RESUMEN
Cholesterol is highly enriched at the plasma membrane (PM), and lipid transfer proteins may deliver cholesterol to the PM in a nonvesicular manner. Here, through a mini-screen, we identified the oxysterol binding protein (OSBP)-related protein 2 (ORP2) as a novel mediator of selective cholesterol delivery to the PM. Interestingly, ORP2-mediated enrichment of PM cholesterol was coupled with the removal of phosphatidylinositol 4, 5-bisphosphate (PI(4,5)P2) from the PM. ORP2 overexpression or deficiency impacted the levels of PM cholesterol and PI(4,5)P2, and ORP2 efficiently transferred both cholesterol and PI(4,5)P2in vitro. We determined the structure of ORP2 in complex with PI(4,5)P2 at 2.7 Å resolution. ORP2 formed a stable tetramer in the presence of PI(4,5)P2, and tetramerization was required for ORP2 to transfer PI(4,5)P2. Our results identify a novel pathway for cholesterol delivery to the PM and establish ORP2 as a key regulator of both cholesterol and PI(4,5)P2 of the PM.
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Membrana Celular/metabolismo , Colesterol/metabolismo , Hepatocitos/metabolismo , Fosfatidilinositol 4,5-Difosfato/metabolismo , Receptores de Esteroides/metabolismo , Transporte Biológico , Línea Celular Tumoral , Células HEK293 , Humanos , Modelos Moleculares , Multimerización de Proteína , Estructura Cuaternaria de Proteína , Receptores de Esteroides/química , Receptores de Esteroides/genética , Relación Estructura-ActividadRESUMEN
BACKGROUND: Postoperative cognitive dysfunction (POCD) is a common complication after anesthesia/surgery, especially among elderly patients, and poses a significant threat to their postoperative quality of life and overall well-being. While it is widely accepted that elderly patients may experience POCD following anesthesia/surgery, the exact mechanism behind this phenomenon remains unclear. Several studies have indicated that the interaction between silent mating type information regulation 2 homologue 1 (SIRT1) and brain-derived neurotrophic factor (BDNF) is crucial in controlling cognitive function and is strongly linked to neurodegenerative disorders. Hence, this research aims to explore how SIRT1/BDNF impacts cognitive decline caused by anesthesia/surgery in aged mice. METHODS: Open field test (OFT) was used to determine whether anesthesia/surgery affected the motor ability of mice, while the postoperative cognitive function of 18 months old mice was evaluated with Novel object recognition test (NORT), Object location test (OLT) and Fear condition test (FC). The expressions of SIRT1 and other molecules were analyzed by western blot and immunofluorescence staining. The hippocampal synaptic plasticity was detected by Golgi staining and Long-term potentiation (LTP). The effects of SIRT1 and BDNF overexpression as well as chemogenetic activation of glutamatergic neurons in hippocampal CA1 region of 18 months old vesicular glutamate transporter 1 (VGLUT1) mice on POCD were further investigated. RESULTS: The research results revealed that older mice exhibited cognitive impairment following intramedullary fixation of tibial fracture. Additionally, a notable decrease in the expression of SIRT1/BDNF and neuronal excitability in hippocampal CA1 glutamatergic neurons was observed. By increasing levels of SIRT1/BDNF or enhancing glutamatergic neuron excitability in the CA1 region, it was possible to effectively mitigate synaptic plasticity impairment and ameliorate postoperative cognitive dysfunction. CONCLUSIONS: The decline in SIRT1/BDNF levels leading to changes in synaptic plasticity and neuronal excitability in older mice could be a significant factor contributing to cognitive impairment after anesthesia/surgery.
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Factor Neurotrófico Derivado del Encéfalo , Región CA1 Hipocampal , Regulación hacia Abajo , Plasticidad Neuronal , Neuronas , Complicaciones Cognitivas Postoperatorias , Sirtuina 1 , Animales , Sirtuina 1/metabolismo , Sirtuina 1/genética , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Factor Neurotrófico Derivado del Encéfalo/genética , Ratones , Neuronas/metabolismo , Complicaciones Cognitivas Postoperatorias/metabolismo , Complicaciones Cognitivas Postoperatorias/etiología , Región CA1 Hipocampal/metabolismo , Masculino , Ratones Endogámicos C57BL , Potenciación a Largo Plazo , Ácido Glutámico/metabolismo , Disfunción Cognitiva/etiología , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/fisiopatologíaRESUMEN
Though the evidence for antibiotic resistance spread via plant microbiome is mounting, studies regarding antibiotic resistome in the plant seed, a reproductive organ and important food resource, are still in their infancy. This study investigated the effects of long-term organic fertilization on seed bacterial endophytes, resistome, and their intergenerational transfer in the microcosm. A total of 99 antibiotic resistance genes (ARGs) and 26 mobile genetic elements (MGEs) were detected by high-throughput quantitative PCR. The amount of organic fertilizer applied was positively correlated to the number and relative abundance of seed-associated ARGs and MGEs. Moreover, the transmission of ARGs from the rhizosphere to the seed was mainly mediated by the shared bacteria and MGEs. Notably, the rhizosphere of progeny seedlings derived from seeds harboring abundant ARGs was found to have a higher relative abundance of ARGs. Using structural equation models, we further revealed that seed resistome and MGEs were key factors affecting the ARGs in the progeny rhizosphere, implying the seed was a potential resistome reservoir for rhizosphere soil. This study highlights the overlooked role of seed endophytes in the dissemination of resistome in the soil-plant continuum, and more attention should be paid to plant seeds as vectors of ARGs within the "One-Health" framework.
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Antibacterianos , Genes Bacterianos , Antibacterianos/farmacología , Suelo/química , Farmacorresistencia Microbiana/genética , Bacterias/genética , Semillas/química , Microbiología del Suelo , EstiércolRESUMEN
Alcohol consumption causes renal injury and compromises kidney function. The underlying mechanism of the alcoholic kidney disease remains largely unknown. In the present study, an alcoholic renal fibrosis animal model was first employed which mice received liquid diet containing alcohol for 4 to 12 weeks. The Masson's Trichrome staining analysis showed that kidney fibrosis increased at week 8 and 12 in the animal model that was further confirmed by albumin assay, Western blot, immunostaining and real-time PCR of fibrotic indexes (collagen I and α-SMA). In vitro analysis also confirmed that alcohol significantly induced fibrotic response (collagen I and α-SMA) in HK2 tubular epithelial cells. Importantly, both in vivo and in vitro studies showed alcohol treatments decreased Smad7 and activated Smad3. We further determined how the alcohol affected the balance of Smad7 (inhibitory Smad) and Smad3 (regulatory Smad). Genome-wide methylation sequencing showed an increased DNA methylation of many genes and bisulfite sequencing analysis showed an increased DNA methylation of Smad7 after alcohol ingestion. We also found DNA methylation of Smad7 was mediated by DNMT1 in ethyl alcohol (EtOH)-treated HK2 cells. Knockdown of Nox2 or Nox4 decreased DNMT1 and rebalanced Smad7/Smad3 axis, and thereby relieved EtOH-induced fibrotic response. The inhibition of reactive oxygen species by the intraperitoneal injection of apocynin attenuated renal fibrosis and restored renal function in the alcoholic mice. Collectively, we established novel in vivo and in vitro alcoholic kidney fibrosis models and found that alcohol induces renal fibrosis by activating oxidative stress-induced DNA methylation of Smad7. Suppression of Nox-mediated oxidative stress may be a potential therapy for long-term alcohol abuse-induced kidney fibrosis.
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Metilación de ADN/genética , Etanol/efectos adversos , Enfermedades Renales/genética , NADPH Oxidasa 2/metabolismo , NADPH Oxidasa 4/metabolismo , Proteína smad7/metabolismo , Acetofenonas/farmacología , Animales , Línea Celular , ADN (Citosina-5-)-Metiltransferasa 1/metabolismo , Metilación de ADN/efectos de los fármacos , Modelos Animales de Enfermedad , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Fibrosis , Humanos , Riñón/efectos de los fármacos , Riñón/patología , Enfermedades Renales/patología , Túbulos Renales/patología , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Ratones Endogámicos C57BL , Modelos Biológicos , Especies Reactivas de Oxígeno/metabolismo , Reproducibilidad de los Resultados , Transducción de Señal/efectos de los fármacos , Proteína smad3/metabolismo , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
BACKGROUND: Bilateral medial medullary infarction (MMI) is uncommon and bilateral medial pons infarction (MPI) is even rarer. "Heart appearance" on magnetic resonance imaging (MRI) is a characteristic presentation of bilateral medial medullary infarction (MMI). CASE PRESENTATION: We present 67-year-old Chinese diabetic and hypertensive female patient affected with "heart appearance-like" infarction in bilateral ponto-medullary junction on MRI. Abnormal signal was observed in the bilateral ponto-medullary junction on T1, T2, fluid-attenuated inversion recovery and apparent diffusion coefficient (ADC). The whole brain digital subtraction angiography (DSA) showed the basilar artery and vertebral artery remained intact. Therefore, we speculated that the bilateral ponto-medullary junction infarction might be caused by the deep perforating branch of the basilar artery. CONCLUSIONS: As far as we know, the "heart appearance-like" infraction in bilateral ponto-medullary junction was not reported. Our case also suggests that bilateral ischemic infraction involvement of the medulla and pon is possible even in the context of an intact basilar artery.
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Infartos del Tronco Encefálico/patología , Imagen por Resonancia Magnética , Bulbo Raquídeo/patología , Anciano , Angiografía de Substracción Digital , Arteria Basilar/patología , Encéfalo/patología , Humanos , Masculino , Puente/patología , Arteria Vertebral/patologíaRESUMEN
Obstructive nephropathy is the end result of a variety of diseases that block drainage from the kidney(s). Transforming growth factor-ß1 (TGF-ß1)/Smad3-driven renal fibrosis is the common pathogenesis of obstructive nephropathy. In this study, we identified petchiether A (petA), a novel small-molecule meroterpenoid from Ganoderma, as a potential inhibitor of TGF-ß1-induced Smad3 phosphorylation. The obstructive nephropathy was induced by unilateral ureteral obstruction (UUO) in mice. Mice received an intraperitoneal injection of petA/vehicle before and after UUO or sham operation. An in vivo study revealed that petA protected against renal inflammation and fibrosis by reducing the infiltration of macrophages, inhibiting the expression of proinflammatory cytokines (interleukin-1ß and tumour necrosis factor-α) and reducing extracellular matrix deposition (α-smooth muscle actin, collagen I and fibronectin) in the obstructed kidney of UUO mice; these changes were associated with suppression of Smad3 and NF-κB p65 phosphorylation. Petchiether A inhibited Smad3 phosphorylation in vitro and down-regulated the expression of the fibrotic marker collagen I in TGF-ß1-treated renal epithelial cells. Further, we found that petA dose-dependently suppressed Smad3-responsive promoter activity, indicating that petA inhibits gene expression downstream of the TGF-ß/Smad3 signalling pathway. In conclusion, our findings suggest that petA protects against renal inflammation and fibrosis by selectively inhibiting TGF-ß/Smad3 signalling.
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Enfermedades Renales/tratamiento farmacológico , Enfermedades Renales/metabolismo , FN-kappa B/metabolismo , Transducción de Señal , Proteína smad3/metabolismo , Terpenos/uso terapéutico , Factor de Crecimiento Transformador beta/metabolismo , Actinas/metabolismo , Animales , Línea Celular , Colágeno/metabolismo , Fibronectinas/metabolismo , Fibrosis , Humanos , Inflamación/patología , Riñón/lesiones , Riñón/patología , Enfermedades Renales/patología , Masculino , Ratones Endogámicos C57BL , Fosforilación , Terpenos/química , Terpenos/farmacología , Terpenos/toxicidad , Obstrucción Ureteral/tratamiento farmacológico , Obstrucción Ureteral/patologíaRESUMEN
To investigate the mechanism of different exercise patterns on neurological function after focal cerebral ischaemia in rats. Rats with focal cerebral cerebral ischaemia were randomly divided into an aerobic exercise group, an exhaustive exercise group and a control group, with 8 rats in each group. A score for nerve function in each group was calculated, and the ultrastructure of nerve cells was observed. Levels of NO and NOS in the brain motor area of the âârats were measured in each group. The aerobic exercise group had lower nerve function scores than the exhaustive exercise group and higher scores than the control group (P<0.05). Under transmission electron microscopy, irregular shapes and organs were observed in nerve cells in the control group, while regular cell shapes and organs were observed in the aerobic exercise group. The aerobic exercise group and exhaustive exercise group had higher measures of NO content, NOS activity and eNOS, nNOS and iNOS gene expression than the control group, but eNOS expression in the aerobic exercise group and iNOS expression in the exhaustive exercise group were clearly higher according to RT-PCR (P<0.05). Aerobic exercise can promote the expression of NOS, mainly in eNOS, which can promote nerve repair.
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Isquemia Encefálica/fisiopatología , Regeneración Nerviosa/fisiología , Óxido Nítrico/fisiología , Condicionamiento Físico Animal/métodos , Animales , Isquemia Encefálica/terapia , Modelos Animales de Enfermedad , Masculino , Óxido Nítrico Sintasa de Tipo III/metabolismo , Ratas Sprague-DawleyRESUMEN
The goal of this study was to elucidate the functional role of Nox4 during acute kidney injury (AKI). NADPH oxidases are a major source of reactive oxygen species (ROS) in the kidney in normal and pathological conditions. Among NADPH oxidase isoforms, NADPH oxidase4 (Nox4) is highly expressed in the kidney and has an important role in kidney diseases, such as diabetic nephropathy and renal carcinoma. We previously found that Nox4 expression significantly increased in the toxic AKI model. However, its functional role and mechanism of action in AKI are still unknown. We scavenged ROS with apocynin in vitro and in vivo and found it attenuated cisplatin-triggered renal function decline. It also alleviated programmed cell death and renal inflammation, indicating a critical role for ROS in mediating AKI. Nox4 protein and mRNA levels were substantially upregulated by cisplatin in vivo and in vitro. Nox4 knockdown alleviated cisplatin-induced cell death and inflammatory response, while Nox4 overexpression aggravated them. Moreover, N-acetyl-L-cysteine (NAC)-mediated inhibition of ROS suppressed cell injury led by Nox4 overexpression, indicating Nox4-mediated ROS generation may be the key mediator in cisplatin-induced nephrotoxicity. Mechanistically, excessive expression of Nox4 induced programmed cell death, especially RIP-mediated necroptosis. Finally, we tested whether Nox4 is a potential therapeutic target using an AKI mouse model by injecting a lentivirus-packaged Nox4 shRNA plasmid through tail vein. Disruption of Nox4 led to renal function recovery, kidney damage relief and reduced inflammation. We conclude that Nox4 aggravates cisplatin-induced nephrotoxicity by promoting ROS-mediated programmed cell death and inflammation. Thus Nox4 may serve as a potential therapeutic target in the treatment of AKI.
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Lesión Renal Aguda/inducido químicamente , Antineoplásicos/efectos adversos , Cisplatino/efectos adversos , Modelos Animales de Enfermedad , Riñón/efectos de los fármacos , NADPH Oxidasa 4/metabolismo , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/patología , Lesión Renal Aguda/prevención & control , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Transformada , Células Cultivadas , Cisplatino/antagonistas & inhibidores , Cisplatino/farmacología , Depuradores de Radicales Libres/farmacología , Depuradores de Radicales Libres/uso terapéutico , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Riñón/inmunología , Riñón/metabolismo , Riñón/patología , Túbulos Renales/efectos de los fármacos , Túbulos Renales/inmunología , Túbulos Renales/metabolismo , Túbulos Renales/patología , Masculino , Ratones , Ratones Endogámicos C57BL , NADPH Oxidasa 4/antagonistas & inhibidores , NADPH Oxidasa 4/genética , Estrés Oxidativo/efectos de los fármacos , Interferencia de ARN , Especies Reactivas de Oxígeno/agonistas , Especies Reactivas de Oxígeno/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismoRESUMEN
Acute kidney injury (AKI), characterized by aggressive inflammatory responses and destruction of renal resident cells, can cause abrupt kidney dysfunction. To date, effective therapy for AKI is lacking. In this study, we evaluated the renoprotective effect of wogonin, an herbal active compound, using a cisplatin-induced AKI mouse model. In vivo results show that wogonin substantially suppressed the increased levels of serum creatinine and blood urea nitrogen (BUN) almost to the normal level. Wogonin also attenuated tubular damage, shown by PAS staining, electron microscopy and molecular analysis of KIM-1. In addition, wogonin suppressed kidney inflammation as indicated by a >60% decrease in macrophage infiltration, a >50% reduction in inflammatory cytokine production and inhibited NF-κB activation in the injured kidney. Mechanistically, molecular docking results show that wogonin effectively inhibited RIPK1 by occupying the ATP-binding pocket of the enzyme, which is a key regulator of necroptosis. Moreover, inhibition of RIPK1, or RIPK3, reversed the protective effects of wogonin in cisplatin-treated HK2 cells, indicating wogonin works in a RIPK1/RIPK3-dependent manner. Surprisingly, wogonin enhanced the anti-proliferative effect of cisplatin on human hepatoma HepG2 cells. Thus, our findings suggest wogonin may be a renoprotective adjuvant for cisplatin-based anticancer therapy.
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Lesión Renal Aguda/prevención & control , Antineoplásicos/efectos adversos , Apoptosis/efectos de los fármacos , Cisplatino/efectos adversos , Flavanonas/uso terapéutico , Riñón/efectos de los fármacos , Sustancias Protectoras/uso terapéutico , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/patología , Animales , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/metabolismo , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/uso terapéutico , Antineoplásicos/química , Antineoplásicos/farmacología , Sitios de Unión , Biomarcadores/sangre , Biomarcadores/metabolismo , Dominio Catalítico , Línea Celular Transformada , Línea Celular Tumoral , Cisplatino/antagonistas & inhibidores , Cisplatino/farmacología , Flavanonas/química , Flavanonas/metabolismo , Flavanonas/farmacología , Humanos , Riñón/inmunología , Riñón/metabolismo , Riñón/patología , Túbulos Renales/efectos de los fármacos , Túbulos Renales/inmunología , Túbulos Renales/metabolismo , Túbulos Renales/ultraestructura , Activación de Macrófagos/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Microscopía Electrónica de Transmisión , Simulación del Acoplamiento Molecular , Sustancias Protectoras/química , Sustancias Protectoras/metabolismo , Sustancias Protectoras/farmacología , Interferencia de ARN , Proteína Serina-Treonina Quinasas de Interacción con Receptores/antagonistas & inhibidores , Proteína Serina-Treonina Quinasas de Interacción con Receptores/química , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismoRESUMEN
E-cadherin is a major component of tubular adherent proteins that maintain intercellular contacts and cell polarity in epithelial tissue. It is involved in pathological processes of renal cell carcinoma and fibrotic diseases via epithelial-mesenchymal transition. Although studies have shown E-cadherin is significantly downregulated in acute kidney injury (AKI), its function in AKI is unknown. Here, we evaluated cell damage and inflammation in cisplatin-stimulated tubular epithelial cell lines after disrupting E-cadherin and restoring it with PPBICA, a small molecule identified by high-throughput screening. We also determined the therapeutic potential of restoring E-cadherin in vivo. Results show cisplatin reduced E-cadherin expression both in mouse kidney and proximal tubular epithelial cell lines (mTECs). PPBICA restored E-cadherin levels, which increased cell viability while attenuating programmed cell death. This may be mediated via deactivation of the RIPK1/RIPK3 axis and decreased caspase3 cleavage. In addition, PPBICA suppressed inflammatory response in cisplatin-treated mTECs, which correlated with suppressed NF-κB phosphorylation and promoter activity. In contrast, disruption of E-cadherin promoted cell damage and inflammation. PPBICA failed to further attenuate kidney damage in E-cadherin knockdown cells, indicating that PPBICA protects against mTECs through E-cadherin restoration. We also found that peritoneal injection of PPBICA in mice prevented loss of renal function and tubular damage by suppressing NF-κB-driven renal inflammation and RIPK-regulated programmed cell death. This was driven by restoration of E-cadherin in cisplatin nephropathy. Additionally, PPBICA attenuated cisplatin-induced kidney damage in an established AKI model, indicating its therapeutic potential in the treatment of AKI. In conclusion, E-cadherin plays functional roles in tubule integrity, programmed cell death, and renal inflammation. Our results underscore the potential of E-cadherin restoration as a novel therapeutic strategy for AKI.
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Lesión Renal Aguda/inducido químicamente , Cadherinas/metabolismo , Cisplatino/efectos adversos , Sustancias Protectoras/farmacología , Bibliotecas de Moléculas Pequeñas/farmacología , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/patología , Animales , Apoptosis/efectos de los fármacos , Línea Celular , Modelos Animales de Enfermedad , Inflamación/metabolismo , Riñón/citología , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
OBJECTIVES: The purpose of this study was to investigate the changes in the morphologic characteristics and performance of the right atrium (RA) that occur secondary to structural remodeling of the right ventricle (RV) in patients with pulmonary hypertension by real-time 3-dimensional echocardiography (3DE). METHODS: Comprehensive 2-dimensional echocardiography and real-time 3DE were performed in 112 patients and 30 healthy control participants. Patients with pulmonary hypertension were divided into 3 subgroups: 1, normal RV dimension (n = 34); 2, RV enlargement and preserved systolic function (n = 36); and 3, RV enlargement and systolic dysfunction (n = 42). RESULTS: Patients had larger RA volume parameters and lower RA passive emptying fractions than controls (P< .01). The RA active emptying fraction was higher in patient groups 1 (mean ± SD, 45.5% ± 10.7%) and 2 (40.1% ± 4.0%) and lower in group 3 (19.3% ± 4.3%) compared to controls (35.4% ± 3.5%). The RA total emptying fraction was similar between groups 1 and 2 (59.3% ± 9.7% and 52.6% ± 3.4%, respectively) but was significantly lower in group 3 compared to controls (26.8% ± 5.1% versus 55.2% ± 5.1%). Right atrial volume and phasic function were substantially affected by RV structure and function. CONCLUSIONS: Real-time 3DE is a feasible, repeatable, and noninvasive method for accessing cyclic RA volume and function changes, such as those that occur with varying RV status in patients with pulmonary hypertension.
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Ecocardiografía Tridimensional/métodos , Atrios Cardíacos/diagnóstico por imagen , Hipertensión Pulmonar/complicaciones , Hipertensión Pulmonar/diagnóstico por imagen , Disfunción Ventricular Derecha/diagnóstico por imagen , Disfunción Ventricular Derecha/etiología , Sistemas de Computación , Estudios de Factibilidad , Femenino , Humanos , Aumento de la Imagen/métodos , Interpretación de Imagen Asistida por Computador/métodos , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
Based on the usual Wigner-Weyl transformation theory we find that the Wigner hyperbolic rotation in phase space will map onto fractional squeezing operator in Hilbert space. The merit of Weyl ordering and the coherent state representation of Fresnel operator is used in our derivation.
RESUMEN
The mechanism of ketamine-induced neurotoxicity development remains elusive. Mitochondrial fusion/fission dynamics play a critical role in regulating neurogenesis. Therefore, this study was aimed to evaluate whether mitochondrial dynamics were involved in ketamine-induced impairment of neurogenesis in neonatal rats and long-term synaptic plasticity dysfunction. In the in vivo study, postnatal day 7 (PND-7) rats received intraperitoneal (i.p.) injection of 40 mg/kg ketamine for four consecutive times at 1 h intervals. The present findings revealed that ketamine induced mitochondrial fusion dysfunction in hippocampal neural stem cells (NSCs) by downregulating Mitofusin 2 (Mfn2) expression. In the in vitro study, ketamine treatment at 100 µM for 6 h significantly decreased the Mfn2 expression, and increased ROS generation, decreased mitochondrial membrane potential and ATP levels in cultured hippocampal NSCs. For the interventional study, lentivirus (LV) overexpressing Mfn2 (LV-Mfn2) or control LV vehicle was microinjected into the hippocampal dentate gyrus (DG) 4 days before ketamine administration. Targeted Mfn2 overexpression in the DG region could restore mitochondrial fusion in NSCs and reverse the inhibitory effect of ketamine on NSC proliferation and its faciliatory effect on neuronal differentiation. In addition, synaptic plasticity was evaluated by transmission electron microscopy, Golgi-Cox staining and long-term potentiation (LTP) recordings at 24 h after the end of the behavioral test. Preconditioning with LV-Mfn2 improved long-term cognitive dysfunction after repeated neonatal ketamine exposure by reversing the inhibitory effect of ketamine on synaptic plasticity in the hippocampal DG. The present findings demonstrated that Mfn2-mediated mitochondrial fusion dysfunction plays a critical role in the impairment of long-term neurocognitive function and synaptic plasticity caused by repeated neonatal ketamine exposure by interfering with hippocampal neurogenesis. Thus, Mfn2 might be a novel therapeutic target for the prevention of the developmental neurotoxicity of ketamine.
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Animales Recién Nacidos , Cognición , GTP Fosfohidrolasas , Hipocampo , Ketamina , Dinámicas Mitocondriales , Células-Madre Neurales , Neurogénesis , Ratas Sprague-Dawley , Animales , Masculino , Ratas , Anestesia/efectos adversos , Cognición/efectos de los fármacos , GTP Fosfohidrolasas/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/patología , Ketamina/administración & dosificación , Ketamina/efectos adversos , Ketamina/toxicidad , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Dinámicas Mitocondriales/efectos de los fármacos , Proteínas Mitocondriales , Células-Madre Neurales/efectos de los fármacos , Células-Madre Neurales/metabolismo , Neurogénesis/efectos de los fármacos , Plasticidad Neuronal/efectos de los fármacosRESUMEN
OBJECTIVE: Qiliqiangxin (QLQX) capsule- a traditional Chinese medicine used for treating heart failure (HF), can modulate inflammatory cytokines in rats with myocardial infarction. However, its immune-regulating effect on dilated cardiomyopathy (DCM) remains unknown. The aim of this study was to investigate whether QLQX has a unique regulatory role in the imbalance of pro- and anti-inflammatory cytokines in patients with DCM. METHODS: The QLQX-DCM is a randomized- double-blind trial conducted at 24 tertiary hospitals in China. A total of 345 patients with newly diagnosed virus-induced DCM were randomly assigned to receive QLQX capsules or placebo while receiving optimal medical therapy for HF. The primary endpoints were changes in plasma inflammatory cytokines and improvements in left ventricular ejection fraction (LVEF) and left ventricular end-diastolic diameter (LVEDd) over the 12-month treatment. RESULTS: At the 12-month follow-up, the levels of IFN-γ, IL-17, TNF-α, and IL-4 decreased significantly, while the level of IL-10 increased in both groups compared with baselines (all P<0.0001). Furthermore-these changes, coupled with improvements in LVEF, NT-proBNP and New York Heart Association (NYHA) functional classification, excluding the LVEDd in the QLQX group, were greater than those in the placebo group (all P<0.001). Additionally, compared with placebo, QLQX treatment also reduced all-cause mortality and rehospitalization rates by 2.17% and 2.28%, respectively, but the difference was not statistically significant. CONCLUSION: QLQX has the potential to alleviate the imbalance of inflammatory cytokines in patients with DCM, potentially leading to further improvements in cardiac function when combined with anti-HF standard medications.
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The phyllosphere is a vital yet often neglected habitat hosting diverse microorganisms with various functions. However, studies regarding how the composition and functions of the phyllosphere microbiome respond to agricultural practices, like nitrogen fertilization, are limited. This study investigated the effects of long-term nitrogen fertilization with different levels (CK, N90, N210, N330) on the functional genes and pathogens of the rice phyllosphere microbiome. Results showed that the relative abundance of many microbial functional genes in the rice phyllosphere was significantly affected by nitrogen fertilization, especially those involved in C fixation and denitrification genes. Different nitrogen fertilization levels have greater effects on fungal communities than bacteria communities in the rice phyllosphere, and network analysis and structural equation models further elucidate that fungal communities not only changed bacterial-fungal inter-kingdom interactions in the phyllosphere but also contributed to the variation of biogeochemical cycle potential. Besides, the moderate nitrogen fertilization level (N210) was associated with an enrichment of beneficial microbes in the phyllosphere, while also resulting in the lowest abundance of pathogenic fungi (1.14 %). In contrast, the highest abundance of pathogenic fungi (1.64 %) was observed in the highest nitrogen fertilization level (N330). This enrichment of pathogen due to high nitrogen level was also regulated by the fungal communities, as revealed through SEM analysis. Together, we demonstrated that the phyllosphere fungal communities were more sensitive to the nitrogen fertilization levels and played a crucial role in influencing phyllosphere functional profiles including element cycling potential and pathogen abundance. This study expands our knowledge regarding the role of phyllosphere fungal communities in modulating the element cycling and plant health in sustainable agriculture.
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Fertilizantes , Hongos , Nitrógeno , Oryza , Oryza/microbiología , Hongos/fisiología , Micobioma , Agricultura , Microbiota , Hojas de la Planta/microbiologíaRESUMEN
OBJECTIVE: To evaluate the efficacy and safety of cardiac resynchronization therapy (CRT) alone or in combination with implantable cardioversion defibrillation (ICD) in patients with mild to severe heart failure. METHOD: Electronic searches of MEDLINE, EMBASE, CENTREN and affiliated clinical trial registration data center, US Food and Drug Administration reports, CBMdisc, VIP, and CNKI databases from establishment to Dec 2010, using the search terms "CRT, heart failure", "biventricular pacer, heart failure", "biventricular pacing, heart failure", and "biventricular pacemaker, heart failure", were performed to identify randomized controlled trials (RCTs). Meta-analysis was performed by using RevMan 5.0 software after the strict evaluation of the methodological quality of the included RCTs. RESULTS: A total of 23 trials including 8521 patients were included. In patients with New York Heart Association (NYHA) class I/II, CRT improved left ventricular ejection fraction (LVEF) [weighted mean difference (WMD) = 0.05, 95% CI 0.01 - 0.08], reduced heart failure hospitalizations [risk ratio (RR) = 0.70, 95%CI 0.61 - 0.81] and all-cause mortality (RR = 0.78, 95%CI 0.65 - 0.93) with increasing complications (RR = 1.74, 95%CI 1.42 - 2.13). In patients with NYHA class III/IV, CRT improved LVEF (WMD = 0.03, 95%CI 0.01 - 0.05), reduced both heart failure hospitalizations (RR = 0.64, 95%CI 0.55 - 0.73) and all-cause mortality (RR = 0.80, 95%CI 0.70 - 0.91) without increasing complications (RR = 1.01, 95%CI 0.91 - 1.12). Compared with ICD alone, CRT in combination with ICD significantly improved LVEF (WMD = 0.03, 95%CI 0.00 - 0.06), reduced heart failure hospitalizations (RR = 0.73, 95%CI 0.64 - 0.82) and all-cause mortality (RR = 0.82, 95%CI 0.72 - 0.95) without increasing complications (RR = 1.36, 95%CI 0.91 - 2.03) in patients with NYHA class I-IV symptoms. CONCLUSIONS: CRT offered additional benefits on top of standard medication for heart failure patients with ventricular dyssynchrony in terms of improving LV function, and reducing heart failure hospitalization and all-cause mortality, regardless of NYHA class. CRT offers also additional benefit in heart failure patients implanted with ICD. However, CRT is associated with more adverse events in patients with NYHA class I/II.
Asunto(s)
Terapia de Resincronización Cardíaca , Desfibriladores Implantables , Insuficiencia Cardíaca/terapia , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del TratamientoRESUMEN
With the ageing of the population, the health problems of elderly individuals have become particularly important. Through a large number of clinical studies and trials, it has been confirmed that elderly patients can experience postoperative cognitive dysfunction after general anesthesia/surgery. However, the mechanism of postoperative cognitive dysfunction is still unknown. In recent years, the role of epigenetics in postoperative cognitive dysfunction has been widely studied and reported. Epigenetics includes the genetic structure and biochemical changes of chromatin not involving changes in the DNA sequence. This article summarizes the epigenetic mechanism of cognitive impairment after general anesthesia/surgery and analyses the broad prospects of epigenetics as a therapeutic target for postoperative cognitive dysfunction.
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Trastornos del Conocimiento , Disfunción Cognitiva , Complicaciones Cognitivas Postoperatorias , Humanos , Anciano , Trastornos del Conocimiento/genética , Trastornos del Conocimiento/psicología , Complicaciones Cognitivas Postoperatorias/genética , Complicaciones Posoperatorias/genética , Complicaciones Posoperatorias/epidemiología , Disfunción Cognitiva/genética , Epigénesis GenéticaRESUMEN
AIMS: To compare the safety and efficacy of a new dilator method vs the traditional needle method for transseptal puncture (TSP) in a large cohort study. METHODS AND RESULTS: From February 1995 to December 2010, 4443 consecutive patients undergoing TSP done either by a needle method or by a new dilator method were reviewed retrospectively. Data as procedure-related time and complications were evaluated. For the standard needle method, TSP was performed by extending out the needle. In comparison, for the new dilator technique, TSP was performed without an outer sheath and with the needle kept within the dilator; the blunt tip of the dilator was used to help locating the position of the fossa ovalis on purpose. Transseptal puncture was performed by the new dilator method in 2151 patients (48.4%) and by the traditional needle method in 2292 patients (51.6%). The average TSP time needed by the dilator method was longer than that needed by the needle method (5.6 ± 3.9 vs. 3.8 ± 2.9 min, P< 0.05). Additional left atrial angiography was required in seven (0.33%) patients for the dilator and in 39 patients (1.70%) for the needle method (P< 0.05). The total rate of severe complications and obvious TSP-related complications was significantly lower in patients who underwent the dilator method than in those who underwent the needle method (0.33 vs. 1.18%, and 0.20 vs. 1.00%, respectively, P < 0.05). CONCLUSION: Our data suggest that the new dilator technique is much safer than that of the standard needle method. It needs relatively longer procedure time but results in significantly fewer episodes of severe complications. Particularly, the blunt tip of the dilator can be used to help locate the fossa ovalis. Therefore, the new dilator technique might be a better choice for relatively less-experienced operators.
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Procedimientos Quirúrgicos Cardíacos/instrumentación , Tabiques Cardíacos/cirugía , Agujas/efectos adversos , Punciones/métodos , Adulto , Anciano , Fibrilación Atrial/cirugía , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Procedimientos Quirúrgicos Cardíacos/métodos , Ablación por Catéter/instrumentación , Ablación por Catéter/métodos , Angiografía Coronaria , Femenino , Atrios Cardíacos/cirugía , Humanos , Masculino , Persona de Mediana Edad , Tempo Operativo , Complicaciones Posoperatorias/etiología , Punciones/instrumentación , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
China's increasingly aging population is resulting in an imbalance between supply and demand for elderly care resources. The theory of "combined medical and elderly care" (CMEC) has introduced a new perspective in the conception of China's elderly care problems. This study employed the service blueprint, fuzzy failure mode and effects analysis (Fuzzy-FMEA), and the theory of inventive problem solving (TIPS or the Russian acronym TRIZ) for the process optimization of CMEC services in three phases. In the first phase (service process analysis), potential service failure points in the service process were analyzed using the service blueprint technique. In the second phase (service failure diagnosis), Fuzzy-FMEA was applied to diagnose the service failure modes and explore the possible causes and effects. The service failure modes were then prioritized based on fuzzy numbers and the cumulative fuzzy risk priority number (Fuzzy-RPN). Finally, in the third phase (generation of service optimization solutions), the TRIZ parameters, inventive principles, and contradiction matrix were first employed to select TRIZ inventive principles. The selected TRIZ inventive principles were then used to inspire inventive solutions for new service processes. Finally, a case study was conducted on the service processes of elderly care institutions to demonstrate the applicability of the optimization solutions.
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Solución de Problemas , Anciano , Humanos , Servicios de Salud para AncianosRESUMEN
Diabetic nephropathy (DN) is the most common chronic kidney disease. Accumulation of glucose and metabolites activates resident macrophages in kidneys. Resident macrophages play diverse roles on diabetic kidney injuries by releasing cytokines/chemokines, recruiting peripheral monocytes/macrophages, enhancing renal cell injuries (podocytes, mesangial cells, endothelial cells and tubular epithelial cells), and macrophage-myofibroblast transition. The differentiation and cross-talks of macrophages ultimately result renal inflammation and fibrosis in DN. Emerging evidence shows that targeting macrophages by suppressing macrophage activation/transition, and macrophages-cell interactions may be a promising approach to attenuate DN. In the review, we summarized the diverse roles of macrophages and the cross-talks to other cells in DN, and highlighted the therapeutic potentials by targeting macrophages.