RESUMEN
Docetaxel (DOC) is commonly used in cancer treatment, especially for breast cancer. However, there are severe side effects in clinical application. In order to deliver docetaxel more effectively, a novel, active targeting acid-responsive polymer called cRGD-PAE-PEG-DSPE was developed. The polymer structure incorporated poly(ethylene glycol) (PEG) as the hydrophilic segment, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE) as the hydrophobic segment, and poly(ß-amino ester) (PAE) as the acid-responsive group, which was grafted onto the PEG. Furthermore, c(RGDyC) was grafted onto PAE to confer active targeting capability. Through self-assembly, docetaxel was encapsulated in RAED@DOC. Through in vitro experiments, it was confirmed that RAED@DOC had good serum stability and acid responsiveness, as well as enhanced uptake by MDA-MB-231 cells. Additionally, the antitumor efficiency in vivo and histopathological analysis showed that RAED@DOC exhibited higher antitumor activity and lower systemic toxicity in comparison to free docetaxel. These results suggested that RAED@DOC had considerable potential clinical use.
Asunto(s)
Antineoplásicos , Neoplasias de la Mama , Nanopartículas , Humanos , Femenino , Docetaxel/farmacología , Antineoplásicos/química , Polietilenglicoles/química , Polímeros/química , Neoplasias de la Mama/tratamiento farmacológico , Nanopartículas/química , Línea Celular TumoralRESUMEN
Neuronal apoptosis is one of the main pathological processes of hypoxic-ischemic brain damage (HIBD) and is involved in the development of hypoxic-ischemic encephalopathy (HIE) in neonates. Atorvastatin has been found to have neuroprotective effects in some nervous system diseases, but its role in regulating the pathogenesis of neonatal HIBD remains elusive. Thus, this study aimed to explore the effects and related mechanisms of atorvastatin on the regulation of neuronal apoptosis after HIBD in newborn rats. The rat HIBD model and the neuronal oxygen glucose deprivation (OGD) model were established routinely. Atorvastatin, cAMP inhibitor (SQ22536), and BDNF inhibitor (ANA-12) were used to treat HIBD rats and OGD neurons. Cerebral infarction, learning and memory ability, cAMP/PKA/p-CREB/BDNF signaling molecules, and apoptosis-related indicators (TUNEL, cleaved caspase-3, and Bax/Bcl2) were then examined. In vivo, atorvastatin reduced cerebral infarction, improved learning and memory ability, decreased the number of TUNEL-positive neurons, inhibited the expression of cleaved caspase-3 and Bax/Bcl2, and activated the cAMP/PKA/p-CREB/BDNF pathway in the cerebral cortex after HIBD. In vitro, atorvastatin also decreased the apoptosis-related indicators and activated the cAMP/PKA/p-CREB/BDNF pathway in neurons after OGD. Furthermore, inhibition of cAMP or BDNF attenuated the effect of atorvastatin on the reduction of neuronal apoptosis, suggesting that atorvastatin inhibits HIBD-induced neuronal apoptosis and alleviates brain injury in neonatal rats mainly by activating the cAMP/PKA/p-CREB/BDNF pathway. In conclusion, atorvastatin may be developed as a potential drug for the treatment of neonatal HIE.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo , Hipoxia-Isquemia Encefálica , Animales , Animales Recién Nacidos , Apoptosis , Atorvastatina/farmacología , Atorvastatina/uso terapéutico , Caspasa 3 , Infarto Cerebral/tratamiento farmacológico , Hipoxia , Hipoxia-Isquemia Encefálica/tratamiento farmacológico , Hipoxia-Isquemia Encefálica/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2 , Ratas , Ratas Sprague-Dawley , Proteína X Asociada a bcl-2RESUMEN
Atopic dermatitis (AD) is a chronic and recurrent inflammation disease associated with immune dysfunction. The high level of reactive oxygen species (ROS) causes high oxidative stress and further results in the deterioration of AD. At the same time, the ROS produced by bacterial infection can further aggravate AD. Here, the prepared PVA-based hydrogel (Gel) has a high ROS scavenging ability, and the antibacterial agent Zn-MOF(ZIF-8) loaded into the hydrogel shows a lasting and effective antibacterial activity. Thus, a Zn-MOF hydrogel (Gel@ZIF-8) is prepared to regulate ROS-mediated inflammatory microenvironment. In vitro experiments show that Gel@ZIF-8 has good antibacterial effect and cell biocompatibility. In the AD-induced mouse model, Gel@ZIF-8 can significantly enhance the therapeutic effect, such as reduce the thickness of epidermis, the number of mast cells and IgE antibodies. The results indicate that the ROS-scavenging hydrogel could treat the AD by regulating the inflammatory microenvironment, providing a promising treatment for managing AD.
Asunto(s)
Dermatitis Atópica , Animales , Ratones , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Dermatitis Atópica/tratamiento farmacológico , Hidrogeles/farmacología , Hidrogeles/uso terapéutico , Especies Reactivas de Oxígeno , Zinc/farmacología , Estructuras Metalorgánicas/química , Estructuras Metalorgánicas/farmacologíaRESUMEN
Progressive loss and dysfunction of islet ß-cells has not yet been solved in the treatment of diabetes. Regenerating protein (Reg) has been identified as a trophic factor which is demonstrated to be associated with pancreatic tissue regeneration. We previously produced recombinant Reg3α protein (rReg3α) and proved that it protects against acute pancreatitis in mice. Whether rReg3α protects islet ß-cells in diabetes has been elusive. In the present study, rReg3α stimulated MIN6 cell proliferation and resisted STZ-caused cell death. The protective effect of rReg3α was also found in mouse primary islets. In BALB/c mice, rReg3α administration largely alleviated STZ-induced diabetes by the preservation of ß-cell mass. The protective mechanism could be attributed to Akt/Bcl-2/-xL activation and GRP78 upregulation. Scattered insulin-expressing cells and clusters with small size, low insulin density, and exocrine distribution were observed and considered to be neogenic. In isolated acinar cells with wheat germ agglutinin (WGA) labeling, rReg3α treatment generated insulin-producing cells through Stat3/Ngn3 signaling, but these cells were not fully functional in response to glucose stimulation. Our results demonstrated that rReg3α resists STZ-induced ß-cell death and promotes ß-cell regeneration. rReg3α could serve as a potential drug for ß-cell maintenance in anti-diabetic treatment.
Asunto(s)
Células Secretoras de Insulina , Insulinas , Islotes Pancreáticos , Pancreatitis , Enfermedad Aguda , Animales , Apoptosis , Glucosa/metabolismo , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Insulinas/metabolismo , Islotes Pancreáticos/metabolismo , Ratones , Ratones Endogámicos BALB C , Pancreatitis/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacología , Aglutininas del Germen de Trigo/farmacologíaRESUMEN
BACKGROUND: Regenerating protein 3a (Reg3a) is a trophic factor that functions as a stimulus in cell proliferation and neogenesis. Previous studies showed that Reg3a is ectopically upregulated in a majority of colorectal cancers (CRC) and detectable in the serum. METHODS: Single-chain variable fragment targeting Reg3a (scFv-Reg3a) was screened from a phage library. The bioactivity of recombinant Reg3a (rReg3a) and scFv-Reg3a were tested in LoVo and RKO cell lines using MTT, flow cytometry, wound healing and transwell analyses. Whether scFv-Reg3a inhibits tumor growth and enhances 5-fluorouracil (5-FU)-caused cell death were further examined in LoVo cell-transplanted nude BALB/c mice. RESULTS: A scFv-Reg3a from clone C2 was obtained and its binding affinity (KD) to rReg3a was determined to be 4.44 × 10-10. In cultured LoVo and RKO cells, rReg3a promoted but scFv-Reg3a inhibited cell proliferation, survival, migration and invasion. In LoVo cell-xenografted nude mice, administration of rReg3a accelerated tumor growth while scFv-Reg3a suppressed cell proliferation and reinforced 5-FU-induced cell death. CONCLUSION: The newly developed scFv-Reg3a is an anti-cancer agent which is potent to suppress CRC cell proliferation and survival. The use of scFv-Reg3a could enhance the effectiveness of 5-FU-based chemotherapy in the cancerous treatment.
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Antineoplásicos Inmunológicos/farmacología , Apoptosis/efectos de los fármacos , Neoplasias Colorrectales/tratamiento farmacológico , Proteínas Asociadas a Pancreatitis/genética , Anticuerpos de Cadena Única/farmacología , Animales , Antineoplásicos Inmunológicos/química , Antineoplásicos Inmunológicos/metabolismo , Apoptosis/genética , Sitios de Unión , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Clonación Molecular , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/patología , Fluorouracilo/farmacología , Expresión Génica , Células HEK293 , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Modelos Moleculares , Proteínas Asociadas a Pancreatitis/antagonistas & inhibidores , Proteínas Asociadas a Pancreatitis/química , Proteínas Asociadas a Pancreatitis/inmunología , Biblioteca de Péptidos , Unión Proteica , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/inmunología , Anticuerpos de Cadena Única/biosíntesis , Anticuerpos de Cadena Única/química , Carga Tumoral/efectos de los fármacosRESUMEN
AIMS: The potential effect of regenerating (Reg) proteins in the treatment of diabetes has been indicated in the past decade, but the clinical use of Reg proteins requires more advances in translational medicine. In the present study, we produced recombinant regenerating protein 2 (rReg2), to prove its protective effect against streptozocin (STZ)-induced diabetes in BALB/c mice. MATERIALS AND METHODS: rReg2 was administrated in STZ-induced diabetic mice. Blood glucose, body weight, serum insulin and islet ß-cell loss were determined. However, Reg2 has also been reported to serve as an autoantigen that induces autoimmune attacks on islets and aggravates diabetic development in non-obese diabetic mice. To address this contradiction, complete Freund's adjuvant was injected to generate a model that was hypersensitive to Reg2. In this model, islet CD8 T-cell infiltration, serum Reg2 antibody and interleukin (IL)-4 and IL-10, and splenic CD4+/interferon (IFN)-γ+ T cells were determined. RESULTS: Direct rReg2 pretreatment preserved islet ß-cell mass against STZ and improved glycaemia, body weight and serum insulin content. The protection against cell death was further confirmed in cultured mouse islets and MIN6 cells. On the other hand, significant elevations of serum Reg2 antibody and splenic CD4+/IFN-γ+ T cells, and decreases in serum IL-4 and IL-10 were detected in rReg2-vaccinated mice, which may contribute to the accelerated diabetes. Interestingly, these mice, upon further rReg2 treatment, exhibited alleviated diabetic conditions with less islet CD8+ T-cell infiltration. CONCLUSION: rReg2 treatment ameliorated STZ-induced diabetes in normal BALB/c mice. By contrast, rReg2 vaccination exacerbated, but further rReg2 treatment alleviated, the severity of STZ-induced diabetes. Thus, the protective effect of rReg2 is predominant over the autoantigenic ß-cell destruction, supporting the potential of rReg2 in the clinical treatment of diabetes.
Asunto(s)
Autoantígenos/sangre , Citoprotección/efectos de los fármacos , Diabetes Mellitus Experimental/tratamiento farmacológico , Células Secretoras de Insulina/efectos de los fármacos , Islotes Pancreáticos/efectos de los fármacos , Proteínas Asociadas a Pancreatitis/farmacología , Animales , Apoptosis/efectos de los fármacos , Células Cultivadas , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/patología , Células Secretoras de Insulina/patología , Células Secretoras de Insulina/fisiología , Islotes Pancreáticos/patología , Islotes Pancreáticos/fisiología , Masculino , Ratones , Ratones Endogámicos BALB C , Proteínas Asociadas a Pancreatitis/química , Fragmentos de Péptidos/farmacología , Sustancias Protectoras/farmacología , Proteínas Recombinantes/química , Proteínas Recombinantes/farmacología , EstreptozocinaRESUMEN
It is known that inhibiting 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2) expression in the placenta can cause fetal over-exposure to maternal glucocorticoids and induce intrauterine growth restriction (IUGR); these effects ultimately increase the risk of adult chronic diseases. This study aimed to investigate the molecular mechanism of the prenatal ethanol exposure (PEE)-induced inhibition of placental 11ß-HSD2 expression. Pregnant Wistar rats were intragastrically administered ethanol (4â¯g/kg/d) from gestational days 9 to 20. The levels of maternal and fetal serum corticosterone and placental 11ß-HSD2-related gene expression were analyzed. Furthermore, we investigated the mechanism of reduced placental 11ß-HSD2 expression induced by ethanol treatment (15-60â¯mM) in HTR-8/SVneo cells. In vivo, PEE decreased fetal body weights and increased maternal and fetal serum corticosterone and early growth response factor 1 (EGR1) expression levels. Moreover, histone modification changes (decreased acetylation and increased di-methylation of H3K9) to the HSD11B2 promoter and lower 11ß-HSD2 expression levels were observed. In vitro, ethanol decreased cAMP/PKA signaling and 11ß-HSD2 expression and increased EGR1 expression in a concentration-dependent manner. A cAMP agonist and EGR1 siRNA reversed the ethanol-induced inhibition of 11ß-HSD2 expression. Together, PEE reduced placental 11ß-HSD2 expression, and the underlying mechanism is associated with ethanol-induced histone modification changes to the HSD11B2 promoter through the cAMP/PKA/EGR1 pathway.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 2/metabolismo , Consumo de Bebidas Alcohólicas/efectos adversos , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , AMP Cíclico/metabolismo , Proteína 1 de la Respuesta de Crecimiento Precoz/metabolismo , Etanol/toxicidad , Placenta/efectos de los fármacos , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 2/genética , Acetilación , Animales , Línea Celular , Proteína 1 de la Respuesta de Crecimiento Precoz/genética , Represión Enzimática , Femenino , Regulación del Desarrollo de la Expresión Génica , Edad Gestacional , Histonas/metabolismo , Humanos , Metilación , Placenta/enzimología , Embarazo , Regiones Promotoras Genéticas , Ratas Wistar , Transducción de Señal/efectos de los fármacosRESUMEN
Impaired placental 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2) activity which inactivates maternal glucocorticoids is associated with poor fetal growth and a higher risk of chronic diseases in adulthood. This study aimed to elucidate the epigenetically regulatory mechanism of nicotine on placental 11ß-HSD2 expression. Pregnant Wistar rats were administered 1.0â¯mg/kg nicotine subcutaneously twice a day from gestational day 9 to 20. The results showed that prenatal nicotine exposure increased corticosterone levels in the placenta and fetal serum, disrupted placental morphology and endocrine function, and reduced fetal bodyweight. Meanwhile, histone modification abnormalities (decreased acetylation and increased di-methylation of histone 3 Lysine 9) on the HSD11B2 promoter and lower-expression of 11ß-HSD2 were observed. Furthermore, the expression of nicotinic acetylcholine receptor (nAChR) α4/ß2, the phosphorylation of extracellular regulated kinase 1/2 (ERK1/2) and Ets-like protein-1 (Elk-1), and the expression of early growth response-1 (Egr-1) were increased in the nicotine groups. In human BeWo cells, nicotine decreased 11ß-HSD2 expression, increased nAChRα9 expression, and activated ERK1/2/Elk-1/Egr-1 signaling in the concentration (0.1-10⯵M)-dependent manner. Antagonism of nAChRs, inhibition of ERK1/2 and Egr-1 knockdown by siRNA were able to block/abrogate the effects of nicotine on histone modification and expression of 11ß-HSD2. Taken together, nicotine can impair placental structure and function, and induce fetal developmental toxicity. The underlying mechanism involves histone modifications and down-regulation of 11ß-HSD2 through nAChRs/ERK1/2/Elk-1/Egr-1 signaling, which increases active glucocorticoids levels in the placenta and fetus, and eventually inhibits the fetal development.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 2/metabolismo , Proteína 1 de la Respuesta de Crecimiento Precoz/metabolismo , Sistema de Señalización de MAP Quinasas/fisiología , Nicotina/toxicidad , Placenta/metabolismo , Receptores Nicotínicos/metabolismo , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 2/antagonistas & inhibidores , Animales , Línea Celular , Relación Dosis-Respuesta a Droga , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/fisiología , Epigénesis Genética/efectos de los fármacos , Epigénesis Genética/fisiología , Femenino , Retardo del Crecimiento Fetal/inducido químicamente , Retardo del Crecimiento Fetal/metabolismo , Peso Fetal/efectos de los fármacos , Peso Fetal/fisiología , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Placenta/efectos de los fármacos , Embarazo , Distribución Aleatoria , Ratas , Ratas WistarRESUMEN
Regenerating family protein 2 (Reg2) is a trophic factor which stimulates ß-cell replication and resists islet destruction. However, Reg2 also serves as an islet autoantigen, which makes it complicated to judge the effectiveness in treating diabetes. How Reg2 treatment behaves in non-obese diabetic (NOD) mice is to be investigated. NOD mice were treated with recombinant Reg2 protein, Complete Freund's adjuvant (CFA) + PBS and CFA+Reg2 vaccinations, CFA+PBS- and CFA+Reg2-immunized antisera, and single chain variable fragment (scFv)-Reg2 and mIgG2a-Reg2 antibodies. Glycemic level, bodyweight, serum Reg2 antibody titer, glucose tolerance, and insulin secretion were determined. Islet morphological characteristics, insulitis, cell apoptosis, islet cell components, and T cell infiltration were analyzed by histological examinations. The autoantigenicity of constructed Reg2C and Reg2X fragments was determined in healthy BALB/c mice, and the bioactivity in stimulating cell proliferation and survival was assessed in insulinoma MIN6 cells. Reg2 administration alleviated diabetes in NOD mice with improved glucose tolerance and insulin secretion but elevated serum Reg2 autoantibodies. Histomorphometry showed reduced inflammatory area, TUNEL signal and CD8 + T cell infiltration, and increased ß-cell proportion in support of the islet-protective effect of Reg2 treatment. CFA+PBS and CFA+Reg2 immunizations prevented diabetic onset and alleviated insulitis while injections of the antisera offered mild protections. Antibody treatments accelerated diabetic onset without increasing the overall incidence. Reg2C fragment depletes antigenicity, but reserves protective activity in streptozotocin (STZ)-treated MIN6 cells. In conclusion, Reg2 treatment alleviates type 1 diabetes (T1D) by preserving islet ß-cells, but induces Reg2 autoantibody production which poses a potential risk of accelerating diabetic progression.
Asunto(s)
Autoanticuerpos , Islotes Pancreáticos , Ratones Endogámicos BALB C , Ratones Endogámicos NOD , Proteínas Asociadas a Pancreatitis , Animales , Autoanticuerpos/inmunología , Autoanticuerpos/sangre , Ratones , Islotes Pancreáticos/inmunología , Islotes Pancreáticos/efectos de los fármacos , Islotes Pancreáticos/metabolismo , Islotes Pancreáticos/patología , Femenino , Proteínas Asociadas a Pancreatitis/inmunología , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/prevención & control , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Litostatina/inmunologíaRESUMEN
Many components (such as tea polyphenols, catechins, theaflavins, theasinensins, thearubigins, flavonoids, gallic acid, etc.) in black tea have antioxidant activities. However, it is not clear which components have a greater influence on the antioxidant activity of black tea. In this study, the antioxidant activity and contents of tea polyphenols, catechins, theaflavins, thearubigins, theabrownins, TSA, total flavonoids, amino acids, caffeine, and total soluble sugar were analyzed in 51 black teas. Principal component analysis (PCA), orthogonal partial least-squares discrimination analysis (OPLS-DA), and the correlation analysis method were used for data analysis. The results showed that catechins in tea polyphenols were the most important components that determine the antioxidant activity of black tea. Among them, epicatechin gallate (ECG), epi-gallocatechin gallate (EGCG), epicatechin (EC), and epi-gallocatechin (EGC) were significantly positively correlated with the antioxidant activity of black tea, and theabrownin was negatively correlated with the antioxidant activity of black tea. Furthermore, this study analyzed the correlation between the changes in catechin and its oxidized polymers with antioxidant activity during black tea fermentation; it verified that catechins were significantly positively correlated with the antioxidant activity of black tea, and theabrownin showed a negative correlation. And the antioxidant activity of catechins and their oxidation products in vitro and their correlation in black tea processing were used as validation. This study provides a comparison method for comparing the antioxidant activity of black tea.
RESUMEN
Regenerating family protein 3 A (Reg3A) is highly expressed in a variety of organs and inflammatory tissues, and is closely related to tumorigenesis and cancer progression. However, clinical statistics show that high expression of Reg3A is associated with better prognosis in colorectal cancer (CRC) patients, suggesting a tumor-suppressive effect. The precise action and underlying mechanism of Reg3A in CRC remain controversial. The present study sought to investigate the relationship among Reg3A expression, CRC development, and immune cell alteration in patients using the TCGA, GEPIA, PrognoScan, TIMER and TISIDB databases. Reg3A-overexpressing LoVo cell line (LoVo-Reg3A), a representative of colon adenocarcinoma (COAD), was constructed and the action of Reg3A was assessed in a xenograft nude mouse model. Our bioinformatical analyses revealed that Reg3A upregulation is highly associated with CRC, along with increased frequency of immune cell infiltration. In the xenograft nude mice, Reg3A overexpression offered a tumor-suppressive effect by inhibiting cell proliferation and promoting apoptosis. The result of RNA-seq suggested a positive regulation of leukocytes and an upregulation of T cells in LoVo-Reg3A tumor tissue. CD4+ and CD8+ T cells in tumors, splenic Reg3A-reactive IFN-γ+/CD4+ T cells, and serum TNF-α, IFN-γ and IL-17 were significantly increased by Reg3A overexpression. In the ex vivo co-culture experiment, elevated cytotoxic effect, increased proportion of CD3ε+ T cells, and upregulated expressions of TNF-α, IFN-γ and IL-17 were detected in the PBMCs isolated from LoVo-Reg3A cell-xenografted nude mice. In conclusion, high expression of Reg3A could activate and recruit T cells in COAD leading to the cytotoxic tumor-suppressive effect.
Asunto(s)
Adenocarcinoma , Neoplasias del Colon , Animales , Humanos , Ratones , Linfocitos T CD8-positivos , Neoplasias del Colon/genética , Interleucina-17 , Ratones Desnudos , Factor de Necrosis Tumoral alfaRESUMEN
BACKGROUND/AIM: Renal cell carcinoma (RCC) of unknown primary origin is rarely identified and accounts for only 5% of cancers of unknown primary origin (CUP). The disease prognosis is typically poor because of no standard and effective therapy. Our review indicated that 23 cases have been reported and treated with conventional chemotherapy or tyrosine-kinase inhibitors alone; accordingly, most patients showed partial response or progression diseases with short survival time. CASE REPORT: Herein, we present two cases of metastatic RCC of unknown primary origin. One case was papillary type and the other was clear cell type. According to the recent clinical trials in patients with metastatic RCC, a combination of immunotherapy and tyrosine-kinase inhibitors exhibited better response than conventional therapy or tyrosine-kinase inhibitors alone. Both present cases accepted a combination treatment with immunotherapy and tyrosine-kinase inhibitor and showed stable diseases. The radiological progression-free time for the case with metastatic papillary RCC was 5 months, and that with clear cell RCC was 6 months until now. CONCLUSION: The combination of immunotherapy and tyrosine-kinase inhibitors is at least as effective as a tyrosine-kinase inhibitor alone, and superior to conventional chemotherapy for treating metastatic RCC of unknown primary origin.
Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Neoplasias Primarias Desconocidas , Humanos , Carcinoma de Células Renales/diagnóstico , Carcinoma de Células Renales/tratamiento farmacológico , Inmunoterapia , Neoplasias Renales/tratamiento farmacológico , Neoplasias Primarias Desconocidas/diagnóstico , Neoplasias Primarias Desconocidas/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Tirosina/metabolismoRESUMEN
Inflammatory reaction plays a key role in the pathogenesis of hypoxic-ischemic encephalopathy (HIE) in neonates. Microglia are resident innate immune cells in the central nervous system and are profoundly involved in neuroinflammation. Studies have revealed that atorvastatin exerts a neuroprotective effect by regulating neuroinflammation in adult animal models of brain stroke and traumatic brain injury, but its role regarding damage to the developing brain remains unclear. This study aimed to clarify the effect and mechanism of atorvastatin on the regulation of microglia function in neonatal hypoxic-ischemic brain damage (HIBD). The oxygen glucose deprivation (OGD) of microglia and neonatal rat HIBD model was established. Atorvastatin, recombinant sclerostin protein (SOST), and XAV939 (degradation of ß-catenin) were administered to OGD microglia and HIBD rats. The pathological changes of brain tissue, cerebral infarction volume, learning and memory ability of rats, pro-inflammatory (CD16+/Iba1+) and anti-inflammatory (CD206+/Iba1+) microglia markers, inflammation-related indicators (Inos, Tnfα, Il6, Arg1, Tgfb, and Mrc1), and Wnt/ß-catenin signaling molecules were examined. Atorvastatin reduced OGD-induced pro-inflammatory microglia and pro-inflammatory factors, while increasing anti-inflammatory microglia and anti-inflammatory factors. In vivo, atorvastatin attenuated hypoxia-ischemia (HI)-induced neuroinflammation and brain damage. Mechanistically, atorvastatin decreased SOST expression and activated the Wnt/ß-catenin signaling pathway, and the administration of recombinant SOST protein or XAV939 inhibited Wnt/ß-catenin signaling and attenuated the anti-inflammatory effect of atorvastatin. Atorvastatin promotes the pro/anti-inflammatory phenotypic transformation of microglia via the Wnt/ß-catenin pathway in HI neonatal rats. Atorvastatin may be developed as a potent agent for the treatment of HIE in neonates.
RESUMEN
Granzyme B (GrB) is a pivotal killer factor in immunotherapy whose application is limited by hyposensitivity and unsatisfactory cellular uptake by tumor cells. In this study, it was proved that SerpinB9 (Sb9) downregulation can enhance the GrB susceptibility of tumor cells. Moreover, a nanocarrier fused with M1 macrophage exosomes (M1 Exo) and photothermal sensitive liposomes was constructed to efficiently transport GrB and siRNA of Sb9 to the cells. The nanocarrier is characterized by cascade tumor targeting acquired by photothermal effect-triggered increased expression of vascular cell adhesion molecule-1 (VCAM-1) in tumor tissue. Furthermore, the innate cytokines in M1 Exo are capable of regulating the tumor microenvironment by repolarizing M2 macrophages to the M1 type. Collectively, the multifunctional nanoplatform (S+G@ELP) enhances the lethality of GrB to tumor cells, activates a widespread immune response uniting with photothermal therapy (PTT), restrains the tumor progression and metastasis effectively, which is expected to provide new insights into GrB-based combinational tumor therapy.
Asunto(s)
Neoplasias , Serpinas , Biomimética , Línea Celular Tumoral , Granzimas/genética , Granzimas/metabolismo , Humanos , Inmunoterapia , Neoplasias/terapia , Inhibidores de Serina Proteinasa , Serpinas/genética , Serpinas/metabolismo , Microambiente TumoralRESUMEN
BACKGROUND: Sepsis, a serious condition with high mortality, usually causes sepsis associated encephalopathy (SAE) that involves neuronal cell death. However, the cell death programs involved and their underlying mechanisms are not clear. This study aimed to explore the regulatory mechanisms of different cell death programs in SAE. METHODS: A neonatal rat model of SAE was established by cecal ligation and perforation. Survival rate and vital signs (mean arterial pressure and heart rate) were monitored, nerve reflexes were evaluated, and cortical pathological changes were observed by hematoxylin and eosin staining. The expression of pyroptosis, apoptosis, and necroptosis (PANoptosis)-related proteins, mitogen- activated protein kinase (MAPK), and its upstream regulator toll-like receptor 9 (TLR9) were detected. The expression of TLR9 in neurons was observed by immunofluorescence staining. The ultrastructure of neurons was observed by transmission electron microscope. RESULTS: First, PANoptosis was found in cortical nerve cells of the SAE rats. Meanwhile, the subunits of MAPKs, p38 MAPK, Jun N- terminal kinase, and extracellular signal-regulated kinase (ERK) were activated. After pharmacologically inhibiting each of the subunits, only p38 MAPK was found to be associated with PANoptosis. Furthermore, blocking the p38 MAPK signaling pathway activated necroptosis but inhibited apoptosis and pyroptosis. When necroptosis was pharmacologically inhibited, apoptosis and pyroptosis were reactivated. Finally, we found that the expression of TLR9, a regulator of MAPKs, was significantly increased in this model. After down-regulation of TLR9, p38 MAPK, and ERK signaling pathways were inhibited, which led to the inhibition of PANoptosis. Further analysis found that down-regulation of TLR9 improved the survival rate and reduced the pathological changes in SAE rats. CONCLUSIONS: Our study showed that the programs comprising PANoptosis are activated simultaneously in SAE rats. TLR9 activated PANoptosis through the p38 MAPK signaling pathway. TLR9 may work as a potential target for SAE treatment.
Asunto(s)
Encefalopatía Asociada a la Sepsis , Proteínas Quinasas p38 Activadas por Mitógenos , Animales , Animales Recién Nacidos , Apoptosis , Eosina Amarillenta-(YS) , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Hematoxilina , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Sistema de Señalización de MAP Quinasas/fisiología , Mitógenos , Ratas , Transducción de Señal , Receptor Toll-Like 9/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Background and aim: Abdominal tuberculosis (TB) is a common type of extrapulmonary TB with an insidious onset and non-specific symptoms. Adenosine deaminase (ADA) levels increase rapidly in the early stages of abdominal TB. However, it remains unclear whether ADA serves as a diagnostic marker for abdominal TB. Methods: We performed a systematic literature search for relevant articles published in PubMed, Web of Science, Cochrane Library, and Embase up to April 2022. First, we used the Quality Assessment of Diagnostic Accuracy Studies tool-2 (QUADAS-2), to evaluate the quality of the included articles. Bivariate and hierarchical summary receiver operating characteristic (HSROC) models were then utilized to analyze pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR) and area under the receiver operating characteristic curve (AUROC). In addition, we explored a subgroup analysis for potential heterogeneity and publication bias among the included literature. Results: Twenty-four articles (3,044 participants, 3,044 samples) which met the eligibility criteria were included in this study. The pooled sensitivity and specificity of ADA for abdominal TB detection were 93% [95% confidence interval (CI): 0.89-0.95] and 95% (95% CI: 0.93-0.96), respectively. PLR and NLR were 18.6 (95% CI: 14.0-24.6) and 0.08 (95% CI: 0.05-0.12), respectively. DOR and AUROC were 236 (95% CI: 134-415) and 0.98 (95% CI: 0.96-0.99), respectively. Furthermore, no heterogeneity or publication bias was found. Conclusions: Our meta-analysis found ADA to be of excellent diagnostic value for abdominal TB and could be used as an auxiliary diagnostic tool. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier: CRD42022297931.
Asunto(s)
Adenosina Desaminasa , Tuberculosis , Humanos , Curva ROC , Sensibilidad y Especificidad , Tuberculosis/diagnósticoRESUMEN
In perovskite solar cells (PSCs), a defective perovskite (PVK) surface and cliff-like energy offset at the interface always slow down the charge extraction; meanwhile, interface ion diffusion causes oxidation of the metal electrode, inducing device instability. Here, the in situ grown 2D-(CH3 NH2 )3 Sb2 I9 (MA3 Sb2 I9 ) on the back surface of MAPbI3 results in a more robust interface. MA3 Sb2 I9 changes the MAPbI3 surface to p-type and thus acts like a back surface field to drive charge extraction and suppress recombination, resulting in an obviously higher fill factor (FF) = 0.8 and power conversion efficiency (PCE) = 20.4% of SnO2 /MAPbI3 /MA3 Sb2 I9 /Spiro-OMeTAD (2,2',7,7'-Tetrakis[N,N-di(4-methoxyphenyl)amino]-9,9'-spirobifluorene) PSC than the pure MAPbI3 device. More importantly, strong chemical bonding of SbI prohibits ion diffusion, largely enhancing the thermal stability and longtime stability. Here, special 2D-MA3 Sb2 I9 constructs' robust band alignment and chemical environment at the interface are highlighted for efficient and stable PSCs.
RESUMEN
Defective grain boundaries (GBs) and surface trap states are detrimental to the efficiency and stability of perovskite solar cells (PSCs). In this research, ionic liquid (IL) is used to control the defect states at the perovskite surface and GBs. The newly formed (EMIm)xMA1-xPb[(BF4)xI1-x]3 interlayer promotes secondary grain growth to diminish GBs; besides, EMIM+ and BF4- fill the vacancies of MA+ and I- and also passivate undercoordinated Pb2+ trap states. The newly formed interface largely reduces the nonradiative recombination, thus enhancing the solar-cell performance to 19.0% (AM 1.5, 1 sun) with higher photovoltage and fill factor than the control device. Due to the hydrophobicity of the (EMIm)xMA1-xPb[(BF4)xI1-x]3 interlayer, the unencapsulated device stability in 30 days is much better than the control device under relative humidity (RH) = 20%. This work highlights IL-induced secondary grain growth and a defect passivation method for efficient and stable PSCs.