RESUMEN
Abnormal lipid homeostasis has been observed in the brain of Parkinson's disease (PD) patients and experimental models, although the mechanism underlying this phenomenon is unclear. Notably, previous studies have reported that the PD-linked protein Parkin functionally interacts with important lipid regulators, including Sterol Regulatory Element-Binding Proteins (SREBPs) and cluster of differentiation 36 (CD36). Here, we demonstrate a functional relationship between Parkin and lipoprotein lipase (LPL), a triglyceride lipase that is widely expressed in the brain. Using a human neuroblastoma cell line and a Parkin knockout mouse model, we demonstrate that Parkin expression level positively correlates with neuronal LPL protein level and activity. Importantly, our study identified SREBP2, a major regulator of sterol and fatty acid synthesis, as a potential mediator between Parkin and LPL. Supporting this, SREBP2 genetic ablation abolished Parkin effect on LPL expression. We further demonstrate that Parkin-LPL pathway regulates the formation of intracellular lipid droplets, and that this pathway is upregulated upon exposure to PD-linked oxidative stress induced by rotenone. Finally, we show that inhibition of either LPL or SREBP2 exacerbates rotenone-induced cell death. Taken together, our findings reveal a novel pathway linking Parkin, SREBP2 and LPL in neuronal lipid homeostasis that may be relevant to the pathogenesis of PD.
Asunto(s)
Lipoproteína Lipasa , Enfermedad de Parkinson , Proteína 2 de Unión a Elementos Reguladores de Esteroles , Ubiquitina-Proteína Ligasas , Animales , Humanos , Ratones , Homeostasis , Metabolismo de los Lípidos/genética , Metabolismo de los Lípidos/fisiología , Lipoproteína Lipasa/genética , Lipoproteína Lipasa/metabolismo , Ratones Noqueados , Neuronas/metabolismo , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , Rotenona/efectos adversos , Transducción de Señal , Proteína 2 de Unión a Elementos Reguladores de Esteroles/genética , Proteína 2 de Unión a Elementos Reguladores de Esteroles/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
L-type CaV1.3 calcium channels are expressed on the dendrites and soma of neurons, and there is a paucity of information about its role in hippocampal plasticity. Here, by genetic targeting to ablate CaV1.3 RNA editing, we demonstrate that unedited CaV1.3ΔECS mice exhibited improved learning and enhanced long-term memory, supporting a functional role of RNA editing in behavior. Significantly, the editing paradox that functional recoding of CaV1.3 RNA editing sites slows Ca2+-dependent inactivation to increase Ca2+ influx but reduces channel open probability to decrease Ca2+ influx was resolved. Mechanistically, using hippocampal slice recordings, we provide evidence that unedited CaV1.3 channels permitted larger Ca2+ influx into the hippocampal pyramidal neurons to bolster neuronal excitability, synaptic transmission, late long-term potentiation, and increased dendritic arborization. Of note, RNA editing of the CaV1.3 IQ-domain was found to be evolutionarily conserved in mammals, which lends support to the importance of the functional recoding of the CaV1.3 channel in brain function.
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Canales de Calcio Tipo L , Hipocampo , Plasticidad Neuronal , Edición de ARN , Animales , Canales de Calcio Tipo L/genética , Canales de Calcio Tipo L/metabolismo , Hipocampo/metabolismo , Mamíferos/metabolismo , Ratones , Plasticidad Neuronal/genética , Neuronas/metabolismo , Células Piramidales/metabolismoRESUMEN
Ferroptosis has been implicated in several neurological disorders and may be therapeutically targeted. However, the susceptibility to ferroptosis varies in different cells, and inconsistent results have been reported even using the same cell line. Understanding the effects of key variables of in vitro studies on ferroptosis susceptibility is of critical importance to facilitate drug discoveries targeting ferroptosis. Here, we showed that increased cell seeding density leads to enhanced resistance to ferroptosis by reducing intracellular iron levels. We further identified iron-responsive protein 1 (IRP1) as the key protein affected by cell density, which affects the expression of ferroportin or transferrin receptor and results in altered iron levels. Such observations were consistent across different cell lines, indicating that cell density should be tightly controlled in studies of ferroptosis. Since cell densities vary in different brain regions, these results may also shed light on selective regional vulnerability observed in neurological disorders.
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Ferroptosis , Homeostasis , Proteína 1 Reguladora de Hierro , Hierro , Hierro/metabolismo , Ferroptosis/fisiología , Homeostasis/fisiología , Humanos , Proteína 1 Reguladora de Hierro/metabolismo , Proteína 1 Reguladora de Hierro/genética , Recuento de Células , Animales , Receptores de Transferrina/metabolismo , Receptores de Transferrina/genética , Proteínas de Transporte de Catión/metabolismo , Proteínas de Transporte de Catión/genética , RatonesRESUMEN
Tau protein is implicated in the pathogenesis of Alzheimer's disease (AD) and other tauopathies, but its physiological function is in debate. Mostly explored in the brain, tau is also expressed in the pancreas. We further explored the mechanism of tau's involvement in the regulation of glucose-stimulated insulin secretion (GSIS) in islet ß-cells, and established a potential relationship between type 2 diabetes mellitus (T2DM) and AD. We demonstrate that pancreatic tau is crucial for insulin secretion regulation and glucose homeostasis. Tau levels were found to be elevated in ß-islet cells of patients with T2DM, and loss of tau enhanced insulin secretion in cell lines, drosophila, and mice. Pharmacological or genetic suppression of tau in the db/db diabetic mouse model normalized glucose levels by promoting insulin secretion and was recapitulated by pharmacological inhibition of microtubule assembly. Clinical studies further showed that serum tau protein was positively correlated with blood glucose levels in healthy controls, which was lost in AD. These findings present tau as a common therapeutic target between AD and T2DM.
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Enfermedad de Alzheimer , Diabetes Mellitus Tipo 2 , Humanos , Ratones , Animales , Insulina/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Secreción de Insulina , Proteínas tau/metabolismo , Páncreas/metabolismo , Páncreas/patología , Glucosa/metabolismo , Enfermedad de Alzheimer/metabolismoRESUMEN
Over 30 million people suffer from the consequences of ischemic stroke. The precise molecular mechanism of neuronal damage during ischemic stroke remains unclear; therefore, the effective treatment of post-ischemic stroke remains a critical challenge. Recently, iron has emerged as a crucial factor in post-reperfusion injuries, participating in cell peroxidation, excitotoxicity, and a distinctive cell death pathway, namely, ferroptosis. Since iron is tightly regulated in the brain and important for brain functions, the imbalance of its metabolism, including its overload and deficiency, has been shown to impact ischemic stroke outcomes. This review summarizes the current understanding of pathological events associated with iron in ischemic stroke and discusses relevant drug development.
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Ferroptosis , Sobrecarga de Hierro , Accidente Cerebrovascular Isquémico , Humanos , Hierro/metabolismo , Ferroptosis/fisiología , Muerte Celular , Sobrecarga de Hierro/patología , Peroxidación de LípidoRESUMEN
Psoriasis and chronic ulcers not only significantly impair quality of life but also pose a challenge in dermatological treatment. This study aimed to identify new therapeutic targets and biomarkers for psoriasis and chronic ulcers by comparing their gene expression profiles. The gene expression profiles of psoriatic, wound and chronic ulcer patients, as well as healthy controls, were determined via RNA extraction and next-generation sequencing of biopsies. In order to identify biomarkers, functional enrichment, differential expression analysis and machine learning algorithms were implemented. It is worth mentioning that the genes IL17A, TNF, KRT16, MMP9, and CD44 exhibited substantial correlations with the pathogenesis of the conditions being studied. As evidenced by their AUC-ROC values approaching 0.90, machine learning models accurately identified these biomarkers. The differential gene expression was consequently validated via qRT-PCR, which highlighted the increased expression of matrix remodelling enzymes and inflammatory cytokines. Additionally, genes essential for maintaining epidermis integrity and facilitating wound healing exhibited downregulation. These insights into the molecular mechanisms of psoriasis and chronic ulcers pave the way for the development of targeted therapies, offering hope for improved treatment strategies.
RESUMEN
Ischemic stroke caused by arterial occlusion is the most common type of stroke, which is among the most frequent causes of disability and death worldwide. Current treatment approaches involve achieving rapid reperfusion either pharmacologically or surgically, both of which are time-sensitive; moreover, blood flow recanalization often causes ischemia/reperfusion injury. However, even though neuroprotective intervention is urgently needed in the event of stroke, the exact mechanisms of neuronal death during ischemic stroke are still unclear, and consequently, the capacity for drug development has remained limited. Multiple cell death pathways are implicated in the pathogenesis of ischemic stroke. Here, we have reviewed these potential neuronal death pathways, including intrinsic and extrinsic apoptosis, necroptosis, autophagy, ferroptosis, parthanatos, phagoptosis, and pyroptosis. We have also reviewed the latest results of pharmacological studies on ischemic stroke and summarized emerging drug targets with a focus on clinical trials. These observations may help to further understand the pathological events in ischemic stroke and bridge the gap between basic and translational research to reveal novel neuroprotective interventions.
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Isquemia Encefálica , Accidente Cerebrovascular Isquémico , Fármacos Neuroprotectores , Accidente Cerebrovascular , Apoptosis , Isquemia Encefálica/tratamiento farmacológico , Muerte Celular , Humanos , Neuroprotección , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Accidente Cerebrovascular/tratamiento farmacológicoRESUMEN
Selenium (Se) is an essential trace element in organism. Se deficiency can cause many diseases, including vascular disease. Studies have shown that inflammation is the main inducement of vascular disease, microRNA (miRNA) can influence inflammation in various ways, and Se deficiency can affect miRNAs expression. To study the mechanism of aorta damage caused by Se deficiency, we constructed a Se deficiency porcine aorta model and found that Se deficiency can significantly inhibit miR-223, which downregulates the expression of nucleotide-binding oligomerization domain-like receptor family 3 (NLRP3). Subsequently, we found that in Se deficiency group, NLRP3, and its downstream (caspase-1, apoptosis-related spot-like protein [ASC], IL-18, IL-1ß) expression was significantly increased. In vitro, we cultured pig iliac endothelium cell lines, and constructed miR-223 knockdown and overexpression models. NLRP3 messenger RNA and protein levels were significant increased in the knockdown group, and decreased in the overexpression group. The results of this study show that Se deficiency in porcine arteries can induce inflammation through miR-223/NLRP3.
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Aorta/metabolismo , Aortitis/metabolismo , Células Endoteliales/metabolismo , Inflamasomas/metabolismo , MicroARNs/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Selenio/deficiencia , Alimentación Animal , Fenómenos Fisiológicos Nutricionales de los Animales , Animales , Aorta/inmunología , Aorta/patología , Aortitis/genética , Aortitis/inmunología , Aortitis/patología , Proteínas Adaptadoras de Señalización CARD/genética , Proteínas Adaptadoras de Señalización CARD/metabolismo , Caspasa 1/genética , Caspasa 1/metabolismo , Células Cultivadas , Modelos Animales de Enfermedad , Células Endoteliales/inmunología , Células Endoteliales/patología , Inflamasomas/genética , Interleucina-18/genética , Interleucina-18/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , MicroARNs/genética , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Transducción de Señal , Sus scrofaRESUMEN
Calcium ions serve as an important intracellular messenger in many diverse pathways, ranging from excitation coupling in muscles to neurotransmitter release in neurons. Physiologically, the concentration of free intracellular Ca2+ is up to 10,000 times less than that of the extracellular concentration, and increases of 10- to 100-fold in intracellular Ca2+ are observed during signaling events. Voltage-gated calcium channels (VGCCs) located on the plasma membrane serve as one of the main ways in which Ca2+ is able to enter the cell. Given that Ca2+ functions as a ubiquitous intracellular messenger, it is imperative that VGCCs are under tight regulation to ensure that intracellular Ca2+ concentration remains within the physiological range. In this chapter, we explore VGCCs' inherent control of Ca2+ entry as well as the effects of alternative splicing in CaV2.1 and posttranslational modifications of CaV1.2/CaV1.3 such as phosphorylation and ubiquitination. Deviation from this physiological range will result in deleterious effects known as calcium channelopathies, some of which will be explored in this chapter.
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Canales de Calcio , Señalización del Calcio , Encéfalo/metabolismo , Calcio/metabolismo , Canales de Calcio/genética , Canales de Calcio/metabolismo , Canales de Calcio Tipo L/genética , Neuronas/metabolismoRESUMEN
Both elevated iron and α-synuclein (α-syn) aggregates are neuropathological hallmarks of Parkinson's disease (PD). It has been previously shown that iron promotes α-synuclein aggregation, and α-synuclein dysfunction impairs iron metabolism. In their latest work, Kim et al. have shown that the H63D variant of the homeostatic iron regulator (HFE) facilitates α-syn degradation via REDD1-mediated autophagy. Mice with the H63D variant of HFE were protected against α-syn toxicity. These results may shed light on recent clinical studies of PD using iron chelation therapy.
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Enfermedad de Parkinson , alfa-Sinucleína , Animales , Autofagia , Proteína de la Hemocromatosis , Hierro , Cinética , RatonesRESUMEN
Factor VIII (FVIII) functions as a cofactor within the intrinsic pathway of blood coagulation in process of FX activation by FIXa, for which deficiency results in the bleeding disorder hemophilia A. The gene of FVIII contains 26 exons that code for a 19 amino acid signal peptide and a 2332 amino acid polypeptide with a domain structure designated A1-A2-B-A3-C1-C2, of which the A domains are homologous with each other, as are the C domains. It has been well-documented that both the domains are the necessary elements for FVIII activities. The B domain is highly glycosylated and has a variable sequence, even among FVIIIs from different species. The B domain plays versatile roles in FVIII lifespan except for coagulation activity, but the functional characteristics of its specific regions remain still obscure. A series of recombinant FVIIIs (rFVIIIs) with B domain truncated were constructed and transiently expressed in hepatocyte cells. Media and cell lysates were collected after 72 h for the analyses of FVIII biosynthesis, secretion, activity and stability in ex vivo plasma relative to the full length wild-type FVIII. Unexpectedly, various regions in B domain exhibited different contribution to these functionalities. The discovery might facilitate the bioengineered rFVIIIs and gene therapeutics.
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Factor VIII/metabolismo , Hepatocitos/metabolismo , Línea Celular , Exones , Factor VIII/química , Factor VIII/genética , Humanos , Mutación , Dominios Proteicos , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismoRESUMEN
Astilbin (ASB), a dihydroflavonol glycoside, is widely found in a variety of plants and in functional foods and acts as a powerful antioxidant. The aim of this study was to investigate the underlying mechanisms involved in the antagonistic effects of ASB on cadmium (Cd)-induced necroptosis in chicken peripheral blood lymphocytes. Peripheral blood lymphocytes were aseptically collected from Roman white hens and then randomly divided into five groups: the control group was incubated without additional reagents, while the other groups were incubated with Cd, ASB, a combination of Cd and ASB, and 0.1% DMSO. After a 24 h treatment, cell samples were collected. The results showed that some morphological changes consistent with necroptosis were observed in the Cd-treated groups, suggesting the occurrence of necroptosis. Simultaneously, antioxidant activity markers (CAT, SOD, GSH, GSH-px, and T-AOC) decreased and indicators of oxidative stress (MDA, iNOS, NO, H2O2, ·OH and ROS) increased. The production of ROS induced the activation of the PI3K/Akt signaling pathway, as the expression levels of PI3K, Akt and PDK1 were significantly elevated. Additionally, the expression levels of RIPK3, RIPK1, MLKL, TAK1, TAB2 and TAB3 were increased and that of Caspase-8 was decreased, which could cause the necroptosis. However, the most important our results was that ASB supplements remarkably attenuated the Cd-induced effects. We conclude that the Cd treatment promoted an imbalance of the antioxidant status and activated the PI3K/Akt pathway, leading to necroptosis in chicken peripheral blood lymphocytes, and that ASB was able to partially ameliorate the effect of Cd-induced necroptosis.
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Cadmio/toxicidad , Flavonoles/farmacología , Necroptosis/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Animales , Antioxidantes/metabolismo , Cadmio/metabolismo , Pollos/metabolismo , Femenino , Linfocitos/efectos de los fármacos , Linfocitos/enzimología , Linfocitos/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Sustancias Protectoras/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismoRESUMEN
To systematically evaluate the efficacy and safety of Yangwei Granules combined with conventional Western medicine for chronic gastritis. CNKI, SinoMed, WanFang, VIP, PubMed, Cochrane Library and EMbase database were electronically retrieved to collect randomized controlled trial(RCT) of Yangwei Granules combined with conventional Western medicine for chronic gastritis. Two reviewers independently screened out literatures according to the inclusion and exclusion criteria and extracted data, and evaluated the risk of bias of included studies. Meta-analysis was conducted by using RevMan 5.3 software. A total of 12 RCTs involving 1 164 patients were included. The results of Meta-analysis showed that:(1) The total effective rate of Yangwei Granules combined with conventional Western medicine for chronic gastritis was better than that of conventional Western medicine group, with a statistically significant difference(RR=1.24,95%CI[1.17,1.31],P<0.000 01).(2) Compared with the conventional Western medicine group, the Yangwei Granules combined with conventional Western medicine group was conducive to improving the Hp eradication rate, with a statistically significant difference(RR=1.24,95%CI[1.15,1.34],P<0.000 01).(3) The incidence of adverse reactions in Yangwei Granules combined with conventional Western medicine group was lower than that in the control group, but with no statistically significant diffe-rence(RR=0.83, 95%CI[0.39, 1.79], P=0.64).(4) Compared with the conventional Western medicine group, the Yangwei Granules combined with conventional Western medicine group was beneficial to the reduction of motilin level(MD=-17.31,95%CI[-21.83,-12.79],P<0.000 01) and endothelin level(MD=-6.60,95%CI[-10.07,-3.13],P=0.000 2), while the increase of gastrin level(SMD=0.94,95%CI[0.50,1.38],P=0.003) was related to calcitonin gene the level of peptide(MD=5.82,95%CI[4.25,7.39],P<0.000 01), with statistically significant differences.(5) Compared with conventional Western medicine group, Yangwei Granules combined with conventional Western medicine group could increase PGâ (MD=6.40,95%CI[4.26,8.54],P<0.000 01) and PGR(MD=0.89,95%CI[0.71,1.07],P<0.000 01), while decrease PGâ ¡(MD=-1.24,95%CI[-2.15,-0.33],P=0.007), with statistically significant differences. Current evidence showed that the clinical efficacy and Hp eradication rate of Yangwei Granules combined with conventional Western medicine in the treatment of chronic gastritis were better than those of the conventional Western medicine group alone, and could effectively improve the level of gastrointestinal hormones, vasoactive peptide and the pepsinogen level in patients with chronic atrophic gastritis, without increasing the incidence of adverse reactions. However, due to the limited quality and quantity of included studies, the above conclusions need to be confirmed by more large-scale and high-quality RCTs.
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Medicamentos Herbarios Chinos , Gastritis Atrófica , Medicamentos Herbarios Chinos/efectos adversos , Humanos , Resultado del TratamientoRESUMEN
Iron has been proposed to be responsible for neuronal loss in several diseases of the central nervous system, including Alzheimer's disease (AD), Parkinson's disease (PD), stroke, Friedreich's ataxia (FRDA), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS). In many diseases, abnormal accumulation of brain iron in disease-affected area has been observed, without clear knowledge of the contribution of iron overload to pathogenesis. Recent evidences implicate that key proteins involved in the disease pathogenesis may also participate in cellular iron metabolism, suggesting that the imbalance of brain iron homeostasis is associated with the diseases. Considering the complicated regulation of iron homeostasis within the brain, a thorough understanding of the molecular events leading to this phenotype is still to be investigated. However, current understanding has already provided the basis for the diagnosis and treatment of iron-related CNS diseases, which will be reviewed here.
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Trastornos del Metabolismo del Hierro/diagnóstico , Trastornos del Metabolismo del Hierro/terapia , Enfermedades Neurodegenerativas/diagnóstico , Enfermedades Neurodegenerativas/terapia , Homeostasis , Humanos , HierroRESUMEN
This study was conducted to investigate the role of different homocysteine metabolism-related vitamin (HMRV) levels in the correlation between hyperhomocysteinemia (HHCY) and ischemic stroke (IS) subtypes. Three hundred and forty-eight IS patients manifesting different vascular subtypes were subclassified on the basis of HMRV deficiencies. Correlation between HHCY and IS subtypes was investigated in all the subgroups. In this study, HHCY was significantly correlated with the IS subtypes in large artery atherosclerosis (OR 1.126, 95%CI: 1.051 ~ 1.206, P = 0.001) and small artery occlusion (OR 1.105, 95%CI: 1.023 ~ 1.193, P = 0.012). Subgroup analysis revealed a correlation between HHCY and IS subgroup (OR 1.201, 1.178, 95%CI: 1.081 ~ 1.334, 1.058 ~ 1.313, P = 0.001, P = 0.003, respectively) in HMRV deficiency, but not significantly with the IS subgroup in normal HMRV levels. Serum vitamin B12 concentrations are inversely correlated with both IS subtypes in HMRV deficiency subgroups (OR 0.992, 0.995, 95%CI: 0.987 ~ 0.996, 0.991 ~ 0.999, P < 0.001, P = 0.007, respectively), which may contribute to HHCY incidence in these populations. The correlation between HHCY and IS subtypes is affected by HMRV levels in this case-control study. Our findings are helpful to understand the inconsistency in prior homocysteine studies. Serum vitamin B12 levels may play a critical role in HHCY incidence in this Chinese population.Cerebrovascular disease has emerged as the leading cause of disability and mortality in both urban and rural areas of China (Neurology branch of Chinese Medical Association 2015). Ischemic stroke (IS) constitutes 60% to 80% of all cerebrovascular disease (Neurology branch of Chinese Medical Association 2014). Among a variety of risk factors, hyperhomocysteinemia (HHCY) has been closely correlated with IS due to intracranial small-vessel disease and extracranial large-artery disease (Selhub et al. 1995; Eikelboom et al. 2000; Alvarez et al. 2012; Jeon et al. 2014). However, the failure to lower homocysteine (HCY) via homocysteine metabolism-related vitamin (HMRV, including folic acid and vitamin B12 but not vitamin B6 in this study) supplementation to reduce stroke morbidity questions the role of HCY as a risk factor for stroke (Lonn et al. 2006; Hankey et al. 2010). Theoretically, HMRV supplementation merely lowers the incidence of stroke induced by HHCY resulting from HMRV deficiency, whereas HHCY-induced stroke concomitant with normal HMRV levels may be refractory to treatment. The correlation between HCY varying with HMRV levels and IS subtypes is still unclear. In this study, we investigated the impact of variation in HMRV levels on the correlation between HHCY and IS subtypes in 348 acute IS patients with large and small vessel diseases. We sought to determine the factors underlying the conflicting results associated with lowering HCY by HMRV supplementation to reduce stroke incidence.
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Ácido Fólico/sangre , Homocisteína/sangre , Hiperhomocisteinemia/sangre , Arteriosclerosis Intracraneal/sangre , Riñón/fisiología , Accidente Cerebrovascular/sangre , Vitamina B 12/sangre , Anciano , Anciano de 80 o más Años , Pueblo Asiatico , Estudios de Casos y Controles , Trastornos Cerebrovasculares/sangre , Trastornos Cerebrovasculares/diagnóstico por imagen , Trastornos Cerebrovasculares/epidemiología , China/epidemiología , Femenino , Humanos , Hiperhomocisteinemia/diagnóstico por imagen , Hiperhomocisteinemia/epidemiología , Arteriosclerosis Intracraneal/diagnóstico por imagen , Arteriosclerosis Intracraneal/epidemiología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Accidente Cerebrovascular/diagnóstico por imagen , Accidente Cerebrovascular/epidemiologíaRESUMEN
OBJECTIVE: To investigate the relationship between the protein expression of calpain-2 and calcineurin (CaN) and atrial fibrillation (AF) in patient with valvular heart disease (VHD). METHODS: A total of 40 patients who underwent valve replacement surgery in our hospital from March 2013 to March 2014, right atrial appendages were excised during operation and patients were divided into sinus rhythm (SR) group (n = 17) and AF group (n = 23). The protein expression of calpain-2 and the α-isoform of CaN catalytic subunit (CnA) in the right atrial appendages were determined by Western blot. RESULTS: The protein levels of the full-length CnAa (60,000), the 45,000 fragment of CnAa without autoinhibitory domain, and calpain-2 were significantly upregulated in the AF group compared to the SR group (1.25 ± 0.51 vs. 0.76 ± 0.37, 1.08 ± 0.37 vs. 0.76 ± 0.25, and 0.82 ± 0.44 vs. 0.51 ± 0.19, respectively, all P < 0.05). CONCLUSION: Activated calpain-2-CaN signal pathway might be involved in the pathogenesis of AF.
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Apéndice Atrial , Fibrilación Atrial , Enfermedades de las Válvulas Cardíacas , Western Blotting , Calcineurina , Calpaína , Humanos , Regulación hacia ArribaRESUMEN
Gastrointestinal (GI) perforation is a serious adverse event associated with aflibercept, a novel vascular endothelial growth factor (VEGF)-targeted agent currently approved as second-line treatment for previously treated metastatic colorectal cancer, but the incidence and risk of GI perforation associated with aflibercept has not been well determined. We thus conducted this meta-analysis to investigate the overall incidence and risk of developing GI perforation associated with aflibercept. Databases from PubMed, Web of Science, and abstracts presented at American Society of Clinical Oncology (ASCO) and European Society of Medical Oncology (ESMO) meeting up to January, 2014 were searched to identify relevant studies. Eligible studies included prospective phase II and III trials evaluating aflibercept in cancer patients with adequate data on GI perforation. Statistical analyses were conducted to calculate the summary incidence, odds ratio, and 95% confidence intervals (CIs) by using either random effects or fixed effect models according to the heterogeneity of included studies. A total of 4,101 patients with a variety of solid tumors from eight clinical trials were included in our analysis. The incidence of GI perforation associated with aflibercept was 1.9% (95%CI, 1.0-3.8%), with a mortality of 10.8% (95%CI, 4.1-25.5%). In addition, patients treated with aflibercept had a significantly increased risk of developing all-grade (OR 3.76; 95%CI, 1.94-7.25; p < 0.001) and high-grade GI (OR 4.14; 95%CI; 2.12-8.06; p < 0.001) perforation compared with patients treated with control medication. No evidence of publication bias was observed. The use of aflibercept is associated with a significantly increased risk of GI perforation compared to controls.
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Enfermedades Gastrointestinales/inducido químicamente , Perforación Intestinal/inducido químicamente , Neoplasias/tratamiento farmacológico , Receptores de Factores de Crecimiento Endotelial Vascular/efectos adversos , Proteínas Recombinantes de Fusión/efectos adversos , Humanos , Neoplasias/complicaciones , Pronóstico , Factores de RiesgoRESUMEN
OBJECTIVES: The low triiodothyronine (T3) syndrome indicates poor prognosis for patients with cerebral infarction. It is unknown, however, whether basic conditions or severities in the patients with the low T3 syndrome are different compared to those without the low T3 syndrome. METHODS: We compared the risk factors and the severity of the disease using the National Institutes of Health stroke scale (NIHSS) score at the worst condition for cerebral infarction in patients with or without the low T3 syndrome in order to better understand the characteristics underlying the worse prognosis in patients with the low T3 syndrome. RESULTS: We found that cerebral infarction patients with the low T3 syndrome were significantly older (p<0.001) and significantly more likely to be female (p=0.002) and had hypertension (p=0.04) or homocystinemia (p=0.001), but less likely to smoke (p=0.008), compared to patients without the low T3 syndrome. The proportion of NIHSS score ≥8 in the patients with LAA-ICA-associated cerebral infarction accompanied by the low T3 syndrome was significantly higher than in those without the low T3 syndrome (p=0.001). CONCLUSION: We concluded that increased numbers of risk factors for cerebral infarction and more severe neurological deficits may be important causes for worse prognosis in the patients with the low T3 syndrome which may more likely occur in patients with LAA-ICA cerebral infarction. Intense secondary prevention in cerebral infarction especially in older women are needed.
Asunto(s)
Enfermedades de las Arterias Carótidas/complicaciones , Enfermedades de las Arterias Carótidas/diagnóstico , Infarto Cerebral/complicaciones , Infarto Cerebral/diagnóstico , Síndromes del Eutiroideo Enfermo/complicaciones , Síndromes del Eutiroideo Enfermo/diagnóstico , Enfermedades del Sistema Nervioso/diagnóstico , Anciano , Anciano de 80 o más Años , Enfermedades de las Arterias Carótidas/epidemiología , Arteria Carótida Interna/patología , Infarto Cerebral/epidemiología , Síndromes del Eutiroideo Enfermo/epidemiología , Femenino , Humanos , Pacientes Internos/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Enfermedades del Sistema Nervioso/epidemiología , Enfermedades del Sistema Nervioso/etiología , Pronóstico , Índice de Severidad de la EnfermedadRESUMEN
Sterol regulatory element-binding proteins (SREBPs) belong to a family of nuclear transcription factors. The question of which is the most important positive regulator in milk fat synthesis in dairy cow mammary epithelial cells (DCMECs) between SREBPs or other nuclear transcription factors, such as peroxisome proliferator-activated receptor γ (PPARγ), remains a controversial one. Recent studies have found that mTORC1 (the mammalian target of rapamycin C1) regulates SREBP1 to promote fat synthesis. Thus far, however, the interaction between the SREBP1 and mTOR (the mammalian target of rapamycin) pathways in the regulation of milk fat synthesis remains poorly understood. This study aimed to identify the function of SREBP1 in milk fat synthesis and to characterize the relationship between SREBP1 and mTOR in DCMECs. The effects of SREBP1 overexpression and gene silencing on milk fat synthesis and the effects of stearic acid and serum on SREBP1 expression in the upregulation of milk fat synthesis were investigated in DCMECs using immunostaining, Western blotting, real-time quantitative PCR, lipid droplet staining, and detection kits for triglyceride content. SREBP1 was found to be a positive regulator of milk fat synthesis and was shown to be regulated by stearic acid and serum. These findings indicate that SREBP1 is the key positive regulator in milk fat synthesis.
Asunto(s)
Bovinos/metabolismo , Lípidos/biosíntesis , Glándulas Mamarias Animales/metabolismo , Leche/metabolismo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/fisiología , Animales , Células Cultivadas , Medio de Cultivo Libre de Suero/farmacología , Células Epiteliales/metabolismo , Proteínas de Unión a Ácidos Grasos/biosíntesis , Proteínas de Unión a Ácidos Grasos/genética , Femenino , Proteínas de la Leche/biosíntesis , Proteínas de la Leche/genética , Interferencia de ARN , ARN Mensajero/biosíntesis , ARN Mensajero/genética , ARN Interferente Pequeño/farmacología , Proteínas Recombinantes/metabolismo , Suero , Ácidos Esteáricos/farmacología , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/antagonistas & inhibidores , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genética , Serina-Treonina Quinasas TOR/fisiología , Transfección , Triglicéridos/biosíntesisRESUMEN
The airlift external circulation membrane bioreactor (AEC-MBR) is a new MBR consisting of a separated aeration tank and membrane tank with circulating pipes fixed between the two tanks. The circulating pipe is called a H circulating pipe (HCP) because of its shape. With the complex configuration, it was difficult but necessary to master the AEC-MBR's hydraulic characteristics. In this paper, simulation and optimization of the AEC-MBR was performed using computational fluid dynamics. The distance from diffusers to membrane modules, i.e. the height of gas-liquid mixing zone (h(m)), and its effect on velocity distribution at membrane surfaces were studied. Additionally, the role of HCP and the effect of HCP's diameter on circulation were simulated and analyzed. The results showed that non-uniformity of cross-flow velocity existed in the flat-plate membrane modules, and the problem could be alleviated by increasing hm to an optimum range (h(m)/B ≥ 0.55; B is total static depth). Also, the low velocity in the boundary layer on the membrane surface was another reason for membrane fouling. The results also suggested that HCP was necessary and it had an optimum diameter to make circulation effective in the AEC-MBR.