RESUMEN
Micro ribonucleic acids (miRNAs) play a pivotal role in governing the human transcriptome in various biological phenomena. Hence, the accumulation of miRNA expression dysregulation frequently assumes a noteworthy role in the initiation and progression of complex diseases. However, accurate identification of dysregulated miRNAs still faces challenges at the current stage. Several bioinformatics tools have recently emerged for forecasting the associations between miRNAs and diseases. Nonetheless, the existing reference tools mainly identify the miRNA-disease associations in a general state and fall short of pinpointing dysregulated miRNAs within a specific disease state. Additionally, no studies adequately consider miRNA-miRNA interactions (MMIs) when analyzing the miRNA-disease associations. Here, we introduced a systematic approach, called IDMIR, which enabled the identification of expression dysregulated miRNAs through an MMI network under the gene expression context, where the network's architecture was designed to implicitly connect miRNAs based on their shared biological functions within a particular disease context. The advantage of IDMIR is that it uses gene expression data for the identification of dysregulated miRNAs by analyzing variations in MMIs. We illustrated the excellent predictive power for dysregulated miRNAs of the IDMIR approach through data analysis on breast cancer and bladder urothelial cancer. IDMIR could surpass several existing miRNA-disease association prediction approaches through comparison. We believe the approach complements the deficiencies in predicting miRNA-disease association and may provide new insights and possibilities for diagnosing and treating diseases. The IDMIR approach is now available as a free R package on CRAN (https://CRAN.R-project.org/package=IDMIR).
Asunto(s)
Biología Computacional , Redes Reguladoras de Genes , MicroARNs , Neoplasias de la Vejiga Urinaria , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Biología Computacional/métodos , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Perfilación de la Expresión Génica , Femenino , Regulación Neoplásica de la Expresión GénicaRESUMEN
High-temperature rechargeable batteries are essential for energy storage in elevated-temperature situations. Due to the resource abundance of potassium, high-temperature K-ion batteries are drawing increasing research interest. However, raising the working temperature would aggravate the chemical and mechanical instability of the KIB anode, resulting in very fast capacity fading, especially when high capacity is pursued. Here, we demonstrated that a porous conductive metal-organic framework (MOF), which is constructed by N-rich aromatic molecules and CuO4 units via π-d conjugation, could provide multiple accessible redox-active sites and promised robust structure stability for efficient potassium storage at high temperatures. Even working at 60 °C, this MOF anode could deliver high initial capacity (455 mAh g-1), impressive rate, and extraordinary cyclability (96.7% capacity retention for 1600 cycles), which is much better than those of reported high-temperature KIB anodes. The mechanistic study revealed that CâN groups and CuO4 units contributed abundant redox-active sites; the synergistic effect of π-d conjugated character and reticular porous architecture facilitated the K+/e- transport and ensured an insoluble electrode with small volume deformation, thus achieving stable high-capacity potassium storage.
RESUMEN
2,3-Allenamides are an important class of unsaturated group-substituted carbonyl compounds. A palladium-catalyzed aminocarbonylation of propargyl acetates with amines for the synthesized tri-/tetrasubstituted 2,3-allenamides has been developed. A broad range of tri-/tetrasubstituted 2,3-allenamides have been prepared from propargyl acetates in good to excellent yields. The reaction featured mild reaction conditions and good functional group tolerance. The applicability of this methodology was further highlighted by the late-stage modification of several natural products and pharmaceuticals.
RESUMEN
The large size of K-ion makes the pursuit of stable high-capacity anodes for K-ion batteries (KIBs) a formidable challenge, particularly for high temperature KIBs as the electrode instability becomes more aggravated with temperature climbing. Herein, we demonstrate that a hollow ZnS@C nanocomposite (h-ZnS@C) with a precise shell modulation can resist electrode disintegration to enable stable high-capacity potassium storage at room and high temperature. Based on a model electrode, we identify an interesting structure-function correlation of the h-ZnS@C: with an increase in the shell thickness, the cyclability increases while the rate and capacity decrease, shedding light on the design of high-performance h-ZnS@C anodes via engineering the shell thickness. Typically, the h-ZnS@C anode with a shell thickness of 60â nm can deliver an impressive comprehensive performance at room temperature; the h-ZnS@C with shell thickness increasing to 75â nm can achieve an extraordinary stability (88.6 % capacity retention over 450 cycles) with a high capacity (450â mAh g-1) and a superb rate even at an extreme temperature of 60 °C, which is much superior than those reported anodes. This contribution envisions new perspectives on rational design of functional metal sulfides composite toward high-performance KIBs with insights into the significant structure-function correlation.
RESUMEN
Multidrug resistance of tumors has been a severe obstacle to the success of cancer chemotherapy. The study wants to investigate the reversal effects of imperatorin (IMP) on doxorubicin (DOX) resistance in K562/DOX leukemia cells, A2780/Taxol cells and in NOD/SCID mice, to explore the possible molecular mechanisms. K562/DOX and A2780/Taxol cells were treated with various concentrations of DOX and Taol with or without different concentrations of IMP, respectively. K562/DOX xenograft model was used to assess anti-tumor effect of IMP combined with DOX. MTT assay, Rhodamine 123 efflux assay, RT-PCR, and Western blot analysis were determined in vivo and in vitro. Results showed that IMP significantly enhanced the cytotoxicity of DOX and Taxol toward corresponding resistance cells. In vivo results illustrated both the tumor volume and tumor weight were significantly decreased after 2-week treatment with IMP combined with DOX compared to the DOX alone group. Western blotting and RT-PCR analyses indicated that IMP downregulated the expression of P-gp in K562/DOX xenograft tumors in NOD/SCID mice. We also evaluated glycolysis and glutamine metabolism in K562/DOX cells by measuring glucose consumption and lactate production. The results revealed that IMP could significantly reduce the glucose consumption and lactate production of K562/DOX cells. Furthermore, IMP could also remarkably repress the glutamine consumption, α-KG and ATP production of K562/DOX cells. Thus, IMP may sensitize K562/DOX cells to DOX and enhance the anti-tumor effect of DOX in K562/DOX xenograft tumors in NOD/SCID mice. IMP may be an adjuvant therapy to mitigate the multidrug resistance in leukemia chemotherapy.
RESUMEN
Hypothalamic neuropeptide orexin has been implicated in the pathophysiology of psychiatric disorders and accumulating clinical evidence indicates a potential link between orexin and depression. However, the exact role of orexin in depression, particularly the underlying neural substrates and mechanisms, remains unknown. In this study, we reveal a direct projection from the hypothalamic orexinergic neurons to the ventral pallidum (VP), a structure that receives an increasing attention for its critical position in rewarding processing, stress responses, and depression. We find that orexin directly excites GABAergic VP neurons and prevents depressive-like behaviors in rats. Two orexin receptors, OX1R and OX2R, and their downstream Na+-Ca2+ exchanger and L-type Ca2+ channel co-mediate the effect of orexin. Furthermore, pharmacological blockade or genetic knockdown of orexin receptors in VP increases depressive-like behaviors in forced swim test and sucrose preference test. Intriguingly, blockage of orexinergic inputs in VP has no impact on social proximity in social interaction test between novel partners, but remarkably strengthens social avoidance under an acute psychosocial stress triggered by social rank. Notably, a significantly increased orexin level in VP is accompanied by an increase in serum corticosterone in animals exposed to acute stresses, including forced swimming, food/water deprivation and social rank stress, rather than non-stress situations. These results suggest that endogenous orexinergic modulation on VP is especially critical for protecting against depressive reactions to stressful events. The findings define an indispensable role for the central orexinergic system in preventing depression by promoting stress resilience.
Asunto(s)
Depresión/tratamiento farmacológico , Orexinas/metabolismo , Orexinas/farmacología , Animales , Conducta Animal/efectos de los fármacos , Depresión/fisiopatología , Modelos Animales de Enfermedad , Neuronas GABAérgicas/metabolismo , Hipotálamo/metabolismo , Masculino , Neuropéptidos/metabolismo , Receptores de Orexina/metabolismo , Receptores de Orexina/fisiología , Ratas , Ratas Sprague-Dawley , Conducta Social , Estrés Psicológico/metabolismoRESUMEN
BACKGROUND: Livestock production aims to provide meats of high and consistent eating quality. Insufficient intramuscular (IM) fat and excessive subcutaneous (SC) fat are paramount pork quality challenges. IM fat and SC fat, which are modulated by the adipogenesis of IM and SC adipocytes, play key roles in pork quality. Galectin-12 (LGALS12) was proven to be an important regulator of fat deposition in porcine. However, the current knowledge of the transcriptome-wide role of LGALS12 in adipocytes is still limited. This study was aimed to discover the different regulatory mechanisms of LGALS12 in porcine IM and SC adipocyte. RESULTS: The siRNA-mediated knockdown of the expression of LGALS12 identified 1075 and 3016 differentially expressed genes (DEGs) in IM and SC adipocytes, respectively. Among these, 585 were up- and 490 were downregulated in the IM adipocytes, while 2186 were up- and 830 were downregulated in the SC adipocytes. Moreover, 418 DGEs were observed only in the IM adipocytes, 2359 DGEs only in the SC adipocytes, and 657 DGEs in both types of adipocytes. According to Gene Ontology (GO) analysis, DEGs in both IM and SC adipocytes were mainly enriched in categories related to lipids or fat cell differentiation. Pathway analysis of the DEGs revealed 88 changed signaling pathways in the IM adipocytes and 86 in the SC adipocytes. The signaling pathways present in only one type of adipocyte were identified from among the top 50 signaling pathways in each type of adipocyte. Four signaling pathways, encompassing PI3K-AKT, cardiac muscle contraction, fatty acid metabolism and Ras, were significantly enriched in the IM adipocytes. On the other hand, four different signaling pathways, encompassing TNF, WNT, cGMP-PKG and NF-kappa B, were greatly enriched in the SC ones. The pathway changes were confirmed by chemical inhibition assays. CONCLUSIONS: Our data reveals that LGALS12 knockdown alters the expression of numerous genes involved in key biological processes in the development of adipocytes. These observations provide a global view of the role of LGALS12 in porcine IM and SC adipocytes; thus, improving our understanding of the regulatory mechanisms by which this gene acts in fat development.
Asunto(s)
Adipocitos/metabolismo , Galectinas/genética , Perfilación de la Expresión Génica , Músculos/citología , Grasa Subcutánea/citología , Porcinos/metabolismo , Animales , Galectinas/deficiencia , Regulación de la Expresión Génica/genética , Ontología de Genes , Silenciador del Gen , Factores de Transcripción/metabolismoRESUMEN
BACKGROUND: Emerging data have demonstrated that peroxisome proliferator-activated receptor δ (PPARδ) activation confers a potentially neuroprotective role in some neurodegenerative diseases. However, whether PPARδ is involved in depression is unknown. METHODS: In this study, PPARδ was firstly investigated in the chronic mild stress (CMS) and learned helplessness (LH) models of depression. The changes in depressive behaviors and hippocampal neurogenesis were investigated after PPARδ overexpression by microinfusion of the lentiviral vector, containing the coding sequence of mouse PPARδ (LV-PPARδ), into the bilateral dentate gyri of the hippocampus or PPARδ activation by repeated systemic administration of PPARδ agonist GW0742 (5 or 10mg/kg.d, i.p., for 21 d). RESULTS: We found that both CMS and LH resulted in a significant decrease in the PPARδ expression in the hippocampi of mice, and this change was reversed by treatment with the antidepressant fluoxetine. PPARδ overexpression and PPARδ activation each suppressed the CMS- and LH-induced depressive-like behavior and produced an antidepressive effect. In vivo or in vitro studies also showed that both overexpression and activation of PPARδ enhanced proliferation or differentiation of neural stem cells in the hippocampi of mice. CONCLUSIONS: These results suggest that hippocampal PPARδ upregulation represses stress-induced depressive behaviors, accompanied by enhancement of neurogenesis.
Asunto(s)
Depresión/complicaciones , Depresión/patología , Hipocampo/metabolismo , Neurogénesis/fisiología , PPAR delta/metabolismo , Estrés Psicológico/complicaciones , Animales , Diferenciación Celular , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/fisiología , Proteína Ácida Fibrilar de la Glía/metabolismo , Suspensión Trasera , Masculino , Ratones , Ratones Endogámicos ICR , Células-Madre Neurales/fisiología , PPAR delta/genética , Fosfopiruvato Hidratasa/metabolismo , Sincalida/metabolismo , Tiazoles/farmacología , Factores de Tiempo , Transducción GenéticaRESUMEN
Deposition of extracellular amyloid-ß (Aß) peptide is one of the pathological hallmarks of Alzheimer's disease (AD). Accumulation of Aß is thought to associate with cognition deficits, neuroinflammation and apoptosis observed in AD. However, effective neuroprotective approaches against Aß neurotoxicity are unavailable. In the present study, we analysed the effects of pranlukast, a selective cysteinyl leukotriene receptor 1 (CysLT1R) antagonist, on the impairment of learning and memory formation induced by Aß and the probable underlying electrophysiological and molecular mechanisms. We found that bilateral intrahippocampal injection of Aß1â42 resulted in a significant decline of spatial learning and memory of mice in the Morris water maze (MWM) and Y-maze tests, together with a serious depression of in vivo hippocampal long-term potentiation (LTP) in the CA1 region of the mice. Importantly, this treatment caused significant increases in CysLT1R expression and subsequent NF-κB signaling, caspase-3 activation and Bcl-2 downregulation in the hippocampus or prefrontal cortex. Oral administration of pranlukast at 0.4 or 0.8 mg/kg for 4 wk significantly reversed Aß1â42-induced impairments of cognitive function and hippocampal LTP in mice. Furthermore, pranlukast reversed Aß1â42-induced CysLT1R upregulation, and markedly suppressed the Aß1â42-triggered NF-κB pathway, caspase-3 activation and Bcl-2 downregulation in the hippocampus and prefrontal cortex in mice. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay confirmed its presence in the brain after oral administration of pranlukast in mice. These data disclose novel findings about the therapeutic potential of pranlukast, revealing a previously unknown therapeutic possibility to treat memory deficits associated with AD.
Asunto(s)
Péptidos beta-Amiloides/farmacología , Cromonas/farmacología , Trastornos del Conocimiento/tratamiento farmacológico , Hipocampo/efectos de los fármacos , Antagonistas de Leucotrieno/farmacología , Fragmentos de Péptidos/farmacología , Péptidos beta-Amiloides/administración & dosificación , Animales , Conducta Animal/efectos de los fármacos , Región CA1 Hipocampal/efectos de los fármacos , Región CA1 Hipocampal/fisiopatología , Cromonas/administración & dosificación , Trastornos del Conocimiento/inducido químicamente , Trastornos del Conocimiento/fisiopatología , Modelos Animales de Enfermedad , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/fisiología , Hipocampo/fisiopatología , Aprendizaje/efectos de los fármacos , Antagonistas de Leucotrieno/administración & dosificación , Potenciación a Largo Plazo/efectos de los fármacos , Potenciación a Largo Plazo/fisiología , Masculino , Memoria/efectos de los fármacos , Ratones Endogámicos ICR , Fragmentos de Péptidos/administración & dosificación , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/fisiopatología , Receptores de Leucotrienos/efectos de los fármacosRESUMEN
The COP9 signalosome subunit 6 (COPS6) is abnormally overexpressed in many malignancies, yet its precise role in carcinogenesis is unknown. To gain a better understanding of COPS6's role, the authors conducted a pan-cancer analysis using various bioinformatics techniques such as differential expression patterns, prognostic value, gene mutations, immune infiltration, correlation analysis, and functional enrichment assessment. Results showed that COPS6 was highly correlated with prognosis, immune cell infiltration level, tumor mutation burden, and microsatellite instability in patients with a range of tumor types. This suggests that COPS6 may be a potential target for cancer treatment. Overall, this research provides insight into COPS6's role in cancer development and its potential therapeutic applications.
RESUMEN
A palladium-catalyzed cascade carbonylation reaction of 2-bromo-N-(2-iodophenyl)benzamides with benzylidenecyclopropanes for the synthesis of fused isoindolinone derivatives has been developed. A broad range of 6/5/6/6 tetracyclic isoindolinone products were efficiently prepared in moderate to good yields with diverse substitution. Two carbonyl groups were incorporated into the substrates in a single step with the formation of four carbon-carbon bonds and two carbon-heteroatom bonds.
RESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Salvia divinorum (Epling and Játiva) is a psychoactive plant traditionally used by the Latinos for various medicinal purposes. Salvinorin A (Sal A), the main bioactive constituent of S. divinorum, is a natural highly selective kappa opioid receptor (KOR) agonist. Considering the anti-inflammatory effect of S. divinorum and endogenous hippocampal dynorphin/ kappa opioid receptor (KOR) system playing an anticonvulsant function, we hypothesis that Sal A can be a potential candidate to treat epilepsy. Here, we identified whether Sal A ameliorated epileptic seizures and neuronal damages in animal model and in vitro model and investigated its underlying mechanisms. MATERIALS AND METHODS: Mice epilepsy model was induced by pilocarpine following seizures assessed by Racine classification. Hippocampus tissues were obtained for genetic, protein, and histological investigation. Furthermore, lipopolysaccharide (LPS)-activated BV2 microglial cells were utilized to validate the anti-inflammatory and microglia polarization regulation effects of Sal A. RESULTS: Sal A treatment significantly prolonged the latency to status epileptics (SE) and shortened the duration of SE in the pilocarpine-induced model. It also alleviated neuronal damages via activation of the AMPK/JNK/p-38 MAPK pathway and inhibition of apoptosis-related protein in hippocampus tissues. Furthermore, Sal A dose-dependently reduced microglia-mediated expression of pro-inflammatory cytokines and increased anti-inflammatory factors levels in SE mice and LPS-activated BV2 microglial cells by regulating microglia polarization. In addition, the effect of Sal A in vitro was totally blocked by KOR antagonist nor-BNI. CONCLUSION: Sal A treatment protects against epileptic seizures and neuronal damages in pilocarpine-induced models by suppressing the inflammation response through regulating microglial M1/M2 polarization. This study might serve as a theoretical basis for clinical applications of Sal A and its analogs and provide a new insight into the development of anti-seizure drugs.
RESUMEN
The synthesis of medium-sized lactams is a great challenge because of the unfavorable transannular interactions and entropic barriers in the transition state. We have developed a ruthenium-catalyzed carbonylation of α-aminoaryl-tethered alkylidenecyclopropanes (ACPs) that allows for the efficient preparation of valuable eight-membered benzolactams under ligand-free conditions. The amino group served a dual role of both directing group and nucleophile to facilitate the metallacycle formation and the carbonylation.
RESUMEN
Complexes of polysaccharides and proteins have superior physicochemical and functional properties compared to single proteins or polysaccharides. In this study, lactoferrin-hyaluronic acid (LF-HA) complexes were prepared by both ultrasonic and thermal treatment. Appropriate preparation conditions, including ultrasonic and thermal treatment conditions, have been established. The complexes formed by different methods were structurally characterized by sodium dodecyl sulfate polyacrylamide gel electrophoresis, fourier transform infrared spectroscopy, and circular dichroism spectroscopy. Ultrasound formed non-covalent binding, while thermal treatment generated covalent bonding, altering the structure of LF. The LF-HA complexes showed improved heat stability, foaming stability, emulsifying activity and antioxidant capacity, but deceased foaming ability. Iron binding ability could only be improved by HA through thermal treatment. Moreover, the in vitro digestibility of LF-HA complexes decreased to below 80 % compared to LF.
Asunto(s)
Ácido Hialurónico , Lactoferrina , Lactoferrina/química , Ácido Hialurónico/química , Antioxidantes/química , Calor , Ondas Ultrasónicas , Hierro/química , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
In dairy products, the added sodium hyaluronate may form complexes with proteins, thereby affecting product properties. In the present study, the interaction between whey protein isolate (WPI)/ whey protein hydrolysate (WPH) and sodium hyaluronate (SH) was characterized under thermal treatment at different temperatures (25 â, 65 â, 90 â and 121 â) after studying effects of protein/SH ratio and pH on complex formation. The addition of SH reduced the particle size of WPI/WPH and increased potential value in the system, with greater variation with increasing treatment temperature. The structural properties of complexes were studied. The binding with SH decreased the contents of free amino group and free thiol group, as well as the fluorescence intensity and surface hydrophobicity. FTIR results and browning intensity measurement demonstrated the formation of Maillard reaction products. Moreover, the attachment of SH improved the thermal stability of WPI/WPH and decreased their antigenicity.
Asunto(s)
Calor , Ácido Hialurónico , Hidrolisados de Proteína , Proteína de Suero de Leche , Proteína de Suero de Leche/química , Ácido Hialurónico/química , Hidrolisados de Proteína/química , Concentración de Iones de Hidrógeno , Reacción de Maillard , Interacciones Hidrofóbicas e Hidrofílicas , Tamaño de la Partícula , Espectroscopía Infrarroja por Transformada de Fourier , Manipulación de Alimentos/métodosRESUMEN
Physical exercise is known to reduce anxiety, but the underlying brain mechanisms remain unclear. Here, we explore a hypothalamo-cerebello-amygdalar circuit that may mediate motor-dependent alleviation of anxiety. This three-neuron loop, in which the cerebellar dentate nucleus takes center stage, bridges the motor system with the emotional system. Subjecting animals to a constant rotarod engages glutamatergic cerebellar dentate neurons that drive PKCδ+ amygdalar neurons to elicit an anxiolytic effect. Moreover, challenging animals on an accelerated rather than a constant rotarod engages hypothalamic neurons that provide a superimposed anxiolytic effect via an orexinergic projection to the dentate neurons that activate the amygdala. Our findings reveal a cerebello-limbic pathway that may contribute to motor-triggered alleviation of anxiety and that may be optimally exploited during challenging physical exercise.
Asunto(s)
Ansiolíticos , Animales , Ansiedad/metabolismo , Hipotálamo , Cerebelo , Trastornos de AnsiedadRESUMEN
AIM: Endogenous dynorphin signaling via kappa opioid receptors (KORs) plays a key role in producing the depressive and aversive consequences of stress. We investigated the behavioral effects of the dynorphin/KOR system in the ventral pallidum (VP) and studied the underlying mechanisms. METHODS: To investigate the effects of dynorphin on the VP, we conducted behavioral experiments after microinjection of drugs or shRNA and brain-slice electrophysiological recordings. Histological tracing and molecular biological experiments were used to identify the distribution of KORs and the possible sources of dynorphin projections to the VP. RESULTS: An elevated dynorphin concentration and increased KOR activity were observed in the VP after acute stress. Infusion of dynorphin-A into the VP produced depressive-like phenotypes including anhedonia and despair and anxiety behaviors, but did not alter locomotor behavior. Mechanistically, dynorphin had an inhibitory effect on VP neurons-reducing their firing rate and inhibiting excitatory transmission-through direct activation of KORs and modulation of downstream G-protein-gated inwardly rectifying potassium (GIRK) channels and high-voltage gated calcium channels (VGCCs). Tracing revealed direct innervation of VP neurons by dynorphin-positive projections; potential sources of these dynorphinergic projections include the nucleus accumbens, amygdala, and hypothalamus. Blockade of dynorphin/KOR signaling in the VP by drugs or viral knock-down of KORs significantly reduced despair behavior in rats. CONCLUSIONS: Endogenous dynorphinergic modulation of the VP plays a critical role in mediating depressive reactions to stress.
Asunto(s)
Prosencéfalo Basal , Dinorfinas , Animales , Ratones , Ratas , Prosencéfalo Basal/metabolismo , Canales de Calcio , Dinorfinas/genética , Dinorfinas/metabolismo , Dinorfinas/farmacología , Ratones Endogámicos C57BL , Neuronas/metabolismo , Potasio/farmacología , Receptores Opioides kappa/genética , Receptores Opioides kappa/metabolismo , ARN Interferente Pequeño , Depresión , Conducta Animal , Estrés FisiológicoRESUMEN
Viruses exploit host cell machinery to support their replication. Defining the cellular proteins and processes required for a virus during infection is crucial to understanding the mechanisms of virally induced disease and designing host-directed therapeutics. Here, we perform a genome-wide CRISPR-Cas9-based screening in lung epithelial cells infected with the PR/8/NS1-GFP virus and use GFPhi cell as a unique screening marker to identify host factors that inhibit influenza A virus (IAV) infection. We discovered that APOE affects influenza virus infection both in vitro and in vivo. Cell deficiency in APOE conferred substantially increased susceptibility to IAV; mice deficient in APOE manifested more severe lung pathology, increased virus load, and decreased survival rate. Mechanistically, lack of cell-produced APOE results in impaired cell cholesterol homeostasis, enhancing influenza virus attachment. Thus, we identified a previously unrecognized role of APOE in restraining IAV infection.
Asunto(s)
Enfermedades Transmisibles , Virus de la Influenza A , Gripe Humana , Infecciones por Orthomyxoviridae , Animales , Apolipoproteínas , Apolipoproteínas E/genética , Colesterol , Interacciones Huésped-Patógeno , Humanos , Gripe Humana/genética , Ratones , Infecciones por Orthomyxoviridae/genética , Replicación ViralRESUMEN
As one of the most common complications of diabetes, nephropathy develops in approximately 40% of diabetic individuals. Although end stage kidney disease is known as one of the most consequences of diabetic nephropathy, the majority of diabetic individuals might die from cardiovascular diseases and infections before renal replacement treatment. Moreover, the routine medical treatments for diabetes hold undesirable side effects. The explosive prevalence of diabetes urges clinicians and scientists to investigate the complementary or alternative therapies. Phytochemicals are emerging as alternatives with a wide range of therapeutic effects on various pathologies, including diabetic kidney disease. Of those phytochemicals, resveratrol, a natural polyphenolic stilbene, has been found to exert a broad spectrum of health benefits via various signaling molecules. In particular, resveratrol has gained a great deal of attention because of its anti-oxidative, anti-inflammatory, anti-diabetic, anti-obesity, cardiovascular-protective, and anti-tumor properties. In the renal system, emerging evidence shows that resveratrol has already been used to ameliorate chronic or acute kidney injury. This review critically summarizes the current findings and molecular mechanisms of resveratrol in diabetic renal damage. In addition, we will discuss the adverse and inconsistent effects of resveratrol in diabetic nephropathy. Although there is increasing evidence that resveratrol affords great potential in diabetic nephropathy therapy, these results should be treated with caution before its clinical translation. In addition, the unfavorable pharmacokinetics and/or pharmacodynamics profiles, such as poor bioavailability, may limit its extensive clinical applications. It is clear that further research is needed to unravel these limitations and improve its efficacy against diabetic nephropathy. Increasing investigation of resveratrol in diabetic kidney disease will not only help us better understand its pharmacological actions, but also provide novel potential targets for therapeutic intervention.
Asunto(s)
Nefropatías Diabéticas/tratamiento farmacológico , Resveratrol/farmacocinética , Resveratrol/uso terapéutico , Animales , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/patología , HumanosRESUMEN
Alzheimer's disease (AD) is a neurodegenerative disease that contributes to 60-70% dementia around the world. One of the hallmarks of AD undoubtedly lies on accumulation of amyloid-ß (Aß) in the brain. Aß is produced from the proteolytic cleavage of the beta-amyloid precursor protein (APP) by ß-secretase and γ-secretase. In pathological circumstances, the increased ß-cleavage of APP leads to overproduction of Aß, which aggregates into Aß plaques. Since Aß plaques are a characteristic of AD pathology, detecting the amount of Aß is very important in AD research. In this protocol, we introduce the immunofluorescent staining method to visualize Aß deposition. The mouse model used in our experiments is 5×FAD, which carries five mutations found in human familial AD. The neuropathological and behavioral deficits of 5xFAD mice are well-documented, which makes it a good animal model to study Aß pathology. We will introduce the procedure including transcardial perfusion, cryosectioning, immunofluorescent staining and quantification to detect Aß accumulation in 5×FAD mice. With this protocol, researchers can investigate Aß pathology in an AD mouse model.