RESUMEN
Cholecystokinin (CCK) enables excitatory circuit long-term potentiation (LTP). Here, we investigated its involvement in the enhancement of inhibitory synapses. Activation of GABA neurons suppressed neuronal responses in the neocortex to a forthcoming auditory stimulus in mice of both sexes. High-frequency laser stimulation (HFLS) of GABAergic neurons potentiated this suppression. HFLS of CCK interneurons could induce the LTP of their inhibition toward pyramidal neurons. This potentiation was abolished in CCK knock-out mice but intact in mice with both CCK1R and 2R knockout of both sexes. Next, we combined bioinformatics analysis, multiple unbiased cell-based assays, and histology examinations to identify a novel CCK receptor, GPR173. We propose GPR173 as CCK3R, which mediates the relationship between cortical CCK interneuron signaling and inhibitory LTP in the mice of either sex. Thus, GPR173 might represent a promising therapeutic target for brain disorders related to excitation and inhibition imbalance in the cortex.SIGNIFICANCE STATEMENT CCK, the most abundant and widely distributed neuropeptide in the CNS, colocalizes with many neurotransmitters and modulators. GABA is one of the important inhibitory neurotransmitters, and much evidence shows that CCK may be involved in modulating GABA signaling in many brain areas. However, the role of CCK-GABA neurons in the cortical microcircuits is still unclear. We identified a novel CCK receptor, GPR173, localized in the CCK-GABA synapses and mediated the enhancement of the GABA inhibition effect, which might represent a promising therapeutic target for brain disorders related to excitation and inhibition imbalance in the cortex.
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GABAérgicos , Receptores de Colecistoquinina , Masculino , Femenino , Ratones , Animales , GABAérgicos/farmacología , Células Piramidales/fisiología , Sinapsis/fisiología , Neuronas GABAérgicas/fisiología , Ratones Noqueados , Interneuronas , Colecistoquinina , Ácido gamma-Aminobutírico/fisiología , Potenciación a Largo Plazo/fisiología , Receptores Acoplados a Proteínas G/genéticaRESUMEN
Ischemic stroke is associated with a high mortality rate, and effective treatment strategies are currently lacking. In this study, we aimed to develop a novel nano delivery system to treat ischemic stroke via intranasal administration. A three-factor Box-Behnken experimental design was used to optimize the formulation of liposomes co-loaded with Panax notoginseng saponins (PNSs) and Ginsenoside Rg3 (Rg3) (Lip-Rg3/PNS). Macrophage membranes were coated onto the surface of the optimized liposomes to target the ischemic site of the brain. The double-loaded liposomes disguised by macrophage membranes (MM-Lip-Rg3/PNS) were spherical, in a "shell-core" structure, with encapsulation rates of 81.41% (PNS) and 93.81% (Rg3), and showed good stability. In vitro, MM-Lip-Rg3/PNS was taken up by brain endothelial cells via the clathrin-dependent endocytosis and micropinocytosis pathways. Network pharmacology experiments predicted that MM-Lip-Rg3/PNS could regulate multiple signaling pathways and treat ischemic stroke by reducing apoptosis and inflammatory responses. After 14 days of treatment with MM-Lip-Rg3/PNS, the survival rate, weight, and neurological score of middle cerebral artery occlusion (MCAO) rats significantly improved. The hematoxylin and eosin (H&E) and TUNEL staining results showed that MM-Lip-Rg3/PNS can reduce neuronal apoptosis and inflammatory cell infiltration and protect the ischemic brain. In vivo biological experiments have shown that free Rg3, PNS, and MM-Lip-Rg3/PNS can alleviate inflammation and apoptosis, especially MM-Lip-Rg3/PNS, indicating that biomimetic liposomes can improve the therapeutic effects of drugs. Overall, MM-Lip-Rg3/PNS is a potential biomimetic nano targeted formulation for ischemic stroke therapy.
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Accidente Cerebrovascular Isquémico , Saponinas , Ratas , Animales , Liposomas/química , Células Endoteliales , Administración Intranasal , Saponinas/farmacología , MacrófagosRESUMEN
Activation of hepatic stellate cells (HSC) is a key event in the initiation of liver fibrosis. Activated HSCs proliferate and secrete excessive amounts of extracellular matrix (ECM), disturbing liver architecture and function, leading to fibrosis and eventually cirrhosis. Collagen is the most abundant constituent of ECM and proline is the most abundant amino acid of collagen. Arginine is the precursor in the biosynthetic pathway of proline. Arginine is the exclusive substrate of both nitric oxide synthase (NOS) and arginase. NOS is an M1 (proinflammatory) marker of macrophage polarization whereas arginase-1 (Arg1) is an M2 (profibrogenic) marker of macrophage polarization. Differential expression of NOS and Arg1 has not been studied in HSCs yet. To identify the expression profile of arginine catabolic enzymes during HSC activation and to investigate their role in HSC activation, primary rat HSCs were cultured-activated for 7 days and expression of iNOS and Arg1 were investigated. Nor-NOHA was used as a specific and reversible arginase inhibitor. During HSC activation, iNOS expression decreased whereas Arg1 expression increased. Inhibition of Arg1 in activated HSCs efficiently inhibited collagen production but not cell proliferation. HSC activation is accompanied by a switch of arginine catabolism from iNOS to Arg1. Inhibition of Arg1 decreases collagen synthesis. Therefore, we conclude that Arg1 can be a therapeutic target for the inhibition of liver fibrogenesis.
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Arginasa , Células Estrelladas Hepáticas , Ratas , Animales , Células Estrelladas Hepáticas/metabolismo , Arginasa/genética , Arginasa/metabolismo , Cirrosis Hepática/metabolismo , Colágeno/metabolismo , ArgininaRESUMEN
Salmonella typhimurium (S. typhimurium) and Staphylococcus aureus (S. aureus) are common food-borne pahogens that cause food poisoning in humans. In this study, we developed a method for the simultaneous determination of S. typhimurium and S. aureus based on multiplex polymerase spiral reaction (m-PSR) and melting curve analysis. Two pairs of primers were designed specifically to target the conserved invA gene of S. typhimurium and nuc gene of S. aureus, and the nucleic acid amplification reaction was achieved under isothermal conditions in the same reaction tube for 40 min at 61 °C, melting curve analysis of the amplification product was carried out. The distinct mean melting temperature allowed simultaneous differentiation of the two target bacteria in the m-PSR assay. The limit of detection of S. typhimurium and S. aureus that could be detected simultaneously was 4.1 × 10-4 ng genomic DNA and 2 × 101 CFU/mL pure bacterial culture. Based on this method, analysis of artificially contaminated samples showed excellent sensitivity and specificity consistent with those of pure bacterial cultures. This method is rapid, simultaneous and promises to be a useful tool for the detection of food-borne pathogens in the food industry.
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Salmonella typhimurium , Staphylococcus aureus , Humanos , Salmonella typhimurium/genética , Staphylococcus aureus/genética , Microbiología de Alimentos , Técnicas de Amplificación de Ácido Nucleico , Sensibilidad y EspecificidadRESUMEN
Nervous necrosis virus (NNV) could infect more than 200 fish species worldwide, with almost 100% mortality in affected larvae and juvenile fish. Among different genotypes of NNV, the red-grouper nervous necrosis virus (RGNNV) genotype is the most widely reported with the highest number of susceptible species. Interferon (IFN) is a crucial antiviral cytokine and RGNNV needs to develop some efficient strategies to resist host IFN-stimulated antiviral immune. Although considerable researches on RGNNV, whether RGNNV B1 protein participates in regulating the host's IFN response remains unknown. Here, we reported that B1 protein acted as a transcript inhibition factor to suppress fish IFN production. We firstly found that ectopic expression of B1 protein significantly decreased IFN and IFN-stimulated genes (ISGs) mRNA levels and IFNφ1 promoter activity induced by polyinosinic:polycytidylic acid [poly (I:C)]. Further studies showed that B1 protein inhibited the IFNφ1 promoter activity stimulated by the key RIG-I-like receptors (RLRs) factors, including MDA5, MAVS, TBK1, IRF3, and IRF7 and decreased their protein levels. Moreover, B1 protein significantly inhibited the activity of constitutively active cytomegalovirus (CMV) promoter, which suggested that B1 protein was a transcription inhibitor. Western blot indicated that B1 protein decreased the Ser5 phosphorylation of RNA polymerase II (RNAP II) C-terminal domain (CTD). Together, our data demonstrated that RGNNV B1 protein was a host transcript antagonist, which intervened RNAP II Ser5-phosphorylation, inhibiting host IFN response and facilitating RGNNV replication.
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Lubina , Enfermedades de los Peces , Nodaviridae , Infecciones por Virus ARN , Animales , Inmunidad Innata/genética , ARN Polimerasa II/genética , ARN Polimerasa II/metabolismo , Regulación de la Expresión Génica , Proteínas de Peces/genética , Secuencia de Aminoácidos , Alineación de Secuencia , Antivirales , Poli I-C/farmacología , Replicación Viral , Necrosis , Nodaviridae/fisiologíaRESUMEN
Type I IFNs (IFN-I) are important for tumor immune surveillance and contribute to the therapeutic responses for numerous treatment regimens. Nevertheless, certain protumoral activities by IFN-I have been increasingly recognized. Indeed, our recent work showed that systemic poly(I:C)/IFN treatment can undesirably trigger high arginase (ARG1) expression within the tumor-associated monocyte/macrophage compartment. Using a line of CRISPR-generated Arg1-YFP reporter knock-in mice, we have determined that a subset of tumor-associated macrophages represent the major Arg1-expressing cell type following poly(I:C)/IFN stimulation. More detailed analyses from in vitro and in vivo models demonstrate a surprising IFN-to-IL-4 cytokine axis in transitional monocytes, which can subsequently stimulate IL-4 target genes, including Arg1, in macrophages. Intriguingly, IFN stimulation of transitional monocytes yielded concurrent M2 (YFP+)- and M1 (YFP-)-skewed macrophage subsets, correlated with an inhibitory crosstalk between IFN-I and IL-4. Genetic abrogation of IL-4 signaling in mice diminished poly(I:C)/IFN-induced ARG1 in tumors, leading to enhanced activation of CD8+ T cells and an improved therapeutic effect. The present work uncovered a monocyte-orchestrated macrophage phenotype conversion mechanism that may have broad implications.
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Citocinas/metabolismo , Interferones/metabolismo , Interleucina-4/metabolismo , Macrófagos/metabolismo , Monocitos/metabolismo , Poli I-C/metabolismo , Animales , Arginasa/inmunología , Arginasa/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Diferenciación Celular/inmunología , Citocinas/inmunología , Femenino , Interferones/inmunología , Interleucina-4/inmunología , Macrófagos/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Monocitos/inmunología , Neoplasias/inmunología , Neoplasias/metabolismo , Fenotipo , Poli I-C/inmunología , Transducción de Señal/inmunología , Transducción de Señal/fisiologíaRESUMEN
Tobacco smoking is associated with deleterious health outcomes. Most smokers want to quit smoking, yet relapse rates are high. Understanding neural differences associated with tobacco use may help generate novel treatment options. Several animal studies have recently highlighted the central role of the thalamus in substance use disorders, but this research focus has been understudied in human smokers. Here, we investigated associations between structural and functional magnetic resonance imaging measures of the thalamus and its subnuclei to distinct smoking characteristics. We acquired anatomical scans of 32 smokers as well as functional resting-state scans before and after a cue-reactivity task. Thalamic functional connectivity was associated with craving and dependence severity, whereas the volume of the thalamus was associated with dependence severity only. Craving, which fluctuates rapidly, was best characterized by differences in brain function, whereas the rather persistent syndrome of dependence severity was associated with both brain structural differences and function. Our study supports the notion that functional versus structural measures tend to be associated with behavioural measures that evolve at faster versus slower temporal scales, respectively. It confirms the importance of the thalamus to understand mechanisms of addiction and highlights it as a potential target for brain-based interventions to support smoking cessation, such as brain stimulation and neurofeedback.
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Cese del Hábito de Fumar , Tabaquismo , Humanos , Tabaquismo/diagnóstico por imagen , Ansia/fisiología , Fumar , Imagen por Resonancia Magnética , Tálamo/diagnóstico por imagenRESUMEN
Metastatic cancer is difficult to cure because of its uncontrollable nature and side effects during treatment. We constructed a reactive oxygen species (ROS)-activated smart theranostic prodrug system based on an ROS active site linked with both a targeting group and an anticancer drug for efficient regional chemotherapy of metastatic cancers. The optimized prodrug (Bio-(8)-MB-CPT) with biotin as the targeting group displayed high sensitivity towards ROS and selectively targeting ability towards cervical cancer cells, showing highly efficient drug release (up to 92 %) in vitro. Bio-(8)-MB-CPT thus exerted strong toxicity towards cervical cancer cells, but unlike the parent drug (camptothecin), showed no toxicity towards normal cells. Moreover, the prodrug displayed significantly enhanced antitumor efficacy in vivo and eradicated the tumor with no obvious side effects (inhibition of the tumor reached up to 99.9 %).
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Antineoplásicos , Nanopartículas , Profármacos , Neoplasias del Cuello Uterino , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Camptotecina/farmacología , Camptotecina/uso terapéutico , Línea Celular Tumoral , Liberación de Fármacos , Femenino , Humanos , Nanopartículas/química , Profármacos/química , Profármacos/farmacología , Profármacos/uso terapéutico , Especies Reactivas de Oxígeno , Nanomedicina Teranóstica , Neoplasias del Cuello Uterino/tratamiento farmacológicoRESUMEN
Active species were introduced into MOFs to prepare multifunctional fluorescent probes by a stepwise postsynthetic modulation strategy. First, two-dimensional HPU-16 (HPU = Henan Polytechnic University; HPU-16 = Zn(L)2(H2O); HL = 2-(5-pyridin-4-yl-5H-[1,2,4]triazol-3-yl)-pyrazine) was transformed into three-dimensional HPU-17 ({Zn3(L)2(btc)2(H2O)}n) through a crystal dissolution-recrystallization process. Second, linker replacement was used to introduce -NH2 into the HPU-17 to generate functional NH2-HPU-17 via a single-crystal to single-crystal transformation. The functional amino groups caused NH2-HPU-17 to show a significant response to ClO-. Because of the interaction of amino groups and ClO-, the fluorescence of NH2-HPU-17 gradually changed from blue to yellow-green. More interestingly, NH2-HPU-17 could encapsulate Tb3+ and sensitize the visible-emitting characteristic fluorescence of Tb3+ in aqueous solution. Then, newly generated Tb3+@NH2-HPU-17 could serve as an effective probe for the determination of DPA. This work paves a new way for the design and modulation of ratiometric fluorescence probes for the selective and sensitive detection of special molecules.
RESUMEN
Hepatic fibrosis is caused by chronic inflammation and characterized as the excessive accumulation of extracellular matrix (ECM) by activated hepatic stellate cells (HSCs). Gasotransmitters like NO and CO are known to modulate inflammation and fibrosis, however, little is known about the role of the gasotransmitter hydrogen sulfide (H2S) in liver fibrogenesis and stellate cell activation. Endogenous H2S is produced by the enzymes cystathionine ß-synthase (CBS), cystathionine γ-lyase (CTH) and 3-mercaptopyruvate sulfur transferase (MPST) [1]. The aim of this study was to elucidate the role of endogenously produced and/or exogenously administered H2S on rat hepatic stellate cell activation and fibrogenesis. Primary rat HSCs were culture-activated for 7 days and treated with different H2S releasing donors (slow releasing donor GYY4137, fast releasing donor NaHS) or inhibitors of the H2S producing enzymes CTH and CBS (DL-PAG, AOAA). The main message of our study is that mRNA and protein expression level of H2S synthesizing enzymes are low in HSCs compared to hepatocytes and Kupffer cells. However, H2S promotes hepatic stellate cell activation. This conclusion is based on the fact that production of H2S and mRNA and protein expression of its producing enzyme CTH are increased during hepatic stellate cell activation. Furthermore, exogenous H2S increased HSC proliferation while inhibitors of endogenous H2S production reduce proliferation and fibrotic makers of HSCs. The effect of H2S on stellate cell activation correlated with increased cellular bioenergetics. Our results indicate that the H2S generation in hepatic stellate cells is a target for anti-fibrotic intervention and that systemic interventions with H2S should take into account cell-specific effects of H2S.
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Células Estrelladas Hepáticas/efectos de los fármacos , Sulfuro de Hidrógeno/farmacología , Animales , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Células Estrelladas Hepáticas/metabolismo , Sulfuro de Hidrógeno/administración & dosificación , Sulfuro de Hidrógeno/análisis , Masculino , Ratas , Ratas WistarRESUMEN
The overproduction of HOCl is highly correlated with diseases such as atherosclerosis, rheumatoid arthritis, and cancer. Whilst acting as a marker of these diseases, HOCl might also be used as an activator of prodrugs or drug delivery systems for the treatment of the corresponding disease. In this work, a new platform of HOCl probes has been developed that integrates detection, imaging, and therapeutic functions. The probes can detect HOCl, using both NIR emission and the naked eye in vitro, with high sensitivity and selectivity at ultralow concentrations (the detection limit is at the nanomolar level). Basal levels of HOCl can be imaged in HL-60 cells without special stimulation. Moreover, the probes provided by this platform can rapidly release either amino- or carboxy-containing compounds from prodrugs, during HOCl detection and imaging, to realize a therapeutic effect.
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Diseño de Fármacos , Ácido Hipocloroso/química , Sondas Moleculares/química , Imagen Óptica , Profármacos/química , Supervivencia Celular/efectos de los fármacos , Células HL-60 , Humanos , Estructura Molecular , Profármacos/síntesis química , Profármacos/farmacologíaRESUMEN
Background The rich neovascularization of renal angiomyolipoma (AML) has a tendency for spontaneous rupture with subsequent hemorrhage. Nephrectomy or nephron-sparing surgery has rarely been used as a primary treatment in urgent situations. Purpose To evaluate the safety and long-term outcomes for patients treated by urgent transcatheter arterial embolization (TAE) for spontaneous ruptured renal AML with severe hemorrhage. Material and Methods A retrospective evaluation was performed of 25 renal AML cases with spontaneous hemorrhage confirmed by imaging. Polyvinyl alcohol (PVA) particles and coils of multiple sizes were used to embolize the spontaneous renal AML ruptures. Results The technical success rate of TAE was 96% (24/25). One week post-TAE, 1 patient with recurrent hemorrhage underwent emergency nephrectomy. Minor complications affected 16 patients with post-embolization syndrome; 15 patients resolved using conservative measures and one patient received nephrectomy post TAE 1 week later. All patients were followed up for 24-72 months (median, 50.2 months). Surgical treatment was avoided for 92% (23/25) of patients, and the re-embolization rate was 0% at 2 years post TAE. In the 23 patients without surgical treatment, the mean maximum diameter of renal AML was reduced from 12.4 ± 5.5 cm to 6.3 ± 2.5 cm and no hemorrhage occurred during follow-up. Conclusion Urgent TAE is a technically feasible and minimally invasive procedure for controlling severe hemorrhage and preservation of renal function following spontaneous ruptured renal AML.
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Angiomiolipoma/complicaciones , Angiomiolipoma/terapia , Quimioembolización Terapéutica/métodos , Hemorragia/etiología , Hemorragia/terapia , Neoplasias Renales/complicaciones , Neoplasias Renales/terapia , Adulto , Anciano , Angiomiolipoma/diagnóstico por imagen , Cuidados Críticos/métodos , Femenino , Hemorragia/diagnóstico por imagen , Humanos , Neoplasias Renales/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Rotura , Resultado del TratamientoRESUMEN
PURPOSE: To determine the safety and feasibility of percutaneous transhepatic cholangiography (PTC) and intraductal radiofrequency (RF) ablation combined with biliary stent placement for malignant biliary obstruction. MATERIALS AND METHODS: Data from patients with unresectable malignant biliary obstruction who underwent PTC, intraductal RF ablation, and biliary stent placement (n = 12) or PTC and biliary stent placement only (control group; n = 14) were reviewed. Postoperative complications, jaundice remission, and stent patency were assessed. RESULTS: All procedures were successful. No severe complications (eg, biliary bleeding, perforation) occurred. Two experimental group patients developed cholangitis, which resolved with conservative treatment. The 1-week jaundice remission and 3-month stent patency rates were similar in both groups, but the 6-month stent patency rate was higher in the experimental group (P < .05). In the experimental group, one death occurred as a result of gastrointestinal hemorrhage (unrelated to stent placement) by 3 months, and there were two cases of recurrent jaundice by 6 months. The latter two patients underwent repeat PTC, ablation, and stent placement. In the control group, one death occurred as a result of hepatic failure caused by progressive jaundice at 3 months, and another death resulted from disseminated intravascular coagulation caused by jaundice recurrence at 138 days after stent placement. In addition, seven patients developed jaundice recurrence (50-151 d after stent placement). PTC and repeat stent placement were performed in these patients. CONCLUSIONS: Percutaneous transhepatic cholangiography and intraductal RF ablation combined with biliary stent placement for malignant biliary obstruction is safe and feasible and effectively prolongs stent patency time.
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Neoplasias de los Conductos Biliares/complicaciones , Ablación por Catéter , Colangiografía/métodos , Colestasis/diagnóstico por imagen , Colestasis/cirugía , Stents , Femenino , Humanos , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias , Resultado del TratamientoRESUMEN
BACKGROUND: Anastomotic bleeding is an infrequent but life-threatening complication after stapled digestive tract anastomosis. Endovascular embolization is one of the available treatments, but precise clinical outcomes are yet to be evaluated. PURPOSE: To evaluate the efficacy and safety of endovascular embolization for managing anastomotic bleeding after stapled digestive tract anastomosis. MATERIAL AND METHODS: Twenty-eight patients were diagnosed with anastomotic bleeding after stapled digestive tract anastomosis by digital subtraction angiography (DSA). Curative effect was summed for analysis. RESULTS: All bleeding arteries were located in the stoma and were identified by contrast agent spillover by DSA. The offending arteries were superselectively catheterized and embolized with microcoils and/or gelatin sponge particles. Laboratory examinations showed normal hemoglobin and red blood cell counts when the patients' abdominal cavity drainage tubes stopped draining blood. The follow-up period was 3.2-84.7 months (median, 19.7 months). Four patients died during this time, of which two had cholangiocarcinoma, one had gastric cancer with tumor recurrence and multiple organ failure, and the final patient had a subarachnoid hemorrhage 4 months after embolization. In the surviving patients, no rebleeding occurred after embolization and no additional intervention or surgery was required. CONCLUSION: Endovascular embolization is safe and effective for managing anastomotic bleeding after stapled digestive tract anastomosis.
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Anastomosis Quirúrgica/métodos , Fuga Anastomótica/terapia , Procedimientos Quirúrgicos del Sistema Digestivo , Embolización Terapéutica/métodos , Hemorragia Gastrointestinal/terapia , Hemorragia Posoperatoria/terapia , Grapado Quirúrgico , Adolescente , Adulto , Anciano , Fuga Anastomótica/diagnóstico por imagen , Angiografía de Substracción Digital , Femenino , Hemorragia Gastrointestinal/diagnóstico por imagen , Humanos , Masculino , Persona de Mediana Edad , Hemorragia Posoperatoria/diagnóstico por imagen , Resultado del TratamientoRESUMEN
PURPOSE: To compare the efficacy of percutaneous transhepatic variceal embolization (PTVE) followed by partial splenic embolization (PSE) with that of PTVE alone for the treatment of acute massive hemorrhage of esophagogastric varices in patients with cirrhosis unable to undergo alternative procedures. MATERIALS AND METHODS: Sixty-five patients with acute variceal massive hemorrhage were retrospectively studied, including 31 who underwent PTVE/PSE and 34 who underwent PTVE and refused PSE. Recurrent bleeding rate, survival rate, postoperative complications, number of days of hospitalization after PTVE, and outcome were evaluated. Peripheral blood cell counts and hemoglobin levels before and at 1 week and 6, 12, and 24 months after intervention were analyzed. RESULTS: Cumulative recurrent bleeding rates at 6, 12, and 24 months after intervention in the PTVE/PSE group were 3.2%, 6.7%, and 13.3%, compared with 20.6%, 36.7%, and 53.6%, respectively, in the PTVE group; the difference at each time point was statistically significant (all P < .01). There were more cases of ascites and portal hypertensive gastropathy after PTVE than after PTVE/PSE (P < .05). Survival rates at 6, 12, and 24 months in the PTVE/PSE group were 100%, 96.8%, and 96.8%, compared with 94.1%, 88.2%, and 82.4%, respectively, in the PTVE group. There were significant differences in peripheral blood cell counts and hemoglobin levels between the PTVE/PSE and PTVE groups at all observed time points (all P < .01). CONCLUSIONS: PTVE/PSE not only has long-term efficacy in alleviating hypersplenism, but decreases recurrent bleeding and maintains hepatic reserve in patients with cirrhosis and esophagogastric variceal massive hemorrhage unable to undergo other procedures.
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Embolización Terapéutica/métodos , Várices Esofágicas y Gástricas/terapia , Hemorragia Gastrointestinal/terapia , Hiperesplenismo/terapia , Cirrosis Hepática/complicaciones , Enfermedad Aguda , Adulto , Várices Esofágicas y Gástricas/complicaciones , Femenino , Estudios de Seguimiento , Hemorragia Gastrointestinal/complicaciones , Humanos , Hiperesplenismo/complicaciones , Hipertensión Portal/complicaciones , Estimación de Kaplan-Meier , Masculino , Recurrencia , Estudios Retrospectivos , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
PURPOSE: This study was done to evaluate the clinical implications and results of a prospective protocol using 64-row computed tomographic angiography (CTA) for diagnosis and pre-treatment planning in pulmonary sequestration (PS). MATERIALS AND METHODS: Forty-five patients with suspected PS were referred for CTA examination. The accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of measures used to detect PS were determined by patient-based and aberrant systemic artery-based evaluations. The location, the size and the number of aberrant systemic arteries, and the feasibility of endovascular treatment were analysed. The capability of CTA to provide a working view and the accuracy of measurements in choosing a coil were also assessed. RESULTS: Digital subtraction angiography and/or surgery revealed PS in 38 patients, and 7 patients had no PS. The patient-based evaluation yielded an accuracy of 97.8 %, sensitivity of 97.4 %, specificity of 100 %, PPV of 100 % and NPV of 87.5 %, in the detection of PS. CTA clearly depicted the PS in all 38 patients, and the aberrant systemic artery was accurately demonstrated in 37 out of 38 patients where endovascular treatment was possible. Working views for endovascular treatment were found in all patients with PS, and the choice of coil was correct in 37 out of 38 patients using CTA. CONCLUSIONS: 64-row CTA appears to be effective in terms of supporting accurate diagnosis and pre-treatment planning in PS. CTA is not only able to provide clear visualisation of aberrant systemic arteries but also provides detailed images of abnormal lung parenchyma and the airways.
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Secuestro Broncopulmonar/diagnóstico por imagen , Tomografía Computarizada por Rayos X/métodos , Adolescente , Adulto , Angiografía de Substracción Digital , Secuestro Broncopulmonar/terapia , Niño , Preescolar , Embolización Terapéutica , Femenino , Humanos , Recién Nacido , Masculino , Persona de Mediana Edad , Planificación de Atención al Paciente , Valor Predictivo de las Pruebas , Sensibilidad y EspecificidadRESUMEN
Purpose: Ginsenoside Rg3 (Rg3) and Panax notoginseng saponins (PNS) can be used for ischemic stroke treatment, however, the lack of targeting to the ischemic region limits the therapeutic effect. To address this, we leveraged the affinity of macrophage membrane proteins for inflamed brain microvascular endothelial cells to develop a macrophage membrane-cloaked liposome loaded with Rg3 and PNS (MM-Lip-Rg3/PNS), which can precisely target brain lesion region through intranasal administration. Methods: MM-Lip-Rg3/PNS was prepared by co-extrusion method and was performed by characterization, stability, surface protein, and morphology. The cellular uptake, immune escape ability, and blood-brain barrier crossing ability of MM-Lip-Rg3/PNS were studied in vitro. The in vivo brain targeting, biodistribution and anti-ischemic efficacy of MM-Lip-Rg3/PNS were evaluated in MACO rats, and we determined the diversity of the nasal brain pathway through the olfactory nerve blockade model in rats. Finally, the pharmacokinetics and brain targeting index of MM-Lip-Rg3/PNS were investigated. Results: Our results indicated that MM-Lip-Rg3/PNS was spherical with a shell-core structure. MM-Lip-Rg3/PNS can avoid mononuclear phagocytosis, actively bind to inflammatory endothelial cells, and have the ability to cross the blood-brain barrier. Moreover, MM-Lip-Rg3/PNS could specifically target ischemic sites, even microglia, increase the cumulative number of drugs in the brain, improve the inflammatory environment of the brain, and reduce the infarct size. By comparing olfactory nerve-blocking rats with normal rats, it was found that there are direct and indirect pathways for nasal entry into the brain. Pharmacokinetics demonstrated that MM-Lip-Rg3/PNS exhibited stronger brain targeting and prolonged drug half-life. Conclusion: MM-Lip-Rg3/PNS might contribute to the accumulation of Rg3 and PNS in the ischemic brain area to improve treatment efficacy. This biomimetic nano-drug delivery system provides a new and promising strategy for the treatment of ischemic stroke.
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Administración Intranasal , Barrera Hematoencefálica , Ginsenósidos , Accidente Cerebrovascular Isquémico , Liposomas , Macrófagos , Animales , Liposomas/química , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Ratas , Masculino , Ginsenósidos/farmacocinética , Ginsenósidos/química , Ginsenósidos/administración & dosificación , Ginsenósidos/farmacología , Barrera Hematoencefálica/efectos de los fármacos , Macrófagos/efectos de los fármacos , Sistemas de Liberación de Medicamentos/métodos , Ratas Sprague-Dawley , Distribución Tisular , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Materiales Biomiméticos/química , Materiales Biomiméticos/farmacocinética , Materiales Biomiméticos/administración & dosificación , Saponinas/farmacocinética , Saponinas/química , Saponinas/administración & dosificación , Saponinas/farmacología , RatonesRESUMEN
A continuously stable moist healing environment is immensely beneficial for wound healing, which can be availably achieved by providing an in situ hydrogel with enough strength resembling skin tissue and self-healing ability. Herein, through a dual-crosslinking strategy, hyaluronic acid-based hydrogels with excellent self-healing capacity and enhanced mechanical properties are fabricated via the acylhydrazone linkages and subsequent photocrosslinking based on hydrazide-modified sodium hyaluronate and aldehyde-modified maleic sodium hyaluronate. The hydrogels demonstrate the fast gelation process (< 1 min), the controlled swelling behaviors, and the good biocompatibility. Notably, they possess enhanced mechanical strength similar to the human dermis (â¼ 2.2 kPa). Also, they can self-heal rapidly with a self-healing efficiency of â¼90 % at 6 h. Based on this, the hyaluronic acid-based hydrogels, without any biological factors involved, can facilitate the full-thickness skin wound reconstruction process by accelerating the three phases of the wound repair, including reducing wound inflammation in the inflammatory phase, promoting angiogenesis in the proliferative phase, and promoting the deposition and reconstruction of collagen in the remodeling phase. The produced hyaluronic acid hydrogel can serve as an ideal candidate for wound healing.
Asunto(s)
Ácido Hialurónico , Hidrogeles , Cicatrización de Heridas , Ácido Hialurónico/química , Ácido Hialurónico/farmacología , Hidrogeles/química , Hidrogeles/farmacología , Cicatrización de Heridas/efectos de los fármacos , Humanos , Animales , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Ratones , Piel/efectos de los fármacos , Fenómenos MecánicosRESUMEN
Breast cancer is the leading cause of cancer-related deaths in women worldwide, with Hormone Receptor (HR)+ being the predominant subtype. Tamoxifen (TAM) serves as the primary treatment for HR+ breast cancer. However, drug resistance often leads to recurrence, underscoring the need to develop new therapies to enhance patient quality of life and reduce recurrence rates. Artemisinin (ART) has demonstrated efficacy in inhibiting the growth of drug-resistant cells, positioning art as a viable option for counteracting endocrine resistance. This study explored the interaction between artemisinin and tamoxifen through a combined approach of bioinformatics analysis and experimental validation. Five characterized genes (ar, cdkn1a, erbb2, esr1, hsp90aa1) and seven drug-disease crossover genes (cyp2e1, rorc, mapk10, glp1r, egfr, pgr, mgll) were identified using WGCNA crossover analysis. Subsequent functional enrichment analyses were conducted. Our findings confirm a significant correlation between key cluster gene expression and immune cell infiltration in tamoxifen-resistant and -sensitized patients. scRNA-seq analysis revealed high expression of key cluster genes in epithelial cells, suggesting artemisinin's specific impact on tumor cells in estrogen receptor (ER)-positive BC tissues. Molecular target docking and in vitro experiments with artemisinin on LCC9 cells demonstrated a reversal effect in reducing migratory and drug resistance of drug-resistant cells by modulating relevant drug resistance genes. These results indicate that artemisinin could potentially reverse tamoxifen resistance in ER-positive breast cancer.
Asunto(s)
Artemisininas , Neoplasias de la Mama , Biología Computacional , Resistencia a Antineoplásicos , Receptores de Estrógenos , Tamoxifeno , Tamoxifeno/farmacología , Tamoxifeno/uso terapéutico , Humanos , Artemisininas/farmacología , Artemisininas/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Femenino , Resistencia a Antineoplásicos/genética , Biología Computacional/métodos , Receptores de Estrógenos/metabolismo , Antineoplásicos Hormonales/farmacología , Antineoplásicos Hormonales/uso terapéutico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Línea Celular Tumoral , Simulación del Acoplamiento Molecular , Proliferación Celular/efectos de los fármacosRESUMEN
Passive radiative cooling (PRC), as an energy-free cooling approach, is ingeniously harnessed for certain natural organisms to withstand extreme high-temperature climates, which has inspired numerous bionic designs. However, it is a great challenge to enhance the durability of the designed materials in practical scenarios while inheriting the natural biological principles. We demonstrate bionic dual-scale structured (BDSS) films for efficient passive radiative cooling accompanied by robust durability after discovering the excellent thermoregulatory properties of the inner surface of Hawaiian scallop shell. We found that the inner surface of the shell consists of large-scale triangular ridges scattered with small-scale terrace steps. This dual-scale structure can enhance the reflectivity of sunlight by efficient Mie scattering and increase the emissivity in the mid-infrared range by lengthening the propagation of photons, thereby decreasing the surface temperature. Underpinned by this finding, we developed a BDSS film that features a strong solar spectrum reflectivity of 0.95 and a high mid-infrared emissivity of 0.98, achieving a sub-ambient cooling of 10.8 °C under direct sunlight. Additionally, the designed films possess robust durability including excellent self-cleaning, flexibility, mechanical strength, chemical stability, and anti-ultraviolet radiation, which is promising for thermal thermoregulation in various harsh scenarios.