RESUMEN
Endothelial senescence, aging-related inflammation, and mitochondrial dysfunction are prominent features of vascular aging and contribute to the development of aging-associated vascular disease. Accumulating evidence indicates that DNA damage occurs in aging vascular cells, especially in endothelial cells (ECs). However, the mechanism of EC senescence has not been completely elucidated, and so far, there is no specific drug in the clinic to treat EC senescence and vascular aging. Here we show that various aging stimuli induce nuclear DNA and mitochondrial damage in ECs, thus facilitating the release of cytoplasmic free DNA (cfDNA), which activates the DNA-sensing adapter protein STING. STING activation led to a senescence-associated secretory phenotype (SASP), thereby releasing pro-aging cytokines and cfDNA to further exacerbate mitochondrial damage and EC senescence, thus forming a vicious circle, all of which can be suppressed by STING knockdown or inhibition. Using next-generation RNA sequencing, we demonstrate that STING activation stimulates, whereas STING inhibition disrupts pathways associated with cell senescence and SASP. In vivo studies unravel that endothelial-specific Sting deficiency alleviates aging-related endothelial inflammation and mitochondrial dysfunction and prevents the development of atherosclerosis in mice. By screening FDA-approved vasoprotective drugs, we identified Cilostazol as a new STING inhibitor that attenuates aging-related endothelial inflammation both in vitro and in vivo. We demonstrated that Cilostazol significantly inhibited STING translocation from the ER to the Golgi apparatus during STING activation by targeting S162 and S243 residues of STING. These results disclose the deleterious effects of a cfDNA-STING-SASP-cfDNA vicious circle on EC senescence and atherogenesis and suggest that the STING pathway is a promising therapeutic target for vascular aging-related diseases. A proposed model illustrates the central role of STING in mediating a vicious circle of cfDNA-STING-SASP-cfDNA to aggravate age-related endothelial inflammation and mitochondrial damage.
Asunto(s)
Senescencia Celular , Cilostazol , Inflamación , Proteínas de la Membrana , Ratones Endogámicos C57BL , Mitocondrias , Animales , Proteínas de la Membrana/metabolismo , Cilostazol/farmacología , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Humanos , Inflamación/metabolismo , Inflamación/tratamiento farmacológico , Senescencia Celular/efectos de los fármacos , Ratones , Envejecimiento/metabolismo , Células Endoteliales/metabolismo , Células Endoteliales/efectos de los fármacos , Citosol/metabolismo , ADN/metabolismo , Masculino , Células Endoteliales de la Vena Umbilical Humana , Fenotipo Secretor Asociado a la Senescencia , Células CultivadasRESUMEN
Atherosclerosis, one of the life-threatening cardiovascular diseases (CVDs), has been demonstrated to be a chronic inflammatory disease, and inflammatory and immune processes are involved in the origin and development of the disease. Toll-like receptors (TLRs), a class of pattern recognition receptors that trigger innate immune responses by identifying pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), regulate numerous acute and chronic inflammatory diseases. Recent studies reveal that TLRs have a vital role in the occurrence and development of atherosclerosis, including the initiation of endothelial dysfunction, interaction of various immune cells, and activation of a number of other inflammatory pathways. We herein summarize some other inflammatory signaling pathways, protein molecules, and cellular responses associated with TLRs, such as NLRP3, Nrf2, PCSK9, autophagy, pyroptosis and necroptosis, which are also involved in the development of AS. Targeting TLRs and their regulated inflammatory events could be a promising new strategy for the treatment of atherosclerotic CVDs. Novel drugs that exert therapeutic effects on AS through TLRs and their related pathways are increasingly being developed. In this article, we comprehensively review the current knowledge of TLR signaling pathways in atherosclerosis and actively seek potential therapeutic strategies using TLRs as a breakthrough point in the prevention and therapy of atherosclerosis.
Asunto(s)
Aterosclerosis , Proproteína Convertasa 9 , Humanos , Proproteína Convertasa 9/metabolismo , Receptores Toll-Like/metabolismo , Transducción de Señal/fisiología , Aterosclerosis/metabolismoRESUMEN
Animal medicine is a large category of Chinese medicinecommonly used in clinical practice and has important scientific and therapeutic value. Animal medicine isscarcer than herbal medicine. In recent years, with the vigorous development of traditional Chinese medicine(TCM),the contradiction between the increasing industrial demand andsupply of scarce and even endangered medicinal animals has become increasingly prominent. The continuous lack of medicinal animal resources affects the clinical demandandalso causes serious damage to the ecological environment. Only relying on artificial breeding is not enough to alleviate the current condition of depletion. In the face of this dilemma, it is a major challenge for the current industrial development to protect animal resources and meet clinical and industrial needs with "available medicines". The application of substitutes for animal medicines isthe key focus to alleviate this problem, and it is also the key scientific issue to be solved urgently in the modernization of TCM. This paper summarizedand reviewedthe history, current situation, strategies, and methods of animal medicinesubstitution and put forward the point of view of "similar chemical characteristics, similar efficacy, and higher safety" to provide references for scientific substitution and resource protection of rare animals.
Asunto(s)
Medicamentos Herbarios Chinos , Plantas Medicinales , Animales , Medicamentos Herbarios Chinos/uso terapéutico , Medicina Tradicional China , Fitomejoramiento , Proyectos de InvestigaciónRESUMEN
The coronavirus disease 2019 (COVID-19) is an epidemic disease caused by the Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) and spreading throughout the world rapidly. Here we evaluated the efficacy of the Lopinavir/Ritonavir (LPV/r) and its combination with other drugs in the treatment of COVID-19. We included 170 confirmed COVID-19 patients who had been cured and discharged. Their antiviral therapies were LPV/r alone or combinations with interferon (IFN), Novaferon and Arbidol. We evaluated the medication efficacy by comparing the time of the negative nucleic acid conversion and the length of hospitalization mainly. The LPV/r + Novaferon [6.00 (4.00-8.00) and 7.50 (5.00-10.00) days] had shorter time of the negative nucleic acid conversion (P = .0036) and shorter time of hospitalization (P < .001) compared with LPV/r alone [9.00 (5.00-12.00) and 12.00 (11.00-15.00) days] and LPV/r + IFN [9.00 (7.25-11.00) and 12.00 (10.00-13.50) days]. On the contrary, LPV/r + IFN [9.00 (7.25-11.00) and 12.00 (10.00-13.50) days] had shorter time of the negative nucleic acid conversion (P = .031) and shorter time of hospitalization (P < .001) compared with LPV/r + IFN +Novaferon [10.00 (8.00-11.25) and 13.50 (11.50-17.00) days] and LPV/r + IFN +Arbidol [14.00 (9.75-19.00) and 19.50 (13.25-24.00) days]. In conclusion, the combination of LPV/r and Novaferon may have better efficacy against COVID-19. However, adding IFN based on LPV/r + Novaferon or adding Arbidol based on LPV/r + IFN may not improve the efficacy.
Asunto(s)
Tratamiento Farmacológico de COVID-19 , Lopinavir/farmacología , Ritonavir/farmacología , Adulto , Interacciones Farmacológicas , Femenino , Humanos , Lopinavir/uso terapéutico , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Ritonavir/uso terapéutico , Resultado del TratamientoRESUMEN
The aim of this study was to observe the effect of baicalin on the growth state of attention deficit hyperactivity disorder animal model and its regulation on Ca MKâ ¡and ERK1/2.In the present study,a total of 40 SHR rats were randomly divided into model group,methylphenidate hydrochloride group,and low,medium,and high dose baicalin groups,with 8 rats in each group.Eight WKYrats were selected as a normal control group.The methylphenidate hydrochloride group(0.07 g·L~(-1))and the low(3.33 g·L~(-1)),medium(6.67 g·L~(-1)),and high dose(10 g·L~(-1))baicalin groups received corresponding drugs by gavage administration according to the body weight(0.015 m L·g~(-1)),while the normal group and the model group received the same volume of normal saline by gavage.Thegavage administration lasted for 4 weeks,twice a day.The body weight of the rats and the amount of remaining feed were weighed daily,and the growth state of the rats was statistically evaluated weekly.Percoll density gradient centrifugation was used to prepare brain synaptosomes and an electron microscope was used to observe their structures.The Ca MKâ ¡and ERK1/2 protein and mRNA expression levels were detected with Western blot and Real-time PCR methods,respectively.RESULTS: showed that baicalin did not affect the normal eating and weight gain of rats,and the weight gain of rats was even more significant than that in the normal group(P<0.05).In the study of its effects on Ca MKâ ¡and ERK1/2 protein expression in rat synaptosomes,the expression of both proteins in each drug-administered group was higher than that in the model group(P<0.05);besides,the expression levels of Ca MKâ ¡and ERK1/2 protein were significantly increased in both baicalin high dose group and the methylphenidate hydrochloride group(P<0.05).The relative expression of Ca MKâ ¡and ERK1/2 mRNA in synaptosome was detected by PCR.The results showed that medium and high doses of baicalin and methylphenidate hydrochloride significantly increased the relative expression of Ca MKâ ¡and ERK1/2 mRNA in synaptosomes of SHR rats(P<0.05).In conclusion,baicalin does not affect the normal growth and development of SHR rats,so it is safe for administration.Both baicalin and methylphenidate hydrochloride could up-regulate the relative expression of Ca MKâ ¡and ERK1/2 in mRNA and protein,and the pharmacodynamic stability of baicalin is in a dose-dependent manner to certain extent.
Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad , Animales , Modelos Animales de Enfermedad , Flavonoides , Péptidos y Proteínas de Señalización Intracelular , Sistema de Señalización de MAP Quinasas , Proteínas Serina-Treonina Quinasas , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKYRESUMEN
The gene therapy of cancer, due to the limit of its efficiency and safety, has not been widely used in clinical. Recently, bacterial magnetic particles (BMPs), which are membrane-bound nanocrystals found in magnetotactic bacteria, have been exploited as a new gene delivery system. However, its application on gene therapy remains to be explored. In our previous study, we found that a combination of cecropin B (ABPs) and apoptin (VP3) could serve as an effective gene therapeutic agent. Thus, in this study, we used BMPs to deliver the co-expression plasmid of these two gene, namely pVAX1-VA, and evaluated its therapeutic effect on human hepatocellular carcinoma (HepG2). Our results showed that BMPs significantly improved the efficiency of gene transfection (almost 3-fold than Lipofectamine 2000â¯at 48â¯h, Pâ¯<â¯.001), which led to stronger apoptosis (in a peak almost 2-fold than Lipofectamine 2000-pVAX1-VA, Pâ¯<â¯.01) and growth inhibition of HepG2 cells. More importantly, compared with Lipofectamine 2000-pVAX1-VA group, BMP-pVAX1-VA strikingly inhibited tumor growth (0.60⯱â¯0.09â¯g vs. 0.88⯱â¯0.11â¯g, Pâ¯<â¯.05) in nude mouse tumor models and increased the tumor-infiltrating lymphocytes considerably without apparent cytotoxicity. These findings suggest that BMPs could be an attractive gene delivery system for gene therapy and provide a potential available treatment for human hepatocellular carcinoma and maybe some other kinds of tumors.
Asunto(s)
Proteínas de la Cápside/genética , Carcinoma Hepatocelular/terapia , Técnicas de Transferencia de Gen , Vectores Genéticos/administración & dosificación , Proteínas de Insectos/genética , Neoplasias Hepáticas/terapia , Magnetosomas/química , Magnetospirillum/química , Animales , Antineoplásicos/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Portadores de Fármacos/química , Femenino , Terapia Genética/métodos , Vectores Genéticos/genética , Vectores Genéticos/uso terapéutico , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Ratones Endogámicos BALB C , Ratones Desnudos , Transfección/métodosRESUMEN
An enantioselective sulfenylation of ß-naphthols has been developed for the first time using a newly synthesized cinchona-derived thiourea as the catalyst and N-(arylthio) succinimide (or phthalimide) as an electrophilic sulfur source. Various enantioenriched naphthalenones with an S-containing all-substituted stereocenter were prepared via a dearomatization strategy under mild reaction conditions.
RESUMEN
An enantioselective arylative dearomatization reaction of ß-naphthols with quinone monoimides has been developed for the first time using a chiral phosphoric acid as the catalyst, the desired enantioenriched cyclohexadienones were prepared with excellent yields and enantioselectivities by a domino Michael addition and aromatization process (up to 99 % yield, up to 98 % ee). This process is operationally simple and readily scaled up, as well as a broad substrate scope which includes 1-substituted-2-naphthols with/without 3-substituents. Furthermore, this organocatalytic procedure allows the lowering of catalyst loading to 0.5â mol % without considerable loss in reactivity and enantioselectivity.
RESUMEN
Here, we report a fiber-optic point-based sensor to measure temperature and weight based on correlated specklegrams induced by spatial multimode interference. The device is realized simply by splicing a multimode fiber (MMF) to a single-mode fiber (SMF) with a core offset. A series of experiments demonstrates the approximately linear relation between the correlation coefficient and variation. Furthermore, we show the potential applications of the refractive index sensing of our device by disconnecting the splicing point of MMF and SMF. A modification of the algorithm in order to improve the sensitivity of the sensor is also discussed at the end of the paper.
RESUMEN
OBJECTIVE: To investigate the effect of baicalin on the behavioral characteristics of rats with attention deficit hyperactivity disorder (ADHD), and to provide a basis for further research on baicalin in the treatment of ADHD. METHODS: A total of 40 SHR rats were randomly divided into model group, methylphenidate hydrochloride (MPH) group, and low-, medium-, and high-dose baicalin groups, with 8 rats in each group. Eight WKY rats were selected as normal control group. The rats in the MPH group (0.07â mg/mL) and the low- (3.33â mg/mL), medium- (6.67â mg/mL), and high-dose (10â mg/mL) baicalin groups were given the corresponding drugs (1.5â mL/100 g) by gavage twice a day, and those in the normal control group and the model group were given an equal volume of normal saline by gavage twice a day. The course of treatment was 4 weeks for all groups. The open field test was performed to observe total moving distance and average moving speed on day 0 of experiment and at 7, 14, 21, and 28 days after gavage and to evaluate the control effects of drugs on hyperactivity and impulsive behavior. The Morris water maze test was used to observe the latency, time spent in the target quadrant, and number of platform crossings and to evaluate the effects of drugs on attention. RESULTS: The open field test showed that the model group and the drug treatment groups had a significantly longer total moving distance and a significantly higher average moving speed than the normal control group on day 0 (P<0.05). On day 7, the MPH group had significant reductions in total moving distance and average moving speed compared with the model group (P<0.05). On day 14, the MPH group and the high-dose baicalin group had significant reductions in total moving distance and average moving speed compared with the model group (P<0.05). The data on days 21 and 28 showed that compared with the model group, the low-, medium-, and high-dose baicalin groups had gradual reductions in total moving distance and average moving speed (P<0.05). The water maze test showed that compared with the model group, the MPH group and the medium- and high-dose baicalin groups had a significantly longer time spent in the target quadrant (P<0.05), and the MPH group and the high-dose baicalin group had a significantly higher proportion of the moving distance in the target quadrant in total moving distance (P<0.05). The high-dose baicalin group had the highest number of platform crossings among all groups (P<0.05). CONCLUSIONS: Both baicalin and MPH can regulate the motor ability and learning and memory abilities of SHR rats with ADHD and thus control the core symptoms of ADHD, i.e., hyperactivity, impulsive behavior, and inattention. Baicalin exerts its effect in a dose-dependent manner, and high-dose baicalin has the most significant effect, but compared with MPH, it needs a longer time to play its therapeutic effect.
Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Conducta Animal/efectos de los fármacos , Flavonoides/uso terapéutico , Animales , Trastorno por Déficit de Atención con Hiperactividad/psicología , Relación Dosis-Respuesta a Droga , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKYRESUMEN
OBJECTIVE: To study the effect of baicalin on synaptosomal adenosine triphosphatase (ATPase) and lactate dehydrogenase (LDH) and its regulatory effect on the adenylate cyclase (AC)/cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling pathway in rats with attention deficit hyperactivity disorder (ADHD). METHODS: A total of 40 SHR rats were randomly divided into five groups: ADHD model, methylphenidate hydrochloride treatment (0.07 mg/mL), and low-dose (3.33 mg/mL), medium-dose (6.67 mg/mL), and high-dose (10 mg/mL) baicalin treatment (n=8 each). Eight WKY rats were selected as normal control group. Percoll density gradient centrifugation was used to prepare brain synaptosomes and an electron microscope was used to observe their structure. Colorimetry was used to measure the activities of ATPase and LDH in synaptosomes. ELISA was used to measure the content of AC, cAMP, and PKA. RESULTS: Compared with the normal control group, the ADHD model group had a significant reduction in the ATPase activity, a significant increase in the LDH activity, and significant reductions in the content of AC, cAMP, and PKA (P<0.05). Compared with the ADHD model group, the methylphenidate hydrochloride group and the medium- and high-dose baicalin groups had a significant increase in the ATPase activity (P<0.05), a significant reduction in the LDH activity (P<0.05), and significant increases in the content of AC, cAMP, and PKA (P<0.05). Compared with the methylphenidate hydrochloride group, the high-dose baicalin group had significantly greater changes in these indices (P<0.05). Compared with the low-dose baicalin group, the high-dose baicalin group had a significant increase in the ATPase activity (P<0.05); the medium- and high-dose baicalin groups had a significant reduction in the LDH activity (P<0.05) and significant increases in the content of AC, cAMP, and PKA (P<0.05). Compared with the medium-dose baicalin group, the high-dose baicalin group had a significant increase in the ATPase activity (P<0.05). CONCLUSIONS: Both methylphenidate hydrochloride and baicalin can improve synaptosomal ATPase and LDH activities in rats with ADHD. The effect of baicalin is dose-dependent, and high-dose baicalin has a significantly greater effect than methylphenidate hydrochloride. Baicalin exerts its therapeutic effect possibly by upregulating the AC/cAMP/PKA signaling pathway.
Asunto(s)
Adenosina Trifosfatasas/metabolismo , Adenilil Ciclasas/fisiología , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Proteínas Quinasas Dependientes de AMP Cíclico/fisiología , AMP Cíclico/fisiología , Flavonoides/farmacología , L-Lactato Deshidrogenasa/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Trastorno por Déficit de Atención con Hiperactividad/fisiopatología , Flavonoides/uso terapéutico , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Sinaptosomas/química , Sinaptosomas/ultraestructuraRESUMEN
Aroma-related volatiles, together with sugars and acids, play an important role in determining fruit flavor quality. Characteristic volatiles of peach fruit are mainly derived from fatty acids such as linoleic acid (18:2) and linolenic acid (18:3). In the present study, six genes encoding fatty acid desaturases (FAD) were cloned, including two ω-6 FAD genes (PpFAD2, PpFAD6) and four ω-3 FAD genes (PpFAD3-1, PpFAD3-2, PpFAD7 and PpFAD8). Heterologous expression of peach FADs in tobacco plants showed that PpFAD3-1, and PpFAD3-2 significantly reduced contents of 18:2, and accumulated significant higher levels of 18:3. In the case of volatiles, transgenic plants produced lower concentrations of hexanal and higher levels of (E)-2-hexenal. Consequently, the ratio of the (E)-2-hexenal and hexanal was about 5- and 3-fold higher than that of wild type (WT) in PpFAD3-1 and PpFAD3-2 transformants, respectively. No significant changes in volatile profiles were observed in transgenic plants overexpressing the four other peach FAD genes. Real-time quantitative polymerase chain reaction (qPCR) analysis showed that ripe fruit had high PpFAD3-1 and low PpFAD3-2 transcript levels. In contrast, high PpFAD3-2 and low PpFAD3-1 transcript levels were observed in young fruit. These results indicate a temporal regulation of these two ω-3 FADs during development and ripening, influencing peach fruit volatile formation.
Asunto(s)
Ácido Graso Desaturasas/metabolismo , Frutas/enzimología , Proteínas de Plantas/metabolismo , Prunus persica/enzimología , Compuestos Orgánicos Volátiles/metabolismo , Análisis por Conglomerados , Ácido Graso Desaturasas/genética , Ácidos Grasos Omega-3/metabolismo , Frutas/química , Frutas/metabolismo , Cromatografía de Gases y Espectrometría de Masas , Ácido Linoleico/metabolismo , Proteínas de Plantas/genética , Plantas Modificadas Genéticamente/metabolismo , Prunus persica/química , Prunus persica/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Análisis de Secuencia de ADN , Nicotiana/genética , Nicotiana/metabolismo , Compuestos Orgánicos Volátiles/análisis , Ácido alfa-Linolénico/metabolismoRESUMEN
BACKGROUND: α-Enolase is a glycolytic enzyme with "second jobs" beyond its catalytic activity. However, its possible contribution to cardiac dysfunction remains to be determined. The present study aimed to investigate the role of α-enolase in doxorubicin (Dox)-induced cardiomyopathy as well as the underlying mechanisms. EXPERIMENTAL APPROACHES: The expression of α-enolase was detected in rat hearts and primary cultured rat cardiomyocytes with or without Dox administration. An adenovirus carrying short-hairpin interfering RNA targeting α-enolase was constructed and transduced specifically into the heart by intramyocardial injection. Heart function, cell apoptosis and mitochondrial function were measured following Dox administration. In addition, by using gain- and loss-of-function approaches to regulate α-enolase expression in primary cultured rat cardiomyocytes, we investigated the role of endogenous, wide type and catalytically inactive mutant α-enolase in cardiomyocyte apoptosis and ATP generation. Furthermore, the involvement of α-enolase in AMPK phosphorylation was also studied. KEY RESULTS: The mRNA and protein expression of cardiac α-enolase was significantly upregulated by Dox. Genetic silencing of α-enolase in rat hearts and cultured cardiomyocytes attenuated Dox-induced apoptosis and mitochondrial dysfunction. In contrast, overexpression of wide-type or catalytically inactive α-enolase in cardiomyocytes mimicked the detrimental role of Dox in inducing apoptosis and ATP reduction. AMPK dephosphorylation was further demonstrated to be involved in the proapoptotic and ATP-depriving effects of α-enolase. CONCLUSION: Our findings provided the evidence that α-enolase has a catalytically independent role in inducing cardiomyocyte apoptosis and mitochondrial dysfunction, which could be at least partially contributed to the inhibition of AMPK phosphorylation.
Asunto(s)
Apoptosis/efectos de los fármacos , Doxorrubicina/farmacología , Mitocondrias/metabolismo , Miocitos Cardíacos/enzimología , Fosfopiruvato Hidratasa/metabolismo , Adenosina Trifosfato/metabolismo , Adenoviridae/metabolismo , Adenilato Quinasa/metabolismo , Animales , Biocatálisis/efectos de los fármacos , Respiración de la Célula/efectos de los fármacos , Células Cultivadas , Regulación hacia Abajo/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Silenciador del Gen/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Miocardio/enzimología , Miocitos Cardíacos/efectos de los fármacos , Fosforilación/efectos de los fármacos , Ratas Sprague-Dawley , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Adipose triglyceride lipase (ATGL), the rate-limiting enzyme of triglyceride (TG) hydrolysis, plays an important role in TG metabolism. ATGL knockout mice suffer from TG accumulation and die from heart failure. However, the mechanisms underlying cardiac hypertrophy caused by ATGL dysfunction remain unknown. In this study, we found that ATGL expression declined in pressure overload-induced cardiac hypertrophy in vivo and phenylephrine (PE)-induced cardiomyocyte hypertrophy in vitro. ATGL knockdown led to cardiomyocyte hypertrophy, while ATGL overexpression prevented PE-induced hypertrophy. In addition, ATGL downregulation increased but ATGL overexpression reduced the contents of ceramide, which has been proved to be closely associated with cardiac hypertrophy. Moreover, the accumulation of ceramide was due to elevation of free fatty acids in ATGL-knockdown cardiomyocytes, which could be explained by the reduced activity of peroxisome proliferator-activated receptor (PPAR) α leading to imbalance of fatty acid uptake and oxidation. These observations suggest that downregulation of ATGL causes the decreased PPARα activity which results in the imbalance of FA uptake and oxidation, elevating intracellular FFA contents to promote the accumulation of ceramides, and finally inducing cardiac hypertrophy. Upregulation of ATGL could be a strategy for ameliorating lipotoxic damage in cardiac hypertrophy.
Asunto(s)
Cardiomegalia/enzimología , Ceramidas/metabolismo , Regulación Enzimológica de la Expresión Génica , Lipasa/biosíntesis , Miocitos Cardíacos/enzimología , Animales , Cardiomegalia/genética , Cardiomegalia/patología , Ceramidas/genética , Técnicas de Silenciamiento del Gen , Lipasa/genética , Masculino , Ratones , Miocitos Cardíacos/patología , Oxidación-Reducción , PPAR alfa/genética , PPAR alfa/metabolismo , Ratas , Ratas Sprague-DawleyAsunto(s)
Maltrato a los Niños/psicología , Responsabilidad Parental , Síntomas Afectivos/terapia , Ansiedad/terapia , Niño , China/epidemiología , Depresión/terapia , Humanos , Discapacidades para el Aprendizaje/terapia , Acontecimientos que Cambian la Vida , Soledad , Salud Mental , Pediatras/provisión & distribución , Pobreza , Psiquiatría , Población Rural , Capital Social , Clase Social , Estudiantes/psicología , Encuestas y Cuestionarios , Migrantes/psicologíaRESUMEN
In the present study, the short- and long-term effects of Zn(II) on the anaerobic ammonium oxidation (anammox) performance and sludge characteristics were evaluated. The anammox activity decreased with increasing Zn(II) concentration and pre-exposure time in short-term tests. The half maximal inhibitory concentration (IC50) of Zn(II) was found to be 25.0 mg L(-1). The 24 and 48-h pre-exposure time was a restricted factor impacting the anammox activity, and washing the inhibited sludge with buffer solution only worked under 0 and 24-h pre-exposure time. The anammox sludge could tolerate 5 mg L(-1) Zn(II) but was suppressed at 8 mg L(-1). The inhibited performance could be remitted, as the combination strategies were applied, and after the short term of recovery period, the inhibited sludge characteristics were remitted to the normal.
Asunto(s)
Amoníaco/metabolismo , Aguas del Alcantarillado/microbiología , Eliminación de Residuos Líquidos/métodos , Zinc/farmacología , Anaerobiosis , Biomasa , Reactores Biológicos/microbiología , Hemo/análogos & derivados , Hemo/metabolismo , Concentración 50 Inhibidora , Cinética , Consorcios Microbianos/efectos de los fármacos , Modelos Teóricos , Oxidación-ReducciónRESUMEN
OBJECTIVES: To observe the effect of moxibustion intervention on the hypothalamus-spinal cord-colon axis of rats with irritable bowel syndrome with diarrhea (IBS-D) and explore the mechanism of moxibustion in improving visceral hypersensitivity in rats with IBS-D. METHODS: A total of 36 SD rats were randomly divided into normal, model, and moxibustion groups, with 12 rats in each group. The IBS-D model was established by maternal separation + acetic acid stimulation + chronic restraint. Rats of the moxibustion group received bilateral moxibustion on "Tianshu" (ST25) and "Shangjuxu" (ST37) for 15 min, once a day for 7 consecutive days. The body weight, loose stool rate, and minimum threshold volume of abdominal withdrawal reflex (AWR) were measured before and after moxibustion intervention, respectively. The histopathological changes in the colon tissue were observed after HE staining. The number of colonic mucosal mast cells (MCs) was measured by toluidine blue staining. The activation of MCs was determined by tryptase positive expression level and examined by immunohistochemical staining. The content, protein and mRNA expression levels and positive expression levels of corticotropin releasing factor (CRF), substance P (SP), and calcitonin gene-related peptide (CGRP) in the hypothalamus, spinal cord and colon tissues were measured by ELISA, Western blot, real-time fluorescent quantitative PCR and immunofluorescence staining, respectively. RESULTS: Compared with the normal group, the loose stool rate was increased (P<0.01)ï¼the body weight and minimum threshold volume of AWR were decreased (P<0.01)ï¼the inflammatory infiltration of colon tissues was obviousï¼the number of MCs and positive expression level of tryptase in the colon tissue were increased (P<0.01)ï¼the contents, positive expression le-vels, protein and mRNA expression levels of CRF, SP and CGRP in the hypothalamus, spinal cord and colon tissues were increased (P<0.01, P<0.05) in the model group. After the intervention, compared with the model group, all these indicators showed opposite trends (P<0.01, P<0.05) in the moxibustion group. CONCLUSIONS: Moxibustion can improve visceral hypersensitivity in rats with IBS-D, and its mechanism may be related to regulating the hypothalamic-spinal-colon axis to reduce the release of CRF, SP and CGRP, and thus to inhibite MC in colon tissue.
Asunto(s)
Síndrome del Colon Irritable , Moxibustión , Ratas , Animales , Síndrome del Colon Irritable/genética , Síndrome del Colon Irritable/terapia , Síndrome del Colon Irritable/metabolismo , Ratas Sprague-Dawley , Hormona Liberadora de Corticotropina/metabolismo , Triptasas/metabolismo , Péptido Relacionado con Gen de Calcitonina/metabolismo , Privación Materna , Diarrea/genética , Diarrea/terapia , Hipotálamo/metabolismo , Sustancia P/metabolismo , Médula Espinal , Peso Corporal , ARN Mensajero/metabolismoRESUMEN
OBJECTIVE: To observe the effects of moxibustion on the stem cell factor (SCF)/tyrosine kinase receptor (c-kit) signaling pathway and immune function in rats with diarrhea irritable bowel syndrome (IBS-D), and to explore the mechanism of moxibustion for IBS-D. METHODS: Among 52 young rats born from 6 healthy pregnant SPF rats, 12 rats were randomly selected into the normal group, and the remaining 40 rats were treated with the three-factor combination method of maternal separation, acetic acid enema and chronic restraint stress to establish the IBS-D rat model. Thirty-six rats with successful IBS-D model were randomly divided into a model group, a moxibustion group, and a medication group, 12 rats in each group. The rats in the moxibustion group were treated with suspension moxibustion at "Tianshu" (ST 25) and "Shangjuxu" (ST 37); the rats in the medication group were treated with intragastric administration of rifaximin suspension (150 mg/kg). All the treatments were given once a day for 7 consecutive days. The body mass, loose stool rate (LSR), the minimum volume threshold when abdominal withdrawal reflex (AWR) scored 3 were measured before acetic acid enema (35 days old), after modeling (45 days old), and after intervention (53 days old). After intervention (53 days old), HE staining was used to observe the morphology of colon tissue, and spleen and thymus coefficients were measured; ELISA method was used to detect serum inflammatory factors (tumor necrosis factor a [TNF-a], interleukin [IL]-10, IL-8), T-lymphocyte subsets (CD+4, CD+8, CD+45), value of CD+4/CD+8 and immune globulin (IgA, IgG, IgM); real-time PCR method and Western blot method was used to detect the expression of SCF, c-kit mRNA and protein in colon tissue; immunofluorescence staining method were used to detect positive expression of SCF and c-kit. RESULTS: After intervention, compared with the normal group, in the model group, the body mass and the minimum volume threshold when AWR scored 3 were decreased (P<0.01), LSR, spleen and thymus coefficients, serum levels of TNF-α, IL-8, CD+4, CD+45, CD+4/CD+8, IgA, IgG, IgM were increased (P<0.01), serum IL-10 level and protein and mRNA expression of SCF and c-kit in colon tissue were decreased (P<0.01), and the positive expression of SCF and c-kit was decreased (P<0.01). Compared with the model group, in the moxibustion group and the medication group, the body mass and the minimum volume threshold when AWR scored 3 were increased (P<0.01, P<0.05), LSR, spleen and thymus coefficients, serum levels of TNF-α, IL-8, CD+4, CD+8, CD+45, CD+4/CD+8, IgA, IgG, IgM were decreased (P<0.01, P<0.05), serum IL-10 level and protein and mRNA expression of SCF and c-kit in colon tissue were increased (P<0.01), and the positive expression of SCF and c-kit was increased (P<0.01). Compared with the medication group, in the moxibustion group, the level of serum CD+4 was decreased (P<0.05), the value of CD+4/CD+8 was increased (P<0.01), and there was no significant difference in other indexes (P>0.05). The expression of SCF and c-kit mRNA was positively correlated with the minimum volume threshold when AWR scored 3 and IL-10 (P<0.01), and negatively correlated with remaining indexes (P<0.01, P<0.05). CONCLUSION: Moxibustion could reduce visceral hypersensitivity, improve symptoms of abdominal pain and diarrhea in IBS-D rats, and its mechanism may be related to up-regulation of the expression of SCF/c-kit signaling pathway and improvement of IBS-D immune function.
Asunto(s)
Síndrome del Colon Irritable , Moxibustión , Ratas , Animales , Síndrome del Colon Irritable/terapia , Moxibustión/métodos , Ratas Sprague-Dawley , Interleucina-10 , Interleucina-8 , Privación Materna , Factor de Necrosis Tumoral alfa , Diarrea , Transducción de Señal , Homeostasis , Proteínas Tirosina Quinasas Receptoras , Inmunidad , Inmunoglobulina A , Inmunoglobulina MRESUMEN
OBJECTIVE: To observe the effect of moxibustion on the expression of miR-345-3p, miR-216a-5p and nuclear factor-κB p65(NF-κB p65) in colonic tissue of rats with diarrhea-predominant irritable bowel syndrome (IBS-D), so as to explore its anti-inflammatory mechanism in relieving IBS-D. METHODS: SD rats were randomly divided into normal control (n=12), model (n=12), moxibustion (n=12) and ammonium pyrrolidine dithiocarbamate (PDTC,n=12) groups. The IBS-D model was established by neonatal mother-child separation combined with acetic acid enema stimulation and chronic binding methods. The rats in the moxibustion group received moxibustion stimulation of "Tianshu"(ST25) and "Shangjuxu"(ST37) for 20 min, once a day, for 7 days, and those of the PDTC group received intraperitoneal injection of PDTC (50 mg·kg-1·d-1) once daily for 7 days. After the intervention, the body weight, loose stool rate and the minimum volume threshold of abdominal withdrawal reflex (AWR) were observed, and histopathological changes of colonic mucosa were observed by HE staining. The contents of interleukin-1ß (IL-1ß), interleukin-4 (IL-4), interleukin-6 (IL-6) and tumor necrosis factor α (TNF- α) in serum were measured by ELISA. The expression of miR-345-3p, miR-216a-5p and NF-κB p65 mRNA in the colon tissue were detected by quantitative real-time PCR, and the immunoactivities of IL-1ß, IL-6, TNF-α and NF-κB p65 in the colon tissue were determined by immunofluorescence histochemistry. RESULTS: Compared with the normal control group, the loose stool rate, contents of IL-1ß, IL-6 and TNF-α, experssion of NF-κB p65 mRNA and the immunoactivities of IL-1ß, IL-6, TNF-α and NF-κB p65 were significantly increased (P<0.01), whereas the body weight, minimum volume threshold of AWR, content of IL-4, and the relative expression of miR-345-3p and miR-216a-5p were remarkably decreased in the model group (P<0.01). In comparison with the model group, the loose stool rate, contents of IL-1ß, IL-6, TNF-α, expression of NF-κB p65 mRNA and the immunoactivities of IL-1ß, IL-6, TNF-α and NF-κB p65 were considerably down-regulated (P<0.01), while the content of IL-4 and the relative expressions of miR-345-3p and miR-216a-5p were obviously up-regulated in both moxibustion and PDTC groups (P<0.01, P<0.05). The content of IL-6 in serum was significantly lower in the PDTC group than in the moxibustion group (P<0.01). CONCLUSION: Moxibustion can reduce the level of intestinal inflammation and visceral hypersensitivity in IBS-D rats, which may be related to its functions in increasing the expression levels of miR-345-3p and miR-216a-5p and in inhibiting the expression of NF-κB p65, thus reducing the levels of inflammatory factors.
Asunto(s)
Síndrome del Colon Irritable , MicroARNs , Moxibustión , Ratas , Animales , Síndrome del Colon Irritable/genética , Síndrome del Colon Irritable/terapia , FN-kappa B/metabolismo , Interleucina-4 , Ratas Sprague-Dawley , Interleucina-6 , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo , Inflamación/genética , Inflamación/terapia , Diarrea/genética , Diarrea/terapia , MicroARNs/genéticaRESUMEN
OBJECTIVE: To investigate the safety and efficacy of novel CD19-KIRS2/Dap12-BB chimeric antigen receptor T cells (CAR-T cells) in the treatment of relapsed/refractory B-cell malignancy (R/R BCM). METHODS: Three patients with R/R BCM treated with novel CD19-KIRS2/Dap12-BB CAR-T cells from June 2020 to November 2020 were enrolled, including 1 case of B-cell acute lymphoblastic leukaemia (B-ALL) and 2 cases of non-Hodgkin's lymphoma (NHL), and the efficacy and adverse reactions were observed. RESULTS: After CAR-T cells infusion, patient with B-ALL achieved complete remission (CR) and minimal residual disease (MRD) turned negative, and 2 patients with NHL achieved partial remission (PR). Grade 2 cytokine release syndrome (CRS) occurred in B-ALL patient, grade 1 CRS occurred in 2 NHL patients, and grade II to IV hematologic adverse reactions occurred in 3 patients, all of which were controllable and reversible. The progression-free survival (PFS) of the 3 patients was 143, 199, and 91 days, and overall survival (OS) was 282, 430, and 338 days, respectively. CONCLUSION: The novel CD19-KIRS2/Dap12-BB CAR-T cells in treatment of 3 patients with R/R BCM have significant short-term efficacy and controllable adverse reactions, but the long-term efficacy needs to be further improved.