of reactive oxygen species (ROS) production by chronic intermittent hypoxia (CIH) and the deposition of iron in the brain. As a central regulator of iron homeostasis, whether hepcidin is involved in OSA-induced cognitive impairment has not been clarified. In order to simulate OSA, we established the mouse model by reducing the percentage of inspired O2 (FiO2) from 21% to 5%, 20 times/h for 8 h/day. We found hepcidin was rising during CIH, along with increasing iron levels and neuron loss. Then, we constructed a mouse with astrocyte-specific knockdown hepcidin gene (shHamp). During CIH exposure, the shHamp mice showed a lower level of total iron and neuronal iron in the hippocampus, via stabilizing ferroportin 1 (FPN1) and decreasing L-ferritin (FTL) levels, when compared with wild-type (WT) mice. Furthermore, the shHamp mice showed a decrease of ROS by downregulating the elevated NADPH oxidase (NOX2) and 4-hydroxynonenal (4-HNE) levels mediated by CIH. In addition, the shHamp mice presented improved cognitive deficit by improving synaptic plasticity and BDNF expression in the hippocampus when subjected to CIH. Therefore, our data revealed that highly expressed hepcidin might promote the degradation of FPN1, resulting in neuronal iron deposition, oxidative stress damage, reduced synaptic plasticity, and impaired cognitive performance during CIH exposure.
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Hepcidinas/metabolismo , Hipoxia , Aldehídos/metabolismo , Animales , Apoptosis , Modelos Animales de Enfermedad , Ferritinas/metabolismo , Hepcidinas/antagonistas & inhibidores , Hepcidinas/genética , Hipocampo/metabolismo , Masculino , Aprendizaje por Laberinto , Ratones , Ratones Endogámicos C57BL , NADPH Oxidasas/metabolismo , Plasticidad Neuronal , Estrés Oxidativo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Apnea Obstructiva del Sueño/metabolismo , Apnea Obstructiva del Sueño/patología , Proteína X Asociada a bcl-2/metabolismoRESUMEN
Ischaemic stroke is becoming the most common cerebral disease in aging populations, but the underlying molecular mechanism of the disease has not yet been fully elucidated. Increasing evidence has indicated that an excess of iron contributes to brain damage in cerebral ischaemia/reperfusion (I/R) injury. Although mitochondrial ferritin (FtMt) plays a critical role in iron homeostasis, the molecular function of FtMt in I/R remains unknown. We herein report that FtMt levels are upregulated in the ischaemic brains of mice. Mice lacking FtMt experience more severe brain damage and neurological deficits, accompanied by typical molecular features of ferroptosis, including increased lipid peroxidation and disturbed glutathione (GSH) after cerebral I/R. Conversely, FtMt overexpression reverses these changes. Further investigation shows that Ftmt ablation promotes I/R-induced inflammation and hepcidin-mediated decreases in ferroportin1, thus markedly increasing total and chelatable iron. The elevated iron consequently facilitates ferroptosis in the brain of I/R. In brief, our results provide evidence that FtMt plays a critical role in protecting against cerebral I/R-induced ferroptosis and subsequent brain damage, thus providing a new potential target for the treatment/prevention of ischaemic stroke.
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Muerte Celular/inmunología , Ferritinas/metabolismo , Ferroptosis/inmunología , Mitocondrias/inmunología , Daño por Reperfusión/inmunología , Animales , Humanos , Ratones , Ratones NoqueadosRESUMEN
AIMS: Many dietary NASH models require a long duration to establish (4-6 months). Chronic intermittent hypoxia (CIH), a cardinal hallmark of obstructive sleep apnea (OSA), may accelerate the progression of pediatric nonalcoholic fatty liver disease (NAFLD). However, diet-induced obese (DIO) mice exposed to CIH have not been perceived as a fast or reliable tool in NASH research. This study was designed to establish a rapid juvenile murine NASH model, and determine whether the combination of CIH and a western-style diet (hypercaloric fatty diet plus high fructose) can fully display key pathologic features of NASH. METHODS: C57BL/6 N mice (3 weeks old) fed a control diet or western diet (WD) were exposed to CIH (9% nadir of inspired oxygen levels) or room air for 6 and 12 weeks. KEY FINDINGS: The Control/CIH group mainly exhibited hyperinsulinemia and insulin resistance (IR). In contrast, mice fed a WD developed weight gain after 3 weeks, microvesicular steatosis in 6 weeks, and indices of metabolic disorders at 12 weeks. Furthermore, CIH exposure accelerated WD- induced macromicrovesicular steatosis (liver triglycerides and de novo lipogenesis), liver injury (ballooned hepatocytes and liver enzymes), lobular/portal inflammation (inflammatory cytokines and macrophage recruitment), and fibrogenesis (hydroxyproline content and TGF-ß protein). Notably, only the WD/CIH group exhibited elevated hepatic MDA content, protein levels of NOX4, α-SMA and collagen I, as well as reduced Nrf2 and HO-1 protein expression. SIGNIFICANCE: WD/CIH treatment rapidly mimics the histological characteristics of pediatric NASH with metabolic dysfunction and fibrosis, representing an appropriate experimental model for NASH research.
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Dieta Occidental/efectos adversos , Hipoxia/fisiopatología , Inflamación/patología , Resistencia a la Insulina , Enfermedad del Hígado Graso no Alcohólico/patología , Estrés Oxidativo , Animales , Animales Recién Nacidos , Inflamación/etiología , Inflamación/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/metabolismoRESUMEN
Chronic intermittent hypoxia (CIH) is a consequence of obstructive sleep apnea (OSA), which increases reactive oxygen species (ROS) generation, resulting in oxidative damage and neurocognitive impairment. This study was designed to determine whether abnormal iron metabolism occurs in the brain under conditions of CIH and whether Huperzine A (HuA) could improve abnormal iron metabolism and neurological damage. The mouse model of CIH was established by reducing the percentage of inspired O2 (FiO2) from 21% to 9% 20 times/h for 8 h/day, and Huperzine A (HuA, 0.1 mg/kg, i.p.) was administered during CIH exposure for 21 days. HuA significantly improved cognitive impairment and neuronal damage in the hippocampus of CIH mice via increasing the ratio of Bcl-2/Bax and inhibiting caspase-3 cleavage. HuA considerably decreased ROS levels by downregulating the high levels of NADPH oxidase (NOX 2, NOX 4) mediated by CIH. There was an overload of iron, which was characterized by high levels of ferritin (FTL and FTH) and transferrin receptor 1 (TfR1) and low levels of ferroportin 1 (FPN1) in the hippocampus of CIH mice. Decreased levels of TfR1 and FTL proteins observed in HuA treated CIH group, could reduce iron overload in hippocampus. HuA increased PSD 95 protein expression, CREB activation and BDNF protein expression to protect against synaptic plasticity impairment induced by CIH. HuA acts as an effective iron chelator to attenuate apoptosis, oxidative stress and synaptic plasticity mediated by CIH.
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Alcaloides/uso terapéutico , Trastornos del Conocimiento/tratamiento farmacológico , Hipocampo/efectos de los fármacos , Hipoxia/patología , Sobrecarga de Hierro/tratamiento farmacológico , Sesquiterpenos/uso terapéutico , Animales , Apoptosis , Conducta Animal , Caspasa 3/metabolismo , Proteínas de Transporte de Catión/metabolismo , Modelos Animales de Enfermedad , Ferritinas/metabolismo , Hipocampo/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Plasticidad Neuronal , Fármacos Neuroprotectores/uso terapéutico , Estrés Oxidativo , Oxígeno/metabolismo , Especies Reactivas de Oxígeno , Receptores de Transferrina/metabolismoRESUMEN
The prominent feature of obstructive sleep apnea (OSA) is chronic intermittent hypoxia (CIH). Given the strong antioxidant ability of resveratrol against oxidative stress, we evaluated the potential protective effects of resveratrol on myocardial injury induced by CIH. Twenty-four rats were divided into normal control group, CIH group, CIH plus resveratrol treated (CIH + Res) group, and resveratrol treated control (Res) group. We proved that CIH impaired cardiac structure and function with an increase in oxidative stress, endoplasmic reticulum (ER) stress and NOD-like receptors (NLRP3) inflammasome induction in heart, which was attenuated after resveratrol administration. NLRP3 inflammasome blockade by resveratrol appeared to be mediated by activating AMP-activated Protein Kinase (AMPK), which could restrain mTOR/TTP/NLRP3 mRNA signalling. Furthermore, resveratrol attenuated CIH-induced oxidative stress through elevation antioxidant molecules expression via NF-E2-related factor-2 (Nrf2). Moreover, AMPK may play a role in Nrf2/HO-1 signalling by resveratrol. These results expand our understanding of the myocardial protective mechanism of resveratrol during CIH and suggest that resveratrol treatment may be useful to counteract OSA-associated cardiac injury.
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Antioxidantes/uso terapéutico , Hipoxia/complicaciones , Inflamasomas/efectos de los fármacos , Isquemia Miocárdica/tratamiento farmacológico , Factor 2 Relacionado con NF-E2/antagonistas & inhibidores , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Resveratrol/uso terapéutico , Animales , Antioxidantes/farmacología , Western Blotting , Ecocardiografía , Técnica del Anticuerpo Fluorescente , Inflamasomas/metabolismo , Masculino , Isquemia Miocárdica/etiología , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/patología , Factor 2 Relacionado con NF-E2/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Reacción en Cadena en Tiempo Real de la Polimerasa , Resveratrol/farmacologíaRESUMEN
AIMS: Resveratrol is a polyphenolic compound that has received much attention for its use in ameliorating various systemic pathological conditions. The present study was performed to investigate whether the resveratrol alleviated cardiac hypertrophy and functional remodelling by regulating autophagy. MATERIALS AND METHODS: Male rats were exposed to CIH 8â¯h/day for five weeks and/or intragastric administration of resveratrol daily. The morphological and echocardiography were used to evaluate the cardiac protective effects. The apoptosis was detected by TUNEL staining. The biochemical assessments were used to evaluate oxidative stress. Further, the effect of resveratrol on autophagy and PI3K/AKT/mTOR pathway was investigated. KEY FINDINGS: The CIH group exhibited increased heart weight/body weight and left ventricle weight/body weight ratios, which was accompanied by left ventricular remodelling. Echocardiography analysis showed that CIH-treated rats had significantly higher left ventricular posterior wall thickness, ejection fraction and fractional shortening than those of controls. In addition, the apoptosis index and oxidative markers were significantly elevated in the CIH group versus the control. The autophagy marker Beclin-1 was elevated, while p62 was decreased by CIH treatment. Resveratrol treatment significantly improved cardiac function and alleviated cardiac hypertrophy, oxidative stress, and apoptosis in CIH rats. Further results indicated that PI3K/AKT pathway-mediated inhibition of the mammalian target of rapamycin (mTOR) pathway played a role in the activation of autophagy by resveratrol after CIH stimulation. SIGNIFICANCE: In conclusion, resveratrol supplementation during CIH upregulates autophagy by targeting the PI3K/AKT/mTOR pathway, which appears to be beneficial for resisting cardiac hypertrophy.
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Cardiomegalia/prevención & control , Regulación de la Expresión Génica/efectos de los fármacos , Hipoxia/complicaciones , Inhibidores de las Quinasa Fosfoinosítidos-3 , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Resveratrol/farmacología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Animales , Antioxidantes/farmacología , Apoptosis , Autofagia , Cardiomegalia/etiología , Cardiomegalia/patología , Masculino , Estrés Oxidativo/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas Sprague-Dawley , Transducción de Señal , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
OBJECTIVE: To investigate the effects of Xiaotan Huayu Liqiao formula (the Chinese Medicine) on mesenteric artery function in rats exposed to chronic intermittent hypoxia (CIH), and to explore the related mechanism. METHODS: Forty-eight male SD rats were randomly divided into four groups as Normoxia, CIH, Formula+CIH and formula group. Rats were exposed to normoxia in the Normoxia and Formula group, or intermittent hypoxia in CIH or Formula+CIH group. Xiaotan Huayu Liqiao formula was given at 24g/kg by intragastric administration before intermittent hypoxia exposure. The pathological changes of mesenteric artery were determined by HE staining, and the relaxation of mesenteric artery (induced by acetylcholine(ACh) and L-arginine(L-Arg)) was recorded by microvascular ring technique. Serums of all rats were collected (0 d and 21 d) and the content of NO was detected by ELISA. The levels of endothelial nitric oxide synthase (eNOS) and p-eNOS were measured by Western blot. RESULTS: Compared with Normoxia group, the mesenteric arterial endothelial injury and media thickening were observed and the relaxation of mesenteric artery was significantly reduced in rats exposed to CIH. The level of NO in serum and the ratio of p-eNOS/eNOS were also decreased in the CIH group. Xiaotan Huayu Liqiao formula administration improved the pathologic changes and dilatation function of mesenteric artery, increased the levels of NO and p-eNOS. Compared with Normoxia group,all the results were not observed significant difference in Formula group. CONCLUSION: Xiaotan Huayu Liqiao formula increased the bioavailability of NO, and ameliorated the CIH induced mesenteric artery function injury.
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Medicamentos Herbarios Chinos/farmacología , Hipoxia/patología , Arterias Mesentéricas/efectos de los fármacos , Acetilcolina , Animales , Masculino , Arterias Mesentéricas/patología , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Distribución Aleatoria , Ratas , Ratas Sprague-DawleyRESUMEN
AIMS: Hydrogen gas (H2) has a diversity of effects such as anti-apoptotic, anti-inflammatory and anti-oxidative properties. However, molecular mechanism underlying the potential effect of H2 on chronic intermittent hypoxia (CIH) induced renal injury remains obscure. MATERIALS AND METHODS: In the present study, adult male Sprague-Dawley rats were randomly allocated into four groups: control (CON) group, CIH group, CIH with H2 treatment (CIHâ¯+â¯H2) group, and control with H2 treatment (CONâ¯+â¯H2) group. Oxidative stress, autophagy and endoplasmic reticulum (ER) stress were detected to determine how H2 affected the renal function of CIH exposed rats. KEY FINDINGS: We demonstrated that rats who inhale hydrogen gas showed improved renal function, alleviated pathological damage, oxidative stress and apoptosis in CIH rats. Meanwhile, CIH-induced endoplasmic reticulum stress was decreased by H2 as the expressions of CHOP, caspase-12, and GRP78 were down-regulated. Furthermore, relative higher levels of LC3-II/I ratio and Beclin-1, with decreased expression of p62, were found after H2 administrated. Inhibition of mTOR may be involved in the upregulation of autophagy by H2. Finally, increased phosphorylation of p38 and JNK was involved in the CIH-induced pathological process. H2 could inhibit the activation of p38 and JNK, suggesting H2 played an active part in resisting renal injury via MAPK. SIGNIFICANCE: Taken together, our study reveals that H2 can ameliorate CIH-induced kidney injury by decreasing endoplasmic reticulum stress and activating autophagy through inhibiting oxidative stress-dependent p38 and JNK MAPK activation.
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Apoptosis/efectos de los fármacos , Autofagia , Hidrógeno/farmacología , Hipoxia/complicaciones , Enfermedades Renales/prevención & control , Estrés Oxidativo/efectos de los fármacos , Sustancias Protectoras/farmacología , Animales , Estrés del Retículo Endoplásmico/efectos de los fármacos , Enfermedades Renales/etiología , Enfermedades Renales/patología , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
Obstructive sleep apnea (OSA) can cause intermittent changes in blood oxygen saturation, resulting in the generation of many reactive oxygen species (ROS). To discover new antioxidants and clarify the endoplasmic reticulum (ER) stress involved in cardiac injury in OSA, we established a chronic intermittent hypoxia (CIH) rat model with a fraction of inspired O2 (FiO2) ranging from 21% to 9%, 20 times/h for 8 h/day, and the rats were treated with H2-O2 mixture (67% hydrogen and 33% oxygen) for 2 h/day for 35 days. Our results showed that H2-O2 mixture remarkably improved cardiac dysfunction and myocardial fibrosis. We found that H2-O2 mixture inhalation declined ER stress-induced apoptosis via three major response pathways: PERK-eIF2α-ATF4, IRE 1-XBP1, and ATF 6. Furthermore, we revealed that H2-O2 mixture blocked c-Jun N-terminal kinase- (JNK-) MAPK activation, increased the ratio of Bcl-2/Bax, and inhibited caspase 3 cleavage to protect against CIH-induced cardiac apoptosis. In addition, H2-O2 mixture considerably decreased ROS levels via upregulating superoxide dismutase (SOD) and glutathione (GSH) as well as downregulating NADPH oxidase (NOX 2) expression in the hearts of CIH rats. All the results demonstrated that H2-O2 mixture significantly reduced ER stress and apoptosis and that H2 might be an efficient antioxidant against the oxidative stress injury induced by CIH.