RESUMEN
BACKGROUND: The incongruity between dietary patterns and the circadian clock poses an elevated risk for metabolic health issues, particularly obesity and associated metabolic disorders. The intestinal microflora engages in regulating various physiological functions of the host through its metabolites. OBJECTIVES: This study aimed to investigate the impact of reversed feeding schedules during the day and night on intestinal flora and lipid metabolism in high-fat diet-induced obese mice. METHODS: Mice aged 8-10 wk were subjected to either daytime or nighttime feeding and were administered a control or high-fat diet for 18 wk. At the end of the experiment, various assessments were conducted, including analysis of serum biochemic indices, histologic examination, evaluation of gene and protein expression in adipose tissue, and scrutiny of changes in intestinal microbial composition. RESULTS: The results showed that day-night reversed feeding caused an increase in fasting blood glucose and exacerbated the high-fat diet-induced weight gain and lipid abnormalities. The mRNA expression levels of Leptin and Dgat1 were increased by day-night reversed feeding, which also reduced the expression level of adiponectin under the high-fat diet. Additionally, there was a significant increase in the protein concentrations of PPARγ, SREBP1c, and CD36. Inverted feeding schedules led to a reduction in intestinal microbial diversity, an increase in the abundance of inflammation-related bacteria, such as Coriobacteriaceae_UCG-002, and a suppression of beneficial bacteria, including Akkermansia, Candidatus_Saccharimonas, Anaeroplasma, Bifidobacterium, Carnobacterium, and Odoribacter. Acinetobacter exhibited a significant negative correlation with Leptin and Fasn, suggesting potential involvement in the regulation of lipid metabolism. CONCLUSIONS: The results elucidated the abnormalities of lipid metabolism and intestinal flora caused by day-night reversed feeding, which exacerbates the adverse effects of a high-fat diet on lipid metabolism and intestinal microflora. This reversal in feeding patterns may disrupt both intestinal and lipid metabolism homeostasis by altering the composition and abundance of intestinal microflora in mice.
RESUMEN
Purpose: This study was designed to investigate the prophylactic effect of oral olanzapine in postoperative nausea and vomiting after gynecologic laparoscopic surgery. Methods: ASA I-II, aged 18-75 years, planned to undergo gynecologic laparoscopic surgery with general anesthesia in adult female patients. Using the randomized numbers table, the patients were placed in two groups. Oral olanzapine 5 mg or placebo was given 1 h before anesthesia. All patients received standard antiemetic prophylaxis with dexamethasone and granisetron. The primary outcome was nausea and/or vomiting in the 24 h after the postoperative. Results: A total of 250 patients were randomized, and 241 were analyzed. The primary outcome occurred in 10 of 120 patients (8.3%) in the olanzapine group and 23 of 121 patients (19.2%) in the placebo group (p = 0.014). According to Kaplan-Meier analysis, the probabilities of nausea and/or vomiting in the 24 h after the postoperative in the olanzapine group were lower than in the placebo group (log-rank p = 0.014). In a multivariate Cox analysis, the variables of use of olanzapine [hazard ratio (HR): 0.35, 95% confidence interval (CI): 0.16-0.79; p = 0.012] and use of vasoactive drugs (HR: 2.48, 95% CI: 1.07-5.75; p = 0.034) were independently associated with nausea and/or vomiting in the 24 h after the postoperative. Conclusion: Our data suggest that olanzapine relative to placebo decreased the risk of nausea and/or vomiting in the 24 h after gynecologic laparoscopic surgery. Trial registration: The trial was registered prior to patient enrollment at The Chinese Clinical Trial Registry (https://www.chictr.org.cn/showproj.html?proj=166900, link to registry page, Principal investigator: Nanjin Chen, Date of registration: 25 April 2022).
Preventing nausea and vomiting after laparoscopic gynecological surgery: the benefits of using olanzapine Why was this study done? Despite the use of antiemetics, postoperative nausea and vomiting remain prevalent. Furthermore, patients who undergo gynecological laparoscopic surgery are at an increased risk. Therefore, this study investigated whether oral Olanzapine could reduce the incidence of nausea and vomiting after gynaecological Laparoscopy? What did the researchers do? The research team examined patients who underwent gynecological laparoscopic surgery under general anesthesia. They observed the occurrence of nausea and vomiting within 24 hours after surgery in patients who either received or did not receive Olanzapine treatment. The goal was to assess the effectiveness of Olanzapine in reducing postoperative nausea and vomiting. What did the researchers find? The addition of Olanzapine, when combined with granisetron and dexamethasone, resulted in a decreased risk of nausea and/or vomiting within the 24 hours following gynecologic laparoscopic surgery, as compared to the placebo. Administering oral Olanzapine at a dosage of 5 mg reduced the incidence of nausea and vomiting after gynecological laparoscopy from 19.2% to 8.3%. What do the findings mean? This study has identified a safe and effective medication for preventing postoperative nausea and vomiting. Implementing Olanzapine as a preventive measure can significantly reduce the incidence of nausea and vomiting following surgery, thereby enhancing the overall medical experience for patients.
RESUMEN
Kidney renal papillary cell carcinoma (KIRP) is a highly heterogeneous type of kidney cancer, resulting in limited effective prognostic targets for KIRP patients. Long non-coding RNAs (lncRNAs) have emerged as crucial regulators in the regulation of ferroptosis and iron metabolism, making them potential targets for the treatment and prognosis of KIRP. In this study, we constructed a ferroptosis-related lncRNA risk score model (FRM) based on the TCGA-KIRP dataset, which represents a novel subtype of KIRP not previously reported. The model demonstrated promising diagnostic accuracy and holds potential for clinical translation. We observed significant differences in metabolic activities, immune microenvironment, mutation landscape, ferroptosis sensitivity, and drug sensitivity between different risk groups. The high-risk groups exhibit significantly higher fractions of cancer-associated fibroblasts (CAFs), hematopoietic stem cells (HSC), and pericytes. Drugs (IC50) analysis provided a range of medication options based on different FRM typing. Additionally, we employed single-cell transcriptomics to further analyze the impact of immune invasion on the occurrence and development of KIRP. Overall, we have developed an accurate prognostic model based on the expression patterns of ferroptosis-related lncRNAs for KIRP. This model has the potential to contribute to the evaluation of patient prognosis, molecular characteristics, and treatment modalities, and can be further translated into clinical applications.
RESUMEN
Disturbances in circadian rhythms are known to affect immune functions. However, the long-term impact of abnormal circadian rhythms on the immune-related functions of the spleen are poorly understood. Hence, we aimed to investigate the immune-related functions of spleen in Per1/Per2 double-knockout (DKO) and wild-type (WT) mice aged 4, 9, and 14 months. Compared to the WT mice, the DKO mice had smaller spleen white pulp (WP) and lymphocyte germinal area, as well as fewer immune cells with age-these differences were especially clear. The spleen lymphocyte mortality, malondialdehyde (MDA) levels, reactive oxygen species (ROS) levels, and ferritin-binding receptor (TFR1) levels were significantly higher in the 14-month-old DKO mice than in WT mice of the same age. Transcriptome analysis showed that most of the differentially expressed mRNAs were enriched in DNA damage repair-related pathways. In DKO mice, spleen cells showed up-regulation of pro-ferroptosis genes, such as Cd36,Atm, and Acsl4, and down-regulation of anti-ferroptosis genes, such as GPX4. We found that long-term abnormalities in the circadian rhythm can induce DNA damage and ferroptosis in mouse spleen.
Asunto(s)
Proteínas Circadianas Period , Bazo , Ratones , Animales , Proteínas Circadianas Period/genética , Bazo/metabolismo , Ritmo Circadiano/fisiología , Factores de Transcripción/metabolismo , Linfocitos/metabolismo , Inmunidad , Ratones NoqueadosRESUMEN
Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer, and it is the major cause of kidney cancer death. Understanding tumor immune microenvironments (TMEs) is critical in cancer immunotherapies. Here, we studied the immune characterization at single-cell resolution by integrating public data of ccRCC across different tissue types, and comparing the transcriptome features and tumor TME differences in tumors, normal adjacent tissue, and peripheral blood. A total of 16 different types of cell components of ccRCC were identified. We revealed that there is an overall increase in T-cell and myeloid populations in tumor-infiltrated immune cells compared to normal renal tissue, and the B-cell population in the tumor showed a sharp decrease, which indicates that the cells in tumor tissue undergo strong immune stress. In addition, the cell-cell communication analysis revealed specific or conserved signals in different tissue types, which may aid to uncover the distinct immune response. By combining and analyzing publicly available ccRCC bulk RNA-seq datasets, 10 genes were identified as marker genes in specific cell types, which were significantly associated with poor prognosis. Of note, UBE2C, which may be a good indicator of tumor proliferation, is positively associated with reductions in overall survival and highly associated with tumor grade. Our integrated analysis provides single-cell transcriptomic profiling of ccRCC and their TME, and it unmasked new correlations between gene expression, survival outcomes, and immune cell-type components, enabling us to dissect the dynamic variables in the tumor development process. This resource provides deeper insight into the transcriptome features and immune response of ccRCC and will be helpful in kidney cancer immunotherapy.
Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/terapia , Humanos , Inmunoterapia , Neoplasias Renales/genética , Neoplasias Renales/metabolismo , Neoplasias Renales/terapia , Pronóstico , Microambiente Tumoral/genéticaRESUMEN
Circadian rhythm disorders caused by genetic or environmental factors lead to decreased male fertility but the mechanisms are poorly understood. The current study reports that the mechanism of Per1/Per2 Double knockout (DKO) reduced the reproductive capacity of elderly male mice. The sperm motility and spermatogenic capacity of male DKO mice were weak. Hormone-targeted metabolomics showed reduced plasma levels of free testosterone in DKO male mice compared with WT male mice. Transcriptomic analysis of testicular tissue showed the down-regulation of testosterone synthesis-related enzymes (Cyp11a1, Cyp17a1, Hsd17b3, Hsd3b1, and Star) in the steroid hormone synthesis pathway. Spermatogenesis genes, Tubd1 and Pafah1b were down-regulated, influencing tubulin dynamics and leading to impaired motility. Seleno-compound metabolic loci, Scly and Sephs2, were up-regulated and Slc7a11 and Selenop were down-regulated. Western-blotting showed that steroid acute regulatory protein (StAR) and p-CREB, PKA and AC1 were reduced in testicular tissue of DKO mice compared to WT. Therefore, Per1/Per2 disruption reduced testosterone synthesis and sperm motility by affecting the PKA-StAR pathway, leading to decreased fertility.
Asunto(s)
Fertilidad , Proteínas Circadianas Period , Motilidad Espermática , Animales , Enzima de Desdoblamiento de la Cadena Lateral del Colesterol/genética , Enzima de Desdoblamiento de la Cadena Lateral del Colesterol/metabolismo , Ritmo Circadiano/fisiología , Fertilidad/genética , Masculino , Ratones , Proteínas Circadianas Period/genética , Proteínas Circadianas Period/metabolismo , Espermatogénesis , TestosteronaRESUMEN
Argonaute (Ago) proteins are programmable nucleases found in eukaryotes and prokaryotes. Prokaryotic Agos (pAgos) share a high degree of structural homology with eukaryotic Agos (eAgos), and eAgos originate from pAgos. Although eAgos exclusively cleave RNA targets, most characterized pAgos cleave DNA targets. This study characterized a novel pAgo, MbpAgo, from the psychrotolerant bacterium Mucilaginibacter paludis which prefers to cleave RNA targets rather than DNA targets. Compared to previously studied Agos, MbpAgo can utilize both 5'phosphorylated(5'P) and 5'hydroxylated(5'OH) DNA guides (gDNAs) to efficiently cleave RNA targets at the canonical cleavage site if the guide is between 15 and 17 nt long. Furthermore, MbpAgo is active at a wide range of temperatures (4-65°C) and displays no obvious preference for the 5'-nucleotide of a guide. Single-nucleotide and most dinucleotide mismatches have no or little effects on cleavage efficiency, except for dinucleotide mismatches at positions 11-13 that dramatically reduce target cleavage. MbpAgo can efficiently cleave highly structured RNA targets using both 5'P and 5'OH gDNAs in the presence of Mg2+ or Mn2+. The biochemical characterization of MbpAgo paves the way for its use in RNA manipulations such as nucleic acid detection and clearance of RNA viruses.
Asunto(s)
Proteínas Argonautas , Técnicas Genéticas , Proteínas Argonautas/metabolismo , Bacterias/genética , Bacteroidetes , ADN/química , Endonucleasas/metabolismo , Eucariontes/genética , Nucleótidos/metabolismo , ARN/metabolismoRESUMEN
A simple and user-friendly nucleic acid sensing platform with 10 aM sensitivity, named USPCRP (combines ultrashort PCR with Pyrococcus furiosus Argonaute cleavage for nuleic acids detection) is reported. The product of this ultrashort PCR could be directly used as a DNA guide to mediate PfAgo cleavage of molecular beacons.
Asunto(s)
Pyrococcus furiosus , ADN/genética , Reacción en Cadena de la Polimerasa , Pyrococcus furiosus/genéticaRESUMEN
Growth arrest and DNA damage-inducible protein 34 (GADD34), one of the key effectors of negative feedback loops, is induced by stress and subsequently attempts to restore homeostasis. It plays a critical role in response to DNA damage and endoplasmic reticulum stress. GADD34 has opposing effects on different stimulus-induced cell apoptosis events in many nervous system diseases, but its role in ischemic stroke is unclear. In this study, we evaluated the role of GADD34 and its distribution in a rat cerebral ischemic model. The results showed that GADD34 was increased in the cortex and contributed to brain injury in ischemic rats. Furthermore, treatment with a GADD34 inhibitor reduced the infarct volume, improved functional outcomes, and inhibited neuronal apoptosis in the cortical penumbra after ischemia. The role of GADD34 in ischemic stroke was associated with the dephosphorylation of eukaryotic translation initiation factor 2α (eIF2α) and phosphorylation of p53. In addition, the GADD34 level was increased in plasma exosomes of cerebral ischemic rats. These findings indicate that GADD34 could be a potential therapeutic target and biomarker for ischemic stroke.
Asunto(s)
Antígenos de Diferenciación/metabolismo , Cinamatos/farmacología , Infarto de la Arteria Cerebral Media/diagnóstico , Proteínas Proto-Oncogénicas/metabolismo , Daño por Reperfusión/prevención & control , Tiourea/análogos & derivados , Animales , Antígenos de Diferenciación/sangre , Biomarcadores/sangre , Biomarcadores/metabolismo , Cinamatos/uso terapéutico , Modelos Animales de Enfermedad , Factor 2 Eucariótico de Iniciación/sangre , Factor 2 Eucariótico de Iniciación/metabolismo , Exosomas/metabolismo , Humanos , Infarto de la Arteria Cerebral Media/sangre , Infarto de la Arteria Cerebral Media/complicaciones , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Masculino , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/sangre , Ratas , Daño por Reperfusión/etiología , Tiourea/farmacología , Tiourea/uso terapéutico , Proteína p53 Supresora de Tumor/sangre , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Infectious diseases caused by viruses such as SARS-CoV-2 and HPV have greatly endangered human health. The nucleic acid detection is essential for the early diagnosis of diseases. Here, we propose a method called PLCR (PfAgo coupled with modified Ligase Chain Reaction for nucleic acid detection) which utilizes PfAgo to only use DNA guides longer than 14-mer to specifically cleave DNA and LCR to precisely distinguish single-base mismatch. PLCR can detect DNA or RNA without PCR at attomolar sensitivities, distinguish single base mutation between the genome of wild type SARS-CoV-2 and its mutant spike D614G, effectively distinguish the novel coronavirus from other coronaviruses and finally achieve multiplexed detection in 70 min. Additionally, LCR products can be directly used as DNA guides without additional input guides to simplify primer design. With desirable sensitivity, specificity and simplicity, the method can be extended for detecting other pathogenic microorganisms.
Asunto(s)
Proteínas Argonautas/química , ADN Viral/análisis , Reacción en Cadena de la Ligasa/métodos , Pyrococcus furiosus/enzimología , ARN Viral/análisis , Alphapapillomavirus/química , Alphapapillomavirus/aislamiento & purificación , COVID-19/diagnóstico , ADN Viral/química , Humanos , Límite de Detección , Mutación , Infecciones por Papillomavirus/diagnóstico , ARN Viral/química , SARS-CoV-2/química , SARS-CoV-2/aislamiento & purificación , Sensibilidad y Especificidad , Glicoproteína de la Espiga del Coronavirus/genéticaRESUMEN
In the present study, we upgraded Pyrococcus furiosus Argonaute (PfAgo) mediated nucleic acid detection method and established a highly sensitive and accurate molecular diagnosis platform for the large-scale screening of COVID-19 infection. Briefly, RT-PCR was performed with the viral RNA extracted from nasopharyngeal or oropharyngeal swabs as template to amplify conserved regions in the viral genome. Next, PfAgo, guide DNAs and molecular beacons in appropriate buffer were added to the PCR products, followed by incubating at 95 °C for 20-30 min. Subsequently, the fluorescence signal was detected. This method was named as SARS-CoV-2 PAND. The whole procedure is accomplished in approximately an hour with the using time of the Real-time fluorescence quantitative PCR instrument shortened from >1 h to only 3-5 min per batch in comparison with RT-qPCR, hence the shortage of the expensive Real-time PCR instrument is alleviated. Moreover, this platform was also applied to identify SARS-CoV-2 D614G mutant due to its single-nucleotide specificity. The diagnostic results of clinic samples with SARS-CoV-2 PAND displayed 100% consistence with RT-qPCR test.
Asunto(s)
Prueba de Ácido Nucleico para COVID-19/métodos , COVID-19/diagnóstico , SARS-CoV-2/aislamiento & purificación , Proteínas Arqueales/genética , Proteínas Argonautas/genética , Técnicas Biosensibles/métodos , COVID-19/virología , Humanos , Límite de Detección , Nasofaringe/virología , Mutación Puntual , Pyrococcus furiosus/genética , ARN Viral/genética , Proteínas Recombinantes/genética , SARS-CoV-2/genéticaRESUMEN
Argonaute (Ago) proteins are conserved nucleic acid-guided proteins present in all domains of life. Eukaryotic Argonaute proteins (eAgos) are key players in RNA interference pathways and function as RNA-guided RNA endonucleases at physiological temperatures. Although eAgos are considered to evolve from prokaryotic Argonaute proteins (pAgos), previously studied pAgos were unable to catalyze RNA-guided RNA cleavage at physiological temperatures. Here, we describe a distinctive pAgo from mesophilic bacteria Kurthia massiliensis (KmAgo). KmAgo utilizes DNA guides to cleave single-stranded DNA (ssDNA) and RNA targets with high activity. KmAgo also utilizes RNA guides to cleave ssDNA and RNA targets at moderate temperatures. We show that KmAgo can use 5' phosphorylated DNA guides as small as 9-mers to cut ssDNA and RNA, like Clostridium butyricum Ago. Small DNA binding confers remarkable thermostability on KmAgo, and we can suppress the guide-independent plasmid processing activity of empty KmAgo by elevating the DNA guide loaded temperature. Moreover, KmAgo performs programmable cleavage of double-stranded DNA and highly structured RNA at 37°C. Therefore, KmAgo can be regarded as a DNA-guided programmable omnipotent nuclease for cleaving most types of nucleic acids efficiently. This study broadens our understanding of Ago proteins and could expand the pAgo-based DNA and RNA manipulation toolbox.
Asunto(s)
Proteínas Argonautas/metabolismo , Proteínas Bacterianas/metabolismo , ADN de Cadena Simple/metabolismo , Planococcaceae/enzimología , ARN/metabolismo , Cationes Bivalentes , Roturas del ADN de Doble Cadena , TemperaturaRESUMEN
The kidney renal papillary cell carcinoma (KIRP) is a relatively rare type of renal cell carcinoma (RCC). Currently, most kidney cancer studies primarily focus on RCC, and there has been no investigation to find a robust signature to predict the survival outcome of KIRP patients. In this study, we constructed a competing endogenous RNA (ceRNA) network, including 1,251 lncRNA-miRNA-mRNA interactions. Eight differentially expressed genes (IGF2BP3, PLK1, LINC00200, NCAPG, CENPF, miR-217, GAS6-As1, and LRRC4) based on the TCGA database were selected. The prognostic signature was established by combining the univariate Cox regression method and a stepwise regression method, with its predictive value validated by time-dependent receiver operating characteristic (ROC) curves. In conclusion, we identified eight prognostic signatures with using ceRNA networks. Our study provided a global view and a systematic dissection on KIRP prognosis biomarkers, and the eight identified genes might be used as new and important prognostic factors involved in KIRP pathogenesis.
RESUMEN
OBJECTIVE: To study the application of ultrasound-guided indwelling epidural catheter in painless labour. METHODS: A total of 300 single-foetus cephalic position and full-term primipara who did not implement labour analgesia under the same conditions were randomly selected. According to the principle of random grouping, 150 pregnant women who requested and signed the informed consent for labour analgesia were selected as the analgesic group (group A). The other 150 pregnant women who experienced natural delivery without any analgesic measures were categorised as the control group. In the analgesic group, epidural anaesthesia was used when the uterine orifice reached 2.5 cm. The pain grade, motor nerve block, uterine contraction, foetal heart rate and the time of the first stage of labuor were recorded. RESULTS: The results showed that the group receiving epidural block had lesser pain compared to the control group. The duration of first stage of labour of the analgesic group was significantly shorter than the group without analgesia.. There were no significant differences in the degree of motor nerve block, uterine contractions and foetal heart rate between the analgesic group and the control group. CONCLUSIONS: The use of ultrasound-guided first stage indwelling epidural catheter had a significant effect in causing painless labour in the parturient.
Asunto(s)
Analgesia Epidural , Analgesia Obstétrica , Anestesia Epidural , Trabajo de Parto , Femenino , Humanos , Embarazo , Ultrasonografía IntervencionalRESUMEN
The pathogenesis of ischemic cerebrovascular disease has revealed that ischemia-reperfusion (I/R) injury often leads to aggravation of metabolic oxidative stress and blood-brain barrier (BBB) destruction, eventually causing secondary brain tissue damage. Accumulated reactive oxygen species (ROS) in focal ischemia activate mitochondria-mediated apoptosis and damage the BBB by degrading tight junction proteins (TJPs). Herein, we report macrophage-derived exosomes (Ex) loaded with curcumin (cur) as a multifunctional biomimetic delivery vehicle (Ex-cur) for targeting ischemic brain tissue and alleviating cerebral I/R injury by inhibiting ROS-mediated mitochondrial apoptosis in a transient cerebral ischemia rat model. The design principle relies on unique features of macrophage-derived exosomes and the natural ingredient cur. Specifically, cur can be entrapped within exosomes when incubated with murine macrophage RAW264.7 cells, and its stability is subsequently significantly improved. The resultant Ex-cur can target ischemic regions by leveraging the targeting migration capability of Ex driven by inflammation. Accumulated Ex-cur in ischemic regions is experimentally proven to be highly effective at reducing ROS accumulation by virtue of the antioxidant properties of cur. Using Ex-cur to down-regulate ROS accumulation in lesions, we alleviate BBB damage and suppress mitochondria-mediated neuronal apoptosis, which is confirmed by a series of relevant protein analysis. These findings demonstrate good therapeutic efficacy of Ex-cur for treating I/R injury, providing experimental evidence for the potential clinical benefits of Ex-cur for other modes of neuroprotection.
Asunto(s)
Curcumina , Exosomas , Daño por Reperfusión , Animales , Apoptosis , Encéfalo/metabolismo , Curcumina/metabolismo , Curcumina/farmacología , Exosomas/metabolismo , Isquemia/metabolismo , Ratones , Mitocondrias , Ratas , Especies Reactivas de Oxígeno/metabolismo , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/metabolismoRESUMEN
AIMS: Ischemic stroke is the leading cause of severe disability and death worldwide. As the pathogenesis of stroke has not been clearly elucidated and the ability of current therapeutic drugs on crossing the blood-brain barrier (BBB) is extremely low, there is no effective strategy to treat stroke. We aim at investigating the specific advantages of using plasma exosomes (Pla-Exo) for targeting ischemic brain and exploring its underlying mechanism in neuroprotection. MAIN METHODS: Pla-Exo was obtained by a gradient ultracentrifugation of fresh plasma. The quantification of penetrated Pla-Exo through BBB was investigated in vitro BBB model, furthermore, the effects of Pla-Exo and exosomal HSP70 on cerebral ischemia/reperfusion injury were evaluated. KEY FINDINGS: Pla-Exo enhanced BBB crossing by specific interaction between Pla-Exo inherited heat shock protein 70 (HSP70) and endothelial Toll-like receptor 4 (TLR4). As expected, Pla-Exo increased HSP70 expression in the ischemic region through the transfer of HSP70, and led to HSP70 mediated suppression of ROS, thus alleviating cerebral ischemia/reperfusion (I/R) injury by attenuating the deterioration of BBB and preventing mitochondria damage. SIGNIFICANCE: These findings indicated that Pla-Exo can provide protection against ischemia-reperfusion injury via the regulation of HSP70 and it should be further studied as a potential candidate for protection against ischemic injury.
Asunto(s)
Isquemia Encefálica/metabolismo , Exosomas/metabolismo , Proteínas HSP70 de Choque Térmico/administración & dosificación , Plasma/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Daño por Reperfusión/metabolismo , Animales , Isquemia Encefálica/prevención & control , Endotelio Vascular/metabolismo , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Especies Reactivas de Oxígeno/antagonistas & inhibidores , Daño por Reperfusión/prevención & controlRESUMEN
Accumulation of amyloid-ß (Aß) peptides in the brain is regarded as a major contributor to the pathogenesis and progression of Alzheimer's disease (AD). P-glycoprotein (P-gp) as a member of ABC transporter family situated in blood brain barrier (BBB) plays a role on cleaning of Aß via its efflux transport effect in the treatment of AD. However, the expression of P-gp in pathological BBB was lower than that in normal BBB, thus impeding the clearance of Aß. Here, we used human brain microvascular endothelial cells (HBMVECs) derived exosomes (HBMVECs-Ex) inheriting P-gp as an extracorporeal Aß cleansing system to remove Aß peptides from the brain by specific capture between P-gp and Aß. The results showed that HBMVECs-Ex inheriting P-gp greatly facilitated the cerebral clearance of Aß by effectively transporting Aß out of brain and potently ameliorated cognitive dysfunction in AD mice. Taken together, HBMVECs-Ex provided a new strategy on the treatment of AD.
Asunto(s)
Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Enfermedad de Alzheimer/terapia , Péptidos beta-Amiloides/metabolismo , Disfunción Cognitiva/terapia , Exosomas , Fármacos Neuroprotectores/uso terapéutico , Animales , Encéfalo/citología , Células Endoteliales/citología , Humanos , Masculino , Ratones Endogámicos C57BL , Prueba del Laberinto Acuático de Morris/efectos de los fármacosRESUMEN
Lung adenocarcinoma (LUAD) is one of the most fatal malignant tumors harmful to human health. The complexity and behavior characteristics of long-non-coding RNA (lncRNA)-associated competing endogenous RNA (ceRNA) network in LUAD patients are still unclear. The purpose of this study was to elucidate the regulatory networks of dysregulated RNAs, view, and identify potential prognosis signatures involved in LUAD. The expression profiles of mRNAs, lncRNAs, and miRNAs were obtained from the TCGA database. In total, 2078 DEmRNAs, 257 DElncRNAs, and 101 DEmiRNAs were sorted out. A PPI network including 45 DEmRNAs was constructed. Ten hub genes in the PPI network associated with cell cycle-related pathways were identified and they played key roles in regulating cell proliferation. A total of three DEmiRNAs, seven DElncRNAs, and six DEmRNAs were enrolled in the ceRNA network. Except for certain genes without any published study reports, all the genes in the ceRNA network played an essential role in controlling tumor cell proliferation and were associated with prognosis in LUAD. Finally, based on step regression and Cox regression survival analysis, we identified four candidate biomarkers, including miR490, miR1293, LINC01740, and IGF2BP1, and established a risk model based on the four genes. Our study provided a global view and systematic dissection of the lncRNA-associated ceRNA network, and the identified four genes might be novel important prognostic factors involved in LUAD pathogenesis.