RESUMEN
Myocardial ischaemia (MI) remains a major cause of death and disability worldwide. Accumulating evidence suggests a significant role for innate immunity, in which the family of toll-like receptors (TLRs) acts as an essential player. We previously reported and reviewed the changes of Tlr expression in models of MI. However, the underlying mechanisms regulating Tlr expression in MI remain unclear. The present study first screened transcription factors (TFs) that potentially regulate Tlr gene transcription based on in silico analyses followed by experimental verification, using both in vivo and in vitro models. Forkhead box C1 (FOXC1) was identified as a putative TF, which was highly responsive to MI. Next, by focusing on two representative TLR subtypes, an intracellular subtype TLR3 and a cell-surface subtype TLR4, the regulation of FOXC1 on Tlr expression was investigated. The overexpression or knockdown of FoxC1 was observed to up- or down-regulate Tlr3/4 mRNA and protein levels, respectively. A dual-luciferase assay showed that FOXC1 trans-activated Tlr3/4 promoter, and a ChIP assay showed direct binding of FOXC1 to Tlr3/4 promoter. Last, a functional study of FOXC1 was performed, which revealed the pro-inflammatory effects of FOXC1 and its destructive effects on infarct size and heart function in a mouse model of MI. The present study for the first time identified FOXC1 as a novel regulator of Tlr expression and described its function in MI.
Asunto(s)
Factores de Transcripción Forkhead/metabolismo , Isquemia Miocárdica/genética , Receptores Toll-Like/genética , Regulación hacia Arriba/genética , Animales , Animales Recién Nacidos , Citocinas/metabolismo , Modelos Animales de Enfermedad , Técnicas de Silenciamiento del Gen , Humanos , Inflamación/genética , Inflamación/patología , Mediadores de Inflamación/metabolismo , Ratones , Regiones Promotoras Genéticas , Unión Proteica/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Receptores Toll-Like/metabolismoRESUMEN
Persistent cardiac hypertrophy eventually leads to deterioration of heart function and changes to normal morphology. Decreased nitric oxide (NO) production plays a critical role in modulating cardiac hypertrophy. Interleukin enhancement binding factor 3 (ILF3), a member of the double-stranded RNA-binding protein family, is known to regulate the transcription and stability of mRNA. Therefore, the major aim of the present study was to determine the role of ILF3 in reduction of NO production in cardiac hypertrophy. Cardiac hypertrophy models of neonatal rat cardiomyocytes (NRCMs) and adult rats were induced by angiotensin II (Ang II) in this study. First, it was found that ILF3 expression, NO production, and nitric oxide synthase (NOS) activity was decreased in cultured cardiomyocytes and adult rats treated with Ang II, compared with NRCMs treated with vehicle and rats treated with saline infusion, respectively. These effects induced by Ang II were significantly exacerbated by specific ILF3 knockdown. Moreover, the level of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NOS, was increased significantly in the Ang II-induced hypertrophic NRCMs and adult rats. Additionally, decreased protein expression and mRNA level of dimethylarginine dimethylaminohydrolases 1 (DDAH1, which degrades ADMA) were observed. Furthermore, specific ILF3 knockdown further aggravated these effects, but didn't reduce the expression level of NOS isoforms. In conclusion, our data show that ADMA accumulation-mediated decrease in NO production plays an important role in cardiomyocyte remodeling, which may be associated with ILF3-mediated DDAH1 reduction.
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Arginina/análogos & derivados , Cardiomegalia/metabolismo , Óxido Nítrico/metabolismo , Proteínas del Factor Nuclear 90/metabolismo , Amidohidrolasas/metabolismo , Angiotensina II , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Animales , Arginina/metabolismo , Cardiomegalia/inducido químicamente , Cardiomegalia/etiología , Regulación hacia Abajo , Técnicas de Silenciamiento del Gen , Losartán/farmacología , Masculino , Miocitos Cardíacos/efectos de los fármacos , Proteínas del Factor Nuclear 90/genética , Ratas Sprague-DawleyRESUMEN
Hypertension is a common chronic disease, and it is the strongest risk factor for cardiovascular disease. Recently, the number of patients with hypertension-related complications has increased significantly, adding a heavy burden to the public health system. It is known that chronic stress plays an important role in the pathogenesis of cardiovascular diseases such as hypertension and stroke. However, the impact of hypertension on the dysfunctions induced by chronic stress remains poorly understood. In this study, using LC-MS-based metabolomics, we established a chronic stress model to demonstrate the mechanisms of stress-induced hypertension. We found that 30 metabolites in chronically stressed rats were changed; of these metabolites, seven had been upregulated, and 23 had been downregulated, including amino acids, phospholipids, carnitines and fatty acids, many of which are involved in amino acid metabolism, cell membrane injury, ATP supply and inflammation. These metabolites are engaged in dysregulated pathways and will provide a targeted approach to study the mechanism of stress-induced hypertension.
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Cromatografía Líquida de Alta Presión/métodos , Hipertensión/metabolismo , Espectrometría de Masas/métodos , Metabolómica/métodos , Estrés Psicológico/metabolismo , Aminoácidos/sangre , Aminoácidos/metabolismo , Animales , Presión Sanguínea/fisiología , Enfermedad Crónica , Corticosterona/sangre , Corticosterona/metabolismo , Modelos Animales de Enfermedad , Metaboloma/fisiología , Norepinefrina/sangre , Norepinefrina/metabolismo , Fosfolípidos/sangre , Fosfolípidos/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
Microglia mediate multiple facets of neuroinflammation. They can be phenotypically divided into a classical phenotype (pro-inflammatory, M1) or an alternative phenotype (anti-inflammatory, M2) with different physiological characteristics and biological functions in the inflammatory process. Betaine has been shown to exert anti-inflammatory effects. In this study, we aimed to verify the anti-inflammatory effects of betaine and elucidate its possible molecular mechanisms of action in vitro. Lipopolysaccharide (LPS)-activated microglial cells were used as an inflammatory model to study the anti-inflammatory efficacy of betaine and explore its mechanism of regulating microglial polarisation by investigating the morphological changes and associated inflammatory changes. Cytokine and inflammatory mediator expression was also measured by ELISA, flow cytometry, immunofluorescence, and western blot analysis. Toll-like receptor (TLR)-myeloid differentiation factor 88 (Myd88)-nuclear factor-kappa B (NF-κB) p65, p-NF-κB p65, IκB, p-IκB, IκB kinase (IKK), and p-IKK expression was determined by western blot analysis. Betaine significantly mitigated the production of pro-inflammatory cytokines and increased the release of anti-inflammatory cytokines. It promoted the conversion of the microglia from M1 to M2 phenotype by decreasing the expression of inducible nitric oxide synthase and CD16/32 and by increasing that of CD206 and arginase-1. Betaine treatment inhibited the TLR4/NF-κB pathways by attenuating the expression of TLR4-Myd88 and blocking the phosphorylation of IκB and IKK. In conclusion, betaine could significantly alleviate LPS-induced inflammation by regulating the polarisation of microglial phenotype; thus, it might be an effective therapeutic agent for neurological disorders.
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Betaína/farmacología , Lipopolisacáridos/inmunología , Microglía/efectos de los fármacos , Microglía/fisiología , FN-kappa B/metabolismo , Transducción de Señal/efectos de los fármacos , Receptor Toll-Like 4/metabolismo , Animales , Biomarcadores , Línea Celular , Supervivencia Celular/efectos de los fármacos , Citocinas/metabolismo , Inmunofenotipificación , Mediadores de Inflamación/metabolismo , Óxido Nítrico , FenotipoRESUMEN
Epilepsy is one of the prevalent and major neurological disorders, and approximately one-third of the individuals with epilepsy experience seizures that do not respond well to available medications. We investigated whether oxysophocarpine (OSC) had anticonvulsant and neuroprotective property in the pilocarpine (PILO)-treated mice. Thirty minutes prior to the PILO injection, the mice were administrated with OSC (20, 40, and 80 mg/kg) once. Seizures and electroencephalography (EEG) were observed, and then the mice were killed for Nissl and Fluoro-jade B (FJB) staining. The oxidative stress was measured at 24 h after convulsion. Western blot analysis was used to examine the expressions of the Bax, Bcl-2, and Caspase-3. In this study, we found that pretreatment with OSC (40, 80 mg/kg) significantly delayed the onset of the first convulsion and status epilepticus (SE) and reduced the incidence of SE and mortality. Analysis of EEG recordings revealed that OSC (40, 80 mg/kg) significantly reduced epileptiform discharges. Furthermore, Nissl and FJB staining showed that OSC (40, 80 mg/kg) attenuated the neuronal cell loss and degeneration in hippocampus. In addition, OSC (40, 80 mg/kg) attenuated the changes in the levels of Malondialdehyde (MDA) and strengthened glutathione peroxidase and catalase activity in the hippocampus. Western blot analysis showed that OSC (40, 80 mg/kg) significantly decreased the expressions of Bax, Caspase-3 and increased the expression of Bcl-2. Collectively, the findings of this study indicated that OSC exerted anticonvulsant and neuroprotective effects on PILO-treated mice. The beneficial effects should encourage further studies to investigate OSC as an adjuvant in epilepsy, both to prevent seizures and to protect neurons in brain.
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Alcaloides/uso terapéutico , Anticonvulsivantes/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , Pilocarpina/toxicidad , Convulsiones/metabolismo , Convulsiones/prevención & control , Factores de Edad , Alcaloides/farmacología , Animales , Anticonvulsivantes/farmacología , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Ratones Endogámicos ICR , Fármacos Neuroprotectores/farmacología , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Convulsiones/inducido químicamente , Resultado del TratamientoRESUMEN
OBJECTIVE: To study the inhibitory effect of flavonoids from Glycyrrhiza uralensis on thioacetamide-induced chonic hepatic fibrosis in rats and the effect on the protein expressions of transforming growth factor-ß1 (TGF-ß1) and Caspase-3 in livers. METHOD: Male Sprague-Dawley rats were randomly divided into totally seven groups: the normal control group, the model group, LF groups s (400, 200, 100, 50 mg · kg(-1) · d(-1)) and the silymarin positive control group (30 mg · kg(-1) · d(-1)). The hepatic fibrosis model was induced in the rats through intraperitoneal injection with 3% thioacetamide (TAA) at a dose of 150 mg · kg(-1) body weight twice a week for 12 weeks. During the course, the control group and the model group were orally administered with saline (1 mL · kg(-1) · d(-1)). After the modeling and drug intervention, the pathologic changes and fibrosis in liver tissues were observed by HE staining and Masson's Trichrome staining. The serum alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP) and liver hydroxyproline (HYP) contents were assayed by biochemical process. The serum hyaluronic acid (HA) was assessed by radioimmunoassay. In addition, the protein expressions of liver TGF-ß1 and Caspase-3 were examined by immunohistochemical method. The mRNA expression of TGF-ß1 in hepatic tissues was examined by quantitative Real-time PCR analysis. RESULT: Compared with the model group, flavonoids can protect the integrity of the structure of liver tissues, significantly reduce the hepatic cell degeneration and necrosis and the proliferation of fibrous tissues, notably reduce the serum AST, ALT, ALP and HA and HYP in hepatic tissues and down-regulate the protein expressions of liver TGF-ß1 and Caspase-3 and the mRNA expression of TGF-ß1 in hepatic tissues. CONCLUSION: The licorice flavonoids can resist the thioacetamide-induced hepatic fibrosis in rats. Its mechanism may be related to the down-regulation of the protein expressions of TGF-ß1 and Caspase-3.
Asunto(s)
Caspasa 3/análisis , Flavonoides/farmacología , Glycyrrhiza uralensis/química , Cirrosis Hepática Experimental/prevención & control , Factor de Crecimiento Transformador beta1/análisis , Animales , Ácido Hialurónico/sangre , Hígado/patología , Cirrosis Hepática Experimental/inducido químicamente , Cirrosis Hepática Experimental/metabolismo , Masculino , ARN Mensajero/análisis , Ratas , Ratas Sprague-Dawley , Tioacetamida , Factor de Crecimiento Transformador beta1/genéticaRESUMEN
BACKGROUND: Malignant peritoneal mesothelioma (MPeM) is a rare cancer with a poor prognosis at advanced stage, and the standard first-line treatment for inoperable patients is chemotherapy. Although combining programmed cell death 1 (PD-1) inhibitors with chemotherapy is generally considered safe and effective in several malignant solid tumors, there are few reports regarding initial immunochemotherapy in advanced MPeM. CASE SUMMARY: Here, to our knowledge, we present the first case of a patient with epithelioid subtype MPeM, who was treatment-naïve and benefited from initial PD-1 inhibitor plus standard chemotherapy with a prolonged progression-free survival (PFS) and good tolerance. A 49-year-old man was admitted to our hospital for a persistent burning sensation in the abdomen. Computed tomography revealed a solid mass in the lower abdomen, which was subsequently diagnosed histologically as epithelioid subtype MPeM by core needle biopsy. The patient received eight cycles of pemetrexed 800 mg (day 1), cisplatin 60/50 mg (day 1-2), and zimberelimab (PD-1 inhibitor) 240 mg (day 1) every 3 wk. He achieved significant reduction of peritoneal tumors with remarkable improvement in symptoms. The best tumor response was partial remission with a final PFS of 7 mo. No immune-related adverse event occurred during the combination treatment. CONCLUSION: The outcome of the present case demonstrates the promising anti-tumor activity of immunochemotherapy to treat inoperable MPeM in the future.
RESUMEN
Clinically, neuropathic pain treatment remains a challenging issue because the major therapy, centred around pharmacological intervention, is not satisfactory enough to patient by reason of low effectiveness and more adverse reaction. Therefore, it is still necessary to find more effective and safe therapy to ameliorate neuropathic pain. The purpose of this study was to explore the antinociceptive effect of Echinacoside (ECH), an active compound of Cistanche deserticola Ma, on peripheral neuropathic pain induced by chronic constriction injury (CCI) in mice, and to demonstrate its potential mechanism in vivo and vitro. In the present study, results showed that intraperitoneal administration of ECH (50, 100, and 200 mg/kg) could alleviate mechanical allodynia, cold allodynia and thermal hyperalgesia via behavioural test. Moreover, the structure and function of injured sciatic nerve by CCI were taken a turn for the better to a certain extent after ECH treatment using histopathological and electrophysiological test. Furthermore, ECH repressed the expression of the P2X7R and FKN and reduced the expression and release of the IL-1ß, IL-6 and TNF-α. Besides, ECH could decrease Ca2+ influx and Cats efflux and inhibit phosphorylation of p38MAPK. To sum up, the present study illustrated that ECH could alleviate peripheral neuropathic pain by inhibiting microglia overactivation and inflammation through P2X7R/FKN/CX3CR1 signalling pathway in spinal cord. This study would provide a new perspective and strategy for the pharmacological treatment on neuropathic pain.
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Neuralgia , Fármacos Neuroprotectores , Animales , Ratones , Analgésicos/farmacología , Analgésicos/uso terapéutico , Analgésicos/metabolismo , Receptor 1 de Quimiocinas CX3C/metabolismo , Hiperalgesia/metabolismo , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Fármacos Neuroprotectores/metabolismo , Nervio Ciático/lesiones , Médula Espinal/metabolismoRESUMEN
Neonatal hypoxic-ischemic brain damage (HIBD) is a prominent contributor to both immediate mortality and long-term impairment in newborns. The elusive nature of the underlying mechanisms responsible for neonatal HIBD presents a significant obstacle in the effective clinical application of numerous pharmaceutical interventions. This comprehensive review aims to concentrate on the potential neuroprotective agents that have demonstrated efficacy in addressing various pathogenic factors associated with neonatal HIBD, encompassing oxidative stress, calcium overload, mitochondrial dysfunction, endoplasmic reticulum stress, inflammatory response, and apoptosis. In this review, we conducted an analysis of the precise molecular pathways by which these drugs elicit neuroprotective effects in animal models of neonatal hypoxic-ischemic brain injury (HIBD). Our objective was to provide a comprehensive overview of potential neuroprotective agents for the treatment of neonatal HIBD in animal experiments, with the ultimate goal of enhancing the feasibility of clinical translation and establishing a solid theoretical foundation for the clinical management of neonatal HIBD.
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Hipoxia-Isquemia Encefálica , Fármacos Neuroprotectores , Animales , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Neuroprotección , Apoptosis , Calcio , Hipoxia-Isquemia Encefálica/tratamiento farmacológico , Hipoxia-Isquemia Encefálica/prevención & control , EncéfaloRESUMEN
Adult rats chronic unpredictable stress model of depression (CUS) was adopted to elucidate the antidepressant pharmacological activity and related neurogenesis protective effect of the total flavonoids extract (licorice flavonoids, LF) from the Glycyrrhiza uralensis Fisch. cultivated locally in Ningxia. The rats were exposed to 9 kinds of unpredictable sequence of stressors and were given flavonoids (300 mg x kg(-1), 100 mg x kg(-1) and 30 mg x kg(-1)) for 28 days. The antidepressant effect was elucidated by open field test, forced swimming test and tail suspension test. The level of serum corticosterone was detected by radioimmunoassay. 5'-Bromo-2'-deoxyuridine (BrdU) labeling experiments was employed to study the neurogenesis protective activities. The flavonoids can increase the sum of line crosses and number of rears, and decrease the number of fecal boli produced in the open field test of the CUS rats. Also the flavonoids can decrease the immobility time in forced swim test as well as in the tail suspension test. In addition, the flavonoids (300 mg x kg(-1)) can decrease the serum corticosterone level of the CUS rats, and increase the number of the new born BrdU positive progenitor cells at the subgranular zone (SGZ) of dentate gyrus (DG) region in hippocampus. The results demonstrated that the total flavonoids extract from the cultivated Glycyrrhiza uralensis Fisch. could produce the anti-depressive effect on chronic unpredictable stress of depression model rats and its mechanism may be associated with its neurogenesis protective effect.
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Antidepresivos/farmacología , Flavonoides/farmacología , Glycyrrhiza uralensis/química , Neurogénesis/efectos de los fármacos , Estrés Psicológico , Animales , Antidepresivos/aislamiento & purificación , Conducta Animal/efectos de los fármacos , Bromodesoxiuridina/metabolismo , Corticosterona/metabolismo , Depresión/metabolismo , Depresión/fisiopatología , Flavonoides/aislamiento & purificación , Suspensión Trasera , Hipocampo/citología , Hipocampo/metabolismo , Masculino , Plantas Medicinales/química , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Estrés Psicológico/metabolismo , Estrés Psicológico/fisiopatología , NataciónRESUMEN
Depression is one of the most important mental illnesses and is closely related to inflammation. Betaine is a natural product with an anti-inflammatory and antioxidant activities. However, the mechanism by which betaine ameliorates depression-like behaviors induced by lipopolysaccharide (LPS) is poorly understood. The purpose of this study was to investigate the neuroprotective effect of betaine on LPS-induced depression-like behavior in mice and its mechanism of action. ICR mice were randomly divided into four groups: the control group, the LPS model group (0.83 mg/kg), the positive drug group (MIDO, 50 mg/kg), and the betaine group (5% and 1% in drinking water). The betaine group was administered for 21 days, and on the 22nd day, except for the blank group, LPS (0.83 mg/kg) was intraperitoneally injected to establish a lipopolysaccharide-induced mice depression-like model. Twenty-four hours after LPS injection, the tail suspension test (TST), open field test (OFT), and sucrose preference test (SPT) were performed to evaluate the effect of betaine on LPS-induced depressive behavior in mice. After the behavioral study, the mouse brain, hippocampus, and serum were taken for detection. The expressions of cytokines and inflammatory mediators were detected by ELISA, HE staining, immunofluorescence, immunohistochemistry, and western blotting. Western blotting was used to detect the protein expression levels of the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3), caspase-1, and ASC, the protein expression levels of the microglial polarization markers COX-2, inducible nitric oxide synthase (iNOS), and CD206. The results showed that betaine significantly ameliorated the depression-like behavior in LPS-induced mice, significantly attenuated the production of proinflammatory cytokines and increased the release of an anti-inflammatory cytokines. Betaine decreased the expression of the NLRP3 inflammasome, decreased the expression of M1 polarization markers, tumor necrosis factor-alpha (TNF-α), interleukin-1ß (IL-1ß), COX-2, and iNOS and promoted the expression of M2 polarization marker CD206. Our study suggests that betaine may promote the transition of microglia from the M1 to the M2 phenotype by inhibiting NLRP3 inflammasome activation, thereby attenuating lipopolysaccharide-induced depression-like behavior.
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Inflamasomas , Lipopolisacáridos , Animales , Ratones , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Antiinflamatorios/metabolismo , Betaína/farmacología , Betaína/metabolismo , Ciclooxigenasa 2/metabolismo , Citocinas/metabolismo , Depresión/tratamiento farmacológico , Inflamasomas/metabolismo , Lipopolisacáridos/farmacología , Ratones Endogámicos ICR , Microglía/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , FenotipoRESUMEN
Microglia are the primary immune cells involved in the immune response, inflammation, and injury repair in the central nervous system. Under different stimuli, the dual polarization of classically-activated M1 microglia and anti-inflammatory selectively-activated M2 microglia is observed. Oxymatrine (OMT) exerts various anti-inflammatory and neuroprotective effects, but the mechanism underlying its action remains unclear. In the present study, we investigated the effects of OMT on the polarization of M1/M2 microglia in a lipopolysaccharide (LPS)-induced inflammation model in order to elucidate the potential molecular mechanism of action of OMT in vitro. We first used a Cell Counting Kit-8 (CCK-8) to evaluate the effects of different concentrations OMT on the viability of N9 microglia to determine the appropriate concentration for follow-up experiments. Next, Griess reagent and enzyme-linked immunosorbent assay (ELISA) kits were used to detect the expression of the inflammation-related factors nitric oxide (NO), tumour necrosis factor-alpha (TNF-α), and interleukin (IL)-6, -1ß, and -10. To evaluate the protective effects of OMT, the ultrastructure of the cells was observed using electron microscopy. Immunofluorescence, flow cytometry, and western blotting were performed to evaluate the effects of OMT on the following markers of M1 and M2 microglia: CD16/32, CD206, Arginase-10 (Arg-1), and inducible nitric oxide synthase (iNOS). Lastly, western blotting and quantitative polymerase chain reaction (qPCR) were used to detect factors associated with the Toll-like receptor 4/nuclear factor-κB (TLR4/NF-κB) signalling pathway in order to explore the potential mechanism by which OMT regulates microglial polarization. The viability of N9 cells did not decrease when treated with a concentration of 1000 µg/mL OMT. Electron microscopy revealed that a concentration of 100 µg/mL OMT exerted a protective effect on N9 cells stimulated by LPS. The results of the present study indicated that OMT inhibited the over-activation of microglia, increased the levels of the M2 marker IL-10, decreased the levels of the M1 markers NO, TNF-α, IL-6, and IL-1ß, promoted the polarization of N9 microglia to the M2 phenotype, and regulated M1/M2 polarization in the microglia by inhibiting TLR4/NF-κB signalling, which effectively attenuated the LPS-induced inflammatory response.
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Alcaloides/farmacología , Antiinflamatorios/farmacología , Plasticidad de la Célula/efectos de los fármacos , Microglía/efectos de los fármacos , FN-kappa B/metabolismo , Enfermedades Neuroinflamatorias/prevención & control , Quinolizinas/farmacología , Receptor Toll-Like 4/metabolismo , Animales , Línea Celular , Citocinas/metabolismo , Mediadores de Inflamación/metabolismo , Lipopolisacáridos/toxicidad , Ratones , Microglía/inmunología , Microglía/metabolismo , Microglía/ultraestructura , FN-kappa B/genética , Enfermedades Neuroinflamatorias/inmunología , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/patología , Óxido Nítrico/metabolismo , Fenotipo , Transducción de Señal , Receptor Toll-Like 4/genéticaRESUMEN
BACKGROUND: Nausea and vomiting are among the most common and distressing side effects of chemotherapy. Difference in views about the effectiveness of auricular acupuncture (AA) versus electroacupuncture (EA) of chemotherapy-induced nausea and vomiting (CINV) lies at the heart of the debate. The aim of this study is to compare the antiemetic efficacy and safety of AA and EA for CINV. METHODS: One hundred twenty participants, 18 to 75âyears old malignant tumors will receiving chemotherapy with cisplatin, will be recruited and randomized into 3 groups equally, Group A (the AA group), Group B (the EA group), and Group C (the control group). The participants in Group A and Group B will receive AA or EA regimens, alternatively, beginning on the day before first day of chemotherapy for a third consecutive cycles. All participants will continue to receive conventional treatment. The incidence and severity of CINV will be assessed using the definition and classification of nausea and vomiting (NCI-CTC AE4.0) and the MASCC (Multinational Association for Supportive Care in Cancer) Antiemesis Tool (MAT). Secondary outcome measures include the degree of abdominal distension, the first time of flatus and defecation, and life quality. Additionally, adverse events will also be documented during the period of the treatment. DISCUSSION: This trial may provide evidence regarding the clinical effectiveness and safety of AA versus EA for CINV following cisplatin-based regimens. TRAIL REGISTRATION: This study is registered with the Chinese Clinical Trial Registry: ChiCTR2000040942.
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Acupuntura Auricular , Antineoplásicos/efectos adversos , Cisplatino/efectos adversos , Electroacupuntura , Náusea/etiología , Náusea/prevención & control , Vómitos/etiología , Vómitos/prevención & control , Adolescente , Adulto , Anciano , China , Femenino , Humanos , Masculino , Persona de Mediana Edad , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
A single cardiomyocyte is a vital tool in the cellular and subcellular level studies of cardiac biology and diseases as a fundamental unit of contraction and electrical activity. Hence, isolating viable, high-quality cardiomyocytes from the heart is the initial and most crucial experimental step. Comparing the various protocols for isolating the cardiomyocytes of adult mice, the Langendorff retrograde perfusion is the most successful and reproducible method reported in the literature, especially for isolating ventricular myocytes. However, isolating quality atrial myocytes from the perfused heart remains challenging, and few successful isolation reports are available. Solving this complicated problem is extremely important because apart from ventricular disease, atrial disease accounts for a large part of heart diseases. Therefore, further investigations on the cellular level to reveal the mechanisms are warranted. In this paper, a protocol based on the Langendorff retrograde perfusion method is introduced and some modifications in the depth of aorta cannulation and the steps that may affect the digestion process to isolate atrial and ventricular myocytes were simultaneously made. Moreover, the isolated cardiomyocytes are confirmed to be amenable to patch clamp investigation.
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Atrios Cardíacos , Ventrículos Cardíacos , Miocitos Cardíacos , Animales , Separación Celular , Ratones , PerfusiónRESUMEN
The critical role of phosphoinositide 3-kinase gamma (PI3Kgamma) in inflammatory cell activation and recruitment makes it an attractive target for immunomodulatory therapy. 5-Quinoxilin-6-methylene-1,3-thiazolidine-2,4-dione (AS605240), a potent PI3Kgamma inhibitor, has been reported to ameliorate chronic inflammatory disorders including rheumatoid arthritis, systemic lupus erythematosus, and atherosclerosis. However, its in vivo effect on intestinal inflammation remains unknown. Here we evaluated the protective and therapeutic potentials of AS605240 in mice with dextran sodium sulfate (DSS)-induced acute and chronic colitis. Our results showed that AS605240 improved survival rate, disease activity index, and histological damage score in mice administered DSS in both preventive and therapeutic studies. AS605240 treatment also significantly inhibited the increase in myeloperoxidase levels, macrophage infiltration, and CD4(+) T-cell number in the colon of DSS-fed mice. The DSS-induced overproduction of colonic proinflammatory cytokines including interleukin (IL)-1beta, tumor necrosis factor-alpha, and interferon-gamma was significantly suppressed in mice undergoing AS605240 therapy, whereas colonic anti-inflammatory cytokines such as IL-4 were up-regulated. The down-regulation of the phospho-Akt level in immunological cells from the inflamed colon tissue and spleen of AS605240-treated mice was detected both by immunohistochemical analysis and Western blotting. These findings demonstrate that AS605240 may represent a promising novel agent for the treatment of inflammatory bowel disease by suppressing leukocyte infiltration as well as by immunoregulating the imbalance between proinflammatory and anti-inflammatory cytokines.
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Colitis/prevención & control , Inhibidores Enzimáticos/uso terapéutico , Inhibidores de las Quinasa Fosfoinosítidos-3 , Quinoxalinas/uso terapéutico , Tiazolidinedionas/uso terapéutico , Enfermedad Aguda , Animales , Western Blotting , Recuento de Linfocito CD4 , Linfocitos T CD4-Positivos/citología , Enfermedad Crónica , Colitis/inducido químicamente , Colitis/enzimología , Colitis/inmunología , Colitis/patología , Colon/efectos de los fármacos , Colon/enzimología , Colon/inmunología , Colon/patología , Citocinas/biosíntesis , Citocinas/inmunología , Sulfato de Dextran , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/farmacología , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Inmunohistoquímica , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/enzimología , Mucosa Intestinal/inmunología , Mucosa Intestinal/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Tamaño de los Órganos , Quinoxalinas/administración & dosificación , Quinoxalinas/farmacología , Índice de Severidad de la Enfermedad , Bazo/efectos de los fármacos , Bazo/inmunología , Tiazolidinedionas/administración & dosificación , Tiazolidinedionas/farmacologíaRESUMEN
OBJECTIVES: This study sought to observe heart injury in rats with insulin resistance and type 2 diabetes mellitus, and to explore the relation between insulin resistance and diabetic cardiomyopathy in the presence of type 2 diabetes mellitus. METHODS: Type 2 diabetes mellitus and insulin resistance were studied in animal models using Wistar rats. Glucose infusion rates (index of insulin resistance, insulin resistance), heart weight, the heart weight to body weight ratio, myocardial apoptotic index, cardiac hydroxyproline content, and cardiac tissue collagen type I and collagen type 3 content were measured. Ultramicrostructure of cardiac muscle cells was also observed. RESULTS: Glucose infusion rates in type 2 diabetes mellitus and insulin resistance rats decreased (P < 0.01). Injury change of the ultramicrostructure of myocardial cells occurred in rats with type 2 diabetes mellitus and insulin resistance. Heart weight, myocardial apoptotic index, cardiac hydroxyproline content, type I and collagen type 3 content increased in rats with type 2 diabetes mellitus, and insulin resistance (P < 0.05) and in rats with insulin resistance were all lower than they were in type 2 diabetes mellitus rats (P < 0.05). In rats with type 2 diabetes mellitus and insulin resistance, associations of glucose infusion rates with heart weight, heart weight to body weight ratio, myocardial apoptotic index, cardiac hydroxyproline content, and cardiac tissue collagen type I and collagen type 3 were all negative; this result was statistically significant (P < 0.05). However, in normal rats, none of these associations was statistically significant. CONCLUSIONS: In the presence of type 2 diabetes mellitus, there exists insulin resistance and heart injury. Insulin resistance can injure the heart and plays a significant role in pathogenesis of diabetic cardiomyopathy in type 2 diabetes mellitus.
Asunto(s)
Diabetes Mellitus Experimental/fisiopatología , Resistencia a la Insulina , Miocardio/patología , Miocitos Cardíacos/ultraestructura , Análisis de Varianza , Animales , Apoptosis , Glucemia/análisis , Peso Corporal , Colágeno/metabolismo , Hidroxiprolina/metabolismo , Etiquetado Corte-Fin in Situ , Masculino , Miocitos Cardíacos/metabolismo , Ratas , Ratas WistarRESUMEN
Depression is a devastating illness with a lifetime prevalence of up to 20%. The neurotransmitter serotonin or 5-hydroxytryptamine (5-HT) is involved in the pathophysiology of depression and in the effects of antidepressant treatments. However, molecular alterations that underlie the pathology or treatment of depression are still poorly understood. The TREK-1 protein is a background K+ channel regulated by various neurotransmitters including 5-HT. In mice, the deletion of its gene (Kcnk2, also called TREK-1) led to animals with an increased efficacy of 5-HT neurotransmission and a resistance to depression in five different models and a substantially reduced elevation of corticosterone levels under stress. TREK-1-deficient (Kcnk2-/-) mice showed behavior similar to that of naive animals treated with classical antidepressants such as fluoxetine. Our results indicate that alterations in the functioning, regulation or both of the TREK-1 channel may alter mood, and that this particular K+ channel may be a potential target for new antidepressants.
Asunto(s)
Trastorno Depresivo/fisiopatología , Eliminación de Gen , Canales de Potasio de Dominio Poro en Tándem/fisiología , Análisis de Varianza , Animales , Antidepresivos/farmacología , Conducta Animal/efectos de los fármacos , Trastorno Depresivo/genética , Trastorno Depresivo/prevención & control , Resistencia a Medicamentos/genética , Fluoxetina/farmacología , Genotipo , Ratones , Ratones Noqueados , Fenotipo , Canales de Potasio de Dominio Poro en Tándem/deficiencia , Canales de Potasio de Dominio Poro en Tándem/genética , Células Piramidales/efectos de los fármacos , Células Piramidales/fisiología , Serotonina/metabolismo , Transmisión Sináptica/efectos de los fármacosRESUMEN
BACKGROUND: There are distinct results for the relationship between new-onset atrial fibrillation (NOAF) and subsequent incident cancer. To date, no systematic analysis has been conducted on this issue. This study aims to explore the relationship between NOAF and the risk of developing cancer through a meta-analysis with a large sample size. METHODS: Electronic databases, such as PubMed and EMBASE, were searched for published relevant studies on NOAF patients diagnosed with cancer after and during follow-ups, including reported records of baseline information and the statistical result of morbidity. Two investigators independently reviewed the articles and extracted the data using uniform standards and definitions. The meta-analysis was conducted using the Cochrane Program Review Manager. RESULTS: This meta-analysis consisted of five cohort studies and one case-control study, which comprised 533,514 participants. The pooled relative risk (RR) for incident cancer was 1.24 (95% CI: 1.10-1.39, P=0.0003). The temporal trend analysis demonstrated that an increased risk of cancer was observed during the initial 90 days (RR: 3.44, 95% CI: 2.29-5.57, P < 0.00001), but not after that. Lung cancer (RR: 1.51, 95% CI: 1.47-1.55, P < 0.00001) was associated with NOAF, but not colorectal cancer and breast cancer. CONCLUSION: This meta-analysis provides evidence that NOAF is associated with increased risk of cancer. The risk of incident cancer particularly increases within 90 days after NOAF diagnosis, but not after that.
RESUMEN
BACKGROUND: The main component of cinobufacini injection is dry toad skin, which is used as adjuvant therapy for stage III/IV non-small cell lung cancer patients in long-term combination with vinorelbine and cisplatin. However, the efficacy and safety of this combination therapy remain unclear. METHODS: A systematic review and meta-analysis will be conducted following the preferred reported items for systematic review and meta-analysis guidelines. Two independent reviewers (LRL and ZLN) will carry out a comprehensive search of the PubMed, Web of Science, Cochrane Library, EMBASE, the Chinese Science and Technology Periodical Database, China National Knowledge Infrastructure, Wanfang Databases, China Biology Medicine. The last search date will be July 30, 2020. Reference list of all selected articles will independently screened to identify additional studies left out in the initial search. The Cochrane Risk of Bias Tool will be used to evaluate the risk of bias of the randomized controlled trials. Outcome index: The main efficacy indicators were based on the objective efficacy evaluation criteria of the World Health Organization antineoplastic drugs or the objective efficacy evaluation criteria of solid tumors established by RECIST. Secondary criteria Karnofsky performance scale (KPS) score, pain efficacy criteria, side effects of chemotherapy such as myelosuppression and gastrointestinal symptoms. Assessment of risk of bias and data synthesis will be conducted using Review Manager V5.3 software. RESULTS: This study will systematically evaluate the efficacy and safety of cinobufacini combined with vinorelbine and cisplatin in the treatment of stage III/IV non-small cell lung cancer. The results of this systematic review will be published in peer-reviewed scientific journals. ETHICS: The ethical approval is not required since systematic review is based on published studies. INPLASY REGISTRATION NUMBER: INPLASY202060091.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bufanólidos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Medicamentos Herbarios Chinos/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bufanólidos/administración & dosificación , Bufanólidos/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/patología , Cisplatino/uso terapéutico , Medicamentos Herbarios Chinos/administración & dosificación , Medicamentos Herbarios Chinos/efectos adversos , Humanos , Neoplasias Pulmonares/patología , Estadificación de Neoplasias , Ensayos Clínicos Controlados Aleatorios como Asunto , Proyectos de Investigación , Vinorelbina/uso terapéutico , Metaanálisis como AsuntoRESUMEN
The aim of this study was to investigate the relationship between anti-fibrotic effect of Panax notoginseng saponins (PNS) and serum cytokines in rat hepatic fibrosis. Hepatic fibrosis induced by carbon tetrachloride (CCl(4)) was studied in animal models using SD rats. Liver index, serum alanine amino transferase (ALT), aspartate amino transferase (AST), transforming growth factor-beta1 (TGF-beta1), tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and interleukin-10 (IL-10) were measured, respectively. Liver index and the degree of liver fibrosis were also determined. Our results showed that the levels of ALT, AST and liver index in PNS-treated group were markedly lower than those in model group. PNS therapy also significantly attenuated the degree of hepatic fibrosis, collagen area and collagen area percent in liver tissue. Furthermore, the levels of serum TGF-beta1, TNF-alpha and IL-6 were strikingly reduced in PNS-treated group compared with model group while the production of IL-10 was up-regulated. These findings demonstrate that PNS has certain therapeutic effects on hepatic fibrosis probably by immunoregulating the imbalance between pro-fibrotic and anti-fibrotic cytokines.