RESUMEN
Helicobacter pylori (HP), a common microanaerobic bacteria that lives in the human mouth and stomach, is reported to infect ≈50% of the global population. The current diagnostic methods for HP are either invasive, time-consuming, or harmful. Therefore, a noninvasive and label-free HP diagnostic method needs to be developed urgently. Herein, reduced graphene oxide (rGO) is composited with different metal-based materials to construct a graphene-based electronic nose (e-nose), which exhibits excellent sensitivity and cross-reactive response to several gases in exhaled breath (EB). Principal component analysis (PCA) shows that four typical types of gases in EB can be well discriminated. Additionally, the potential of the e-nose in label-free detection of HP infection is demonstrated through the measurement and analysis of EB samples. Furthermore, a prototype of an e-nose device is designed and constructed for automatic EB detection and HP diagnosis. The accuracy of the prototype machine integrated with the graphene-based e-nose can reach 92% and 91% in the training and validation sets, respectively. These results demonstrate that the highly sensitive graphene-based e-nose has great potential for the label-free diagnosis of HP and may become a novel tool for non-invasive disease screening and diagnosis.
RESUMEN
Helicobacter pylori (H. pylori) is a globally widespread bacterial infection. Early diagnosis of this infection is vital for public and individual health. Prevalent diagnosis methods like the isotope 13C or 14C labelled urea breath test (UBT) are not convenient and may do harm to the human body. The use of cross-response gas sensor arrays (GSAs) is an alternative way for label-free detection of metabolite changes in exhaled breath (EB). However, conventional GSAs are complex to prepare, lack reliability, and fail to discriminate subtle changes in EB due to the use of numerous sensing elements and single dimensional signal. This work presents a dual-element multimodal GSA empowered with multimodal sensing signals including conductance (G), capacitance (C), and dissipation factor (DF) to improve the ability for gas recognition and H. pylori-infection diagnosis. Sensitized by poly(diallyldimethylammonium chloride) (PDDA) and the metal-organic framework material NH2-UiO66, the dual-element graphene oxide (GO)-composite GSAs exhibited a high specific surface area and abundant adsorption sites, resulting in high sensitivity, repeatability, and fast response/recovery speed in all three signals. The multimodal sensing signals with rich sensing features allowed the GSA to detect various physicochemical properties of gas analytes, such as charge transfer and polarization ability, enhancing the sensing capabilities for gas discrimination. The dual-element GSA could differentiate different typical standard gases and non-dehumidified EB samples, demonstrating the advantages in EB analysis. In a case-control clinical study on 52 clinical EB samples, the diagnosis model based on the multimodal GSA achieved an accuracy of 94.1%, a sensitivity of 100%, and a specificity of 90.9% for diagnosing H. pylori infection, offering a promising strategy for developing an accurate, non-invasive and label-free method for disease diagnosis.
Asunto(s)
Pruebas Respiratorias , Grafito , Infecciones por Helicobacter , Helicobacter pylori , Infecciones por Helicobacter/diagnóstico , Infecciones por Helicobacter/microbiología , Humanos , Helicobacter pylori/aislamiento & purificación , Pruebas Respiratorias/métodos , Pruebas Respiratorias/instrumentación , Grafito/química , Gases/química , Gases/análisis , Adulto , Masculino , Persona de Mediana Edad , FemeninoRESUMEN
BACKGROUND: Cardiac damage induced by ischemic stroke, such as arrhythmia, cardiac dysfunction, and even cardiac arrest, is referred to as cerebral-cardiac syndrome (CCS). Cardiac macrophages are reported to be closely associated with stroke-induced cardiac damage. However, the role of macrophage subsets in CCS is still unclear due to their heterogeneity. Sympathetic nerves play a significant role in regulating macrophages in cardiovascular disease. However, the role of macrophage subsets and sympathetic nerves in CCS is still unclear. METHODS AND RESULTS: In this study, a middle cerebral artery occlusion mouse model was used to simulate ischemic stroke. ECG and echocardiography were used to assess cardiac function. We used Cx3cr1GFPCcr2RFP mice and NLRP3-deficient mice in combination with Smart-seq2 RNA sequencing to confirm the role of macrophage subsets in CCS. We demonstrated that ischemic stroke-induced cardiac damage is characterized by severe cardiac dysfunction and robust infiltration of monocyte-derived macrophages into the heart. Subsequently, we identified that cardiac monocyte-derived macrophages displayed a proinflammatory profile. We also observed that cardiac dysfunction was rescued in ischemic stroke mice by blocking macrophage infiltration using a CCR2 antagonist and NLRP3-deficient mice. In addition, a cardiac sympathetic nerve retrograde tracer and a sympathectomy method were used to explore the relationship between sympathetic nerves and cardiac macrophages. We found that cardiac sympathetic nerves are significantly activated after ischemic stroke, which contributes to the infiltration of monocyte-derived macrophages and subsequent cardiac dysfunction. CONCLUSIONS: Our findings suggest a potential pathogenesis of CCS involving the cardiac sympathetic nerve-monocyte-derived macrophage axis.
Asunto(s)
Modelos Animales de Enfermedad , Accidente Cerebrovascular Isquémico , Macrófagos , Ratones Endogámicos C57BL , Proteína con Dominio Pirina 3 de la Familia NLR , Animales , Macrófagos/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/deficiencia , Accidente Cerebrovascular Isquémico/fisiopatología , Accidente Cerebrovascular Isquémico/metabolismo , Accidente Cerebrovascular Isquémico/patología , Receptores CCR2/genética , Receptores CCR2/metabolismo , Masculino , Ratones Noqueados , Ratones , Infarto de la Arteria Cerebral Media/fisiopatología , Infarto de la Arteria Cerebral Media/patología , Sistema Nervioso Simpático/fisiopatología , Miocardio/patología , Miocardio/metabolismo , Cardiopatías/etiología , Cardiopatías/fisiopatología , Cardiopatías/patología , Receptor 1 de Quimiocinas CX3C/genética , Receptor 1 de Quimiocinas CX3C/metabolismo , Receptor 1 de Quimiocinas CX3C/deficienciaRESUMEN
Water-stable organic radicals are promising photothermal conversion candidates for photothermal therapy (PTT). However, organic radicals are usually unstable in biological environments, which greatly hinders their wide application. Here, we have developed a chaotropic effect-based and photoinduced water-stable supramolecular radical (MB12-2) for efficient antibacterial PTT. The supramolecular radical precursor MB12-1 was constructed by the chaotropic effect between closo-dodecaborate cluster (B12H122-) and N,N'-dimethylated dipyridinium thiazolo [5,4-d] thiazole (MPT2+). Subsequently, with triethanolamine (TEOA) serving as an electron donor, MB12-1 could transform to its radical form MB12-2 through photoinduced electron transfer (PET) under 435-nm laser irradiation. The N2 adsorption-desorption analysis confirmed that MB12-2 was tightly packed through the introduction of B12H122-, which effectively enhanced its stability via a spatial site-blocked effect. Moreover, the half-life of MB12-2 in water was calculated through ultraviolet-visible light (UV-vis) absorption spectra results for periods as long as 20 days. In addition, in the skin infection model, MB12-2, as a wound dressing, showed remarkable photothermal antibacterial activity (>97%) under 660-nm laser irradiation and promoted wound healing. This study presents a simple method for designing long-term water-stable supramolecular radicals, offering a novel avenue for noncontact treatments for bacterial infections.
Asunto(s)
Antibacterianos , Terapia Fototérmica , Antibacterianos/química , Antibacterianos/farmacología , Animales , Agua/química , Ratones , Radicales Libres/química , Boro/química , Boro/farmacología , Staphylococcus aureus/efectos de los fármacos , Escherichia coli/efectos de los fármacosRESUMEN
Hydrogen sulfide (H2S), an important gas signaling molecule, is a regulator of many physiological processes, and its abnormal levels are closely related to the onset and progression of disease. It is vital to develop methods for specific tracking of H2S in clinical diagnosis and treatment. In this study, we designed an ultrasensitive and highly stable coumarin-based fluorescent probe Cou-H2S. Through the H2S-initiated tandem reaction, Cou-H2S successfully achieved highly selective and super-fast detection of H2S. Cou-H2S was successfully applied to the monitoring of endogenous and exogenous H2S at the cellular level and verified the validity of the detection of H2S in the LPS-induced zebrafish model. Therefore, Cou-H2S might provide new insights into the study of H2S-related diseases.
RESUMEN
The incidence and mortality rate of myocardial infarction are increasing per year in China. The polarization of macrophages towards the classically activated macrophages (M1) phenotype is of utmost importance in the progression of inflammatory stress subsequent to myocardial infarction. Poly (ADP-ribose) polymerase 1(PARP1) is the ubiquitous and best characterized member of the PARP family, which has been reported to support macrophage polarization towards the pro-inflammatory phenotype. Yet, the role of PARP1 in myocardial ischemic injury remains to be elucidated. Here, we demonstrated that a myocardial infarction mouse model induced cardiac damage characterized by cardiac dysfunction and increased PARP1 expression in cardiac macrophages. Inhibition of PARP1 by the PJ34 inhibitors could effectively alleviate M1 macrophage polarization, reduce infarction size, decrease inflammation and rescue the cardiac function post-MI in mice. Mechanistically, the suppression of PARP1 increase NLRC5 gene expression, and thus inhibits the NF-κB pathway, thereby decreasing the production of inflammatory cytokines such as IL-1ß and TNF-α. Inhibition of NLRC5 promote infection by effectively abolishing the influence of this mechanism discussed above. Interestingly, inhibition of NLRC5 promotes cardiac macrophage polarization toward an M1 phenotype but without having major effects on M2 macrophages. Our results demonstrate that inhibition of PARP1 increased NLRC5 gene expression, thereby suppressing M1 polarization, improving cardiac function, decreasing infarct area and attenuating inflammatory injury. The aforementioned findings provide new insights into the proinflammatory mechanisms that drive macrophage polarization following myocardial infarction, thereby introducing novel potential targets for future therapeutic interventions in individuals affected by myocardial infarction.
Asunto(s)
Péptidos y Proteínas de Señalización Intracelular , Macrófagos , Infarto del Miocardio , FN-kappa B , Poli(ADP-Ribosa) Polimerasa-1 , Animales , Masculino , Ratones , Modelos Animales de Enfermedad , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Ratones Endogámicos C57BL , Infarto del Miocardio/metabolismo , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/patología , FN-kappa B/metabolismo , Fenantrenos/farmacología , Fenantrenos/uso terapéutico , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Poli(ADP-Ribosa) Polimerasa-1/antagonistas & inhibidores , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Regulación hacia Arriba/efectos de los fármacosRESUMEN
BACKGROUND: Arrhythmia is the most common cardiac complication after ischemic stroke. Connexin 40 is the staple component of gap junctions, which influences the propagation of cardiac electrical signals in the sinoatrial node. However, the role of connexin 40 in post-stroke arrhythmia remains unclear. METHODS: In this study, a permanent middle cerebral artery occlusion model was used to simulate the occurrence of an ischemic stroke. Subsequently, an electrocardiogram was utilized to record and assess variations in electrocardiogram measures. In addition, optical tissue clearing and whole-mount immunofluorescence staining were used to confirm the anatomical localization of the sinoatrial node, and the sinoatrial node tissue was collected for RNA sequencing to screen for potential pathological mechanisms. Lastly, the rAAV9-Gja5 virus was injected with ultrasound guidance into the heart to increase Cx40 expression in the sinoatrial node. RESULTS: We demonstrated that the mice suffering from a permanent middle cerebral artery occlusion displayed significant arrhythmia, including atrial fibrillation, premature ventricular contractions, atrioventricular block, and abnormal electrocardiogram parameters. Of note, we observed a decrease in connexin 40 expression within the sinoatrial node after the ischemic stroke via RNA sequencing and western blot. Furthermore, rAAV9-Gja5 treatment ameliorated the occurrence of arrhythmia following stroke. CONCLUSIONS: In conclusion, decreased connexin 40 expression in the sinoatrial node contributed to the ischemic stroke-induced cardiac arrhythmia. Therefore, enhancing connexin 40 expression holds promise as a potential therapeutic approach for ischemic stroke-induced arrhythmia.
Asunto(s)
Arritmias Cardíacas , Proteína alfa-5 de Unión Comunicante , Accidente Cerebrovascular Isquémico , Nodo Sinoatrial , Animales , Ratones , Arritmias Cardíacas/etiología , Arritmias Cardíacas/genética , Conexinas/genética , Conexinas/metabolismo , Proteína alfa-5 de Unión Comunicante/genética , Proteína alfa-5 de Unión Comunicante/metabolismo , Accidente Cerebrovascular Isquémico/complicaciones , Accidente Cerebrovascular Isquémico/genética , Accidente Cerebrovascular Isquémico/metabolismo , Accidente Cerebrovascular Isquémico/patología , Ratones Endogámicos C57BL , Nodo Sinoatrial/metabolismo , Nodo Sinoatrial/patologíaRESUMEN
Deep-seated bacterial infections (DBIs) are stubborn and deeply penetrate tissues. Eliminating deep-seated bacteria and promoting tissue regeneration remain great challenges. Here, a novel radical-containing hydrogel (SFT-B Gel) cross-linked by a chaotropic effect was designed for the sensing of DBIs and near-infrared photothermal therapy (NIR-II PTT). A silk fibroin solution stained with 4,4',4â³-(1,3,5-triazine-2,4,6-triyl)tris(1-methylpyridin-1-ium) (TPT3+) was employed as the backbone, which could be cross-linked by a closo-dodecaborate cluster (B12H122-) through a chaotropic effect to form the SFT-B Gel. More interestingly, the SFT-B Gel exhibited the ability to sense DBIs, which could generate a TPT2+⢠radical with obvious color changes in the presence of bacteria. The radical-containing SFT-B Gel (SFT-Bâ Gel) possessed strong NIR-II absorption and a remarkable photothermal effect, thus demonstrating excellent NIR-II PTT antibacterial activity for the treatment of DBIs. This work provides a new approach for the construction of intelligent hydrogels with unique properties using a chaotropic effect.
Asunto(s)
Fototerapia , Terapia Fototérmica , Hidrogeles/farmacologíaRESUMEN
Human umbilical cord mesenchymal stem cells (UC-MSCs)-derived hepatocyte-like cells (HLCs) have shown great promise in the treatment of liver diseases. However, most current induction protocols yield hepatocyte-like cells with limited function as compared with primary hepatocytes. Schisandrin B (Sch B) is one of the main components of Schisandra chinensis, which can prevent fibrosis progression and promote liver cell regeneration. Herein, we investigated the effects of Sch B on hepatic differentiation of UC-MSCs. We found that treatment with 10 µM Sch B from the second stage of the differentiation process increased hepatic marker levels and hepatic function. Additionally, RNA-seq analysis revealed that Sch B promoted hepatic differentiation via activating the JAK2/STAT3 pathway. When transplanted HLCs into mice with CCL4-induced liver fibrosis, Sch B-treated HLCs exhibited significant therapeutic effects. This study provides an optimized hepatic differentiation protocol for UC-MSCs based on Sch B, yielding functioning cells for liver disease treatment.
RESUMEN
[This corrects the article DOI: 10.3389/fonc.2020.544288.].
RESUMEN
Ginkgo biloba is a highly valuable medicinal plant known for its rich secondary metabolites, including flavonoids. Zinc oxide nanoparticles (ZnO-NPs) can be used as nanofertilizers and nano-growth regulators to promote plant growth and development. However, little is known about the effects of ZnO-NPs on flavonoids in G. biloba. In this study, G. biloba was treated with different concentrations of ZnO-NPs (25, 50, 100 mg/L), and it was found that 25 mg/L of ZnO-NPs enhanced G. biloba fresh weight, dry weight, zinc content, and flavonoids, while 50 and 100 mg/L had an inhibitory effect on plant growth. Furthermore, quantitative reverse transcription (qRT)-PCR revealed that the increased total flavonoids and flavonols were mainly due to the promotion of the expression of flavonol structural genes such as GbF3H, GbF3'H, and GbFLS. Additionally, when the GbF3H gene was overexpressed in tobacco and G. biloba calli, an increase in total flavonoid content was observed. These findings indicate that 25 mg/L of ZnO-NPs play a crucial role in G. biloba growth and the accumulation of flavonoids, which can potentially promote the yield and quality of G. biloba in production.
Asunto(s)
Nanopartículas , Óxido de Zinc , Ginkgo biloba/química , Óxido de Zinc/análisis , Hojas de la Planta/metabolismo , Flavonoides/química , Flavonoles/metabolismoRESUMEN
Malachite green (MG), a toxic antibacterial agent, is widely used in the farming industry. Effectively regulating the biotoxicity of this highly water-soluble cationic dye is challenging. Here, we present a novel strategy to reduce the biotoxicity of MG through the self-assembly of MG and the closo-dodecaborate cluster ([B12H12]2-) driven by the chaotropic effect. [B12H12]2- and MG in an aqueous solution can rapidly form an insoluble cubic-type supramolecular complex (B12-MG), and the original toxicity of MG is completely suppressed. Surprisingly, this supramolecular complex, B12-MG, has a strong UV-vis absorption peak at 600-800 nm and significant photothermal conversion efficiency under 660 nm laser irradiation. On this basis, B12-MG, the supramolecular complex, can be used as an efficient photothermal agent for antimicrobial photothermal therapy (PTT) both in vitro and in vivo. As a molecular chaperone of MG, [B12H12]2- not only can be applied as an antidote to regulate the biotoxicity of MG but also provides a novel method for the construction of photothermal agents for PTT based on the chaotropic effect.
Asunto(s)
Boro , Terapia Fototérmica , Boro/farmacología , Fototerapia/métodosRESUMEN
Paclitaxel is an extensively used chemotherapy antitumor drug and paclitaxel-induced peripheral neuropathy (PIPN) is one of the most common side effect. Rapamycin, originally used as an adjuvant drug for chemotherapy, has recently been found to possess potential neuroprotective activities. Our purposes of this study are to verify the effect of rapamycin on PIPN, which contributes to a new target for PIPN treatment. Mice were given paclitaxel or rapamycin with different injection methods. Paw withdrawal threshold was tested at different time points for mechanical sensitivity assessment. Administration of paclitaxel, both 2â mg/kg and 5â mg/kg, could induce mechanical hypersensitivity. 0.01â mg intrathecal injection of rapamycin showed the best effect on attenuate the mechanical hyperalgesia of PIPN. Intrathecal injection of only rapamycin would not induce the mechanical hyperalgesia while when rapamycin and paclitaxel were used together the mechanical hyperalgesia induced by paclitaxel could be attenuated. Paclitaxel could induce mechanical hyperalgesia in mice and rapamycin could attenuate such mechanical hyperalgesia of PIPN.
Asunto(s)
Antineoplásicos , Enfermedades del Sistema Nervioso Periférico , Ratones , Animales , Paclitaxel/toxicidad , Hiperalgesia/inducido químicamente , Hiperalgesia/tratamiento farmacológico , Sirolimus/farmacología , Sirolimus/uso terapéutico , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Antineoplásicos/uso terapéuticoRESUMEN
The detection of nitric oxide in human exhaled breath (EB) has received wide attention due to its close relationship with respiratory tract inflammation. Herein, a ppb-level NOx chemiresistive sensor was prepared by assembling graphene oxide (GO) with a conductive π-d conjugated metal-organic framework Co3(HITP)2 (HITP = 2,3,6,7,10,11-hexaiminotriphenylene) in the presence of poly(dimethyldiallylammonium chloride) (PDDA). The construction of a gas sensor chip was achieved by drop-casting the GO/PDDA/Co3(HITP)2 composite onto ITO-PET interdigital electrodes, followed by in situ reduction of GO to reduced graphene oxide (rGO) in hydrazine hydrate vapor. Compared with bare rGO, the nanocomposite shows significantly improved sensitivity and selectivity for NOx among various gas analytes owing to its folded and porous structure as well as its numerous active sites. The limit of detection (LOD) for NO and NO2 can reach as low as 11.2 and 6.8 ppb, respectively, and the response/recovery time to 200 ppb NO is 24/41 s. These results indicate that rGO/PDDA/Co3(HITP)2 can achieve a sensitive and fast response toward NOx at room temperature (RT). Additionally, good repeatability and long-term stability were observed. Furthermore, the sensor shows improved humidity tolerance owing to the presence of hydrophobic benzene rings in Co3(HITP)2. To demonstrate its ability in EB detection, EB samples collected from healthy individuals were spiked with a certain amount of NO to simulate the EB of respiratory inflammatory patients. The sensor can successfully distinguish healthy people from the simulated patients. Furthermore, in real clinical sample detection, the sensor can further differentiate acute respiratory inflammatory patients from the chronic ones.
Asunto(s)
Grafito , Estructuras Metalorgánicas , Humanos , Óxido Nítrico , Inflamación/diagnósticoRESUMEN
BACKGROUND Simultaneous pancreas-kidney transplantation (SPK) is a time-consuming and important surgical procedure, which can provide a physiological mean of achieving normoglycemia and render patients free of dialysis. The potential clinical benefits of sugammadex include fast and predictable reverse deep neuromuscular blockade (NMB), but whether sugammadex affects the function of SPK grafts is uncertain. MATERIAL AND METHODS Forty-eight patients were studied and reversed deep NMB with either sugammadex (n=24) or neostigmine (n=24). The safety variables included serum creatinine (Scr), creatinine clearance rate (CCr), serum amylase (AMS), blood glucose (Glu), mean arterial pressure (MAP), and heart rate (HR). Secondary outcomes were time from administration of sugammadex/neostigmine at the scheduled time to recovery of a TOF ratio to 0.7 and 0.9, and post-acute pulmonary complications. RESULTS Scr at T2-6 was significantly lower than that at T0-1 (P<0.01), while CCr was higher (P<0.05). Between the 2 groups, Scr, CCr, and AMS were similar at the same timepoints (P>0.05). MAP, HR, and Glu were higher in group S than in group N at T1 (P<0.05). The recovery time of TOF=0.7 was 3 (2.4-4.2) min for group S and 12.1 (10.2-15.9) min for group N (P<0.001), and recovery time to TOFr ≥0.9 was 4.8 (3.6-7.1) min for group S and 23.5 (19.8-30.8) in group S. Compared to group N, group S had lower risk for post-acute pulmonary complications: supplemental oxygen requirements 0 vs 4 (16.7%), pulmonary atelectasis 0 vs 2 (0.83%), pneumonia 1 (4.2%) vs 3 (12.5%), and hypoxemia 1 (4.2%) vs 4 (16.7%). CONCLUSIONS Sugammadex administration is safe and effective for SPK transplantation recipients.
Asunto(s)
Trasplante de Riñón , Fármacos Neuromusculares no Despolarizantes , gamma-Ciclodextrinas , Humanos , Sugammadex/uso terapéutico , Neostigmina , Rocuronio , Estudios Prospectivos , Trasplante de Riñón/efectos adversos , Androstanoles , PáncreasRESUMEN
Diabetes-aggravated myocardial ischemia-reperfusion (MI/R) injury remains an urgent medical issue, and the molecular mechanisms involved with diabetes and MI/R injury remain largely unknown. Previous studies have shown that inflammation and P2X7 signaling participate in the pathogenesis of the heart under individual conditions. It remains to be explored if P2X7 signaling is exacerbated or alleviated under double insults. We established a high-fat diet and streptozotocin-induced diabetic mouse model, and we compared the differences in immune cell infiltration and P2X7 expression between diabetic and nondiabetic mice after 24 h of reperfusion. The antagonist and agonist of P2X7 were administered before and after MI/R. Our study showed that the MI/R injury of diabetic mice was characterized by increased infarct area, impaired ventricular contractility, more apoptosis, aggravated immune cell infiltration, and overactive P2X7 signaling compared with nondiabetic mice. The major trigger of increased P2X7 was the MI/R-induced recruitment of monocytes and macrophages, and diabetes can be a synergistic factor in this process. Administration of P2X7 agonist eliminated the differences in MI/R injury between nondiabetic mice and diabetic mice. Both 2 wk of brilliant blue G injection before MI/R and acutely administered A438079 at the time of MI/R injury attenuated the role of diabetes in exacerbating MI/R injury, as evidenced by decreased infarct size, improved cardiac function, and inhibition of apoptosis. Additionally, brilliant blue G blockade decreased the heart rate after MI/R, which was accompanied by downregulation of tyrosine hydroxylase expression and nerve growth factor transcription. In conclusion, targeting P2X7 may be a promising strategy for reducing the risk of MI/R injury in diabetes.
Asunto(s)
Diabetes Mellitus Experimental , Infarto del Miocardio , Daño por Reperfusión Miocárdica , Ratones , Animales , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/patología , Diabetes Mellitus Experimental/metabolismo , Regulación hacia Arriba , Apoptosis , Infarto del Miocardio/patología , Infarto/metabolismo , Inflamación/metabolismo , Miocitos Cardíacos/metabolismoRESUMEN
Fentanyl is widely used for anesthesia and analgesia in cancer patients. Recent studies have revealed its anti-growth effect in several categories of cancer. Gliomas are the most common primary tumors in the central nervous system with poor prognosis. To investigate the effects of fentanyl on gliomas, glioma cells were treated with different concentrations of fentanyl both in vitro and in vivo. Consequences of proliferation and invasive phenotypes, and related protein expression were evaluated in two human glioma cell lines (U251 and U87). Naloxone, Mu Opioid Receptor (MOR) antagonist, was introduced into culture media to assess the involvement of MOR in Fentanyl-mediated changes. When compared with control group, it could be found that Fentanyl inhibited function of glioma cells only at high concentrations. Western blot and immunofluorescence results revealed that Fentanyl exerted its action via modulating NF-κB (P65) activation which is likely independent of MOR. Moreover, overexpression of P65 by transfection P65-expressing vector restored the invasion and migration of glioma cells, which were inhibited by Fentanyl. In summary, this study showed that opioid pain medication Fentanyl was capable of decreasing invasiveness of glioma cells at a high concentration both in vitro and in vivo, likely via modulating P65 activation.
Asunto(s)
Neoplasias Encefálicas , Glioma , Humanos , FN-kappa B/metabolismo , Fentanilo/farmacología , Glioma/metabolismo , Transducción de Señal , Antagonistas de Narcóticos/farmacología , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Invasividad Neoplásica/genética , Neoplasias Encefálicas/metabolismoRESUMEN
OBJECTIVE: Severe neurologic complications after spinal anesthesia are rare but highly distressing, especially in pregnant women. Bupivacaine is widely used in spinal anesthesia, but its neurotoxic effects have gained attention. METHODS: Furthermore, the etiology of bupivacaine-mediated neurotoxicity in obstetric patients remains unclear. Female C57BL/6 mice were intrathecally injected with 0.75% bupivacaine on the 18th day of pregnancy. We used immunohistochemistry to examine DNA damage after bupivacaine treatment in pregnant mice and measured γ-H2AX (Ser139) and 8-OHdG in the spinal cord. A PARP-1 inhibitor (PJ34) and autophagy inhibitor (3-MA) were administered with bupivacaine in pregnant mice. Parp-1flox/flox mice were crossed with Nes-Cre transgenic mice to obtain neuronal conditional knockdown mice. Then, LC3B and P62 staining were performed to evaluate autophagic flux in the spinal cords of pregnant wild-type (WT) and Parp-1-/- mice. We performed transmission electron microscopy (TEM) to evaluate autophagosomes. RESULTS: The present study showed that oxidative stress-mediated DNA damage and neuronal injury were increased after bupivacaine treatment in the spinal cords of pregnant mice. Moreover, PARP-1 was significantly activated, and autophagic flux was disrupted. Further studies revealed that PARP-1 knockdown and autophagy inhibitors could alleviate bupivacaine-mediated neurotoxicity in pregnant mice. CONCLUSION: Bupivacaine may cause neuronal DNA damage and PARP-1 activation in pregnant mice. PARP-1 further obstructed autophagic flux and ultimately led to neurotoxicity.
Asunto(s)
Anestésicos Locales , Bupivacaína , Animales , Femenino , Humanos , Ratones , Embarazo , Anestésicos Locales/toxicidad , Apoptosis , Autofagia , Bupivacaína/toxicidad , Ratones Endogámicos C57BL , Estrés Oxidativo , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacologíaRESUMEN
Bacterial infection has emerged as a grievous threat to public health, and lots of antibacterial agents were developed to solve this issue. However, enhancing the antibacterial activity of antibacterial agents while reducing their side effects remains a challenge. Herein, a supramolecular antibacterial agent based on the host-guest interaction between cucurbit[7]uril (CB[7]) and chlorhexidine (CHX) was designed. CHX can be encapsulated in the cavity of CB[7] to form a 1:3 host-guest complex (CHX-3CB[7]). It was amazingly found that this supramolecular complex could display higher antibacterial activity than CHX alone. Electrospray mass spectrometry and UV-vis spectra revealed that the introduction of CB[7] promoted the protonation of N-atoms on CHX, resulting in stronger ion interaction with phospholipids and thus enhancing the destruction of the bacterial membrane. Scanning electron microscopy (SEM), surface ζ-potentials and outer/inner membrane integrity assays also reveal that the introduction of CB[7] aggravates the rupture of membrane. What is more, the cytotoxicity and irritation of CHX were decreased by forming the host-guest complex with CB[7]. This work provides a paradigm for enhancing antibacterial activity and reducing side effects of drugs through supramolecular chemistry.