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1.
Rev. med. (São Paulo) ; 101(5): e-181721, set-out. 2022.
Article in English, Portuguese | LILACS-Express | LILACS | ID: biblio-1395427

ABSTRACT

Introduction: Acute Lymphoblastic Leukemia (ALL) is the most prevalent malignancy in children; however, when the neoplasm becomes refractory/relapses (R/R) the cure possibilities are practically null. Objectives: To analyze the Anti-CD19 Chimeric Antigen Receptors (CAR) T-Cells immunotherapy efficacy in the treatment of R/R ALL, providing evidence about the efficacy and safety of the therapy for the analyzed group. Methods: The study consisted of a systematic review and meta-analysis based on the analysis of indexed articles. The searches were carried out with the terms: "acute lymphoblastic leukemia", "CAR T", and "CD19-specific chimeric antigen receptor". Results: Only 18 of the 94 articles obtained initially met the inclusion criteria and were selected for review, totaling 637 patients. Thus, it was observed in the responses that approximately 81% of the patients achieved a Complete Response; 7% did not respond; the neoplasm relapsed in 17% of the cases; and 6.1% of the patients died. The main side effects found were Cytokine Release Syndrome (CRS), Severe Cytokine Release Syndrome, and Neurotoxicity, present in 36.3%, 29%, and 24% of patients, respectively. Conclusion: Anti-CD19 CAR T-Cells immunotherapy is an effective therapy, capable of producing high rates of complete remission in R/R ALL treatment. [au]


Introdução: A Leucemia Linfoblástica Aguda (LLA) é a neoplasia maligna mais prevalente em crianças; entretanto, quando se torna refratária/recidivante (R/R) as possibilidades de cura são praticamente nulas. Objetivos: Analisar a eficácia da imunoterapia de Receptores de Antígenos Quiméricos anti-CD19 no tratamento da LLA R/R, fornecendo evidências sobre a efetividade e segurança da terapia para o grupo analisado. Métodos: O estudo consistiu em uma revisão sistemática e metanálise baseada em artigos indexados. As pesquisas foram realizadas com os termos: "acute lymphoblastic leukemia", "CAR T", and "CD19-specific chimeric antigen receptor". Resultados: Dos 94 artigos obtidos, apenas 18 atenderam inicialmente aos critérios de inclusão e foram selecionados para revisão, totalizando 637 pacientes. Assim, observou-se nas respostas que aproximadamente 81% dos pacientes obtiveram resposta completa; 7% não responderam; a neoplasia recidivou em 17% dos casos; e 6,1% dos pacientes morreram. Os principais efeitos colaterais encontrados foram síndrome de liberação de citocinas, síndrome de liberação grave de citocinas e neurotoxicidade, presentes em 36,3%, 29% e 24% dos pacientes, respectivamente. Conclusão: A imunoterapia com células CAR T anti-CD19 é uma terapia eficaz, sendo capaz de produzir altas taxas de remissão completa no tratamento de LLA R / R. [au]

3.
Int. j. cardiovasc. sci. (Impr.) ; 35(4): 444-456, July-Aug. 2022. tab
Article in English | LILACS | ID: biblio-1385277

ABSTRACT

Abstract Background The neuropeptide Y (NPY) is one of the most abundant neurotransmitters in the nervous system. NPY acts as a potent stimulator of angiogenesis, inflammation, and adipogenesis, through the NPY 2 receptor (NPY2R). Changes in the NPY signaling pathway have been linked to Acute Coronary Syndrome (ACS). Objectives The purpose of this study is to determine the association between variants in the NPY and NPY2R genes, as well as the severity of acute coronary syndrome (ACS). Methods Approximately 221 ACS patients and 278 healthy controls were selected for this study. Four variants in NPY and two variants in NPY2R genes were genotyped using Taqman allelic discrimination and sequencing. The Chi-square and Fisher's exact tests were used to verify the genotype frequencies. The logistic regression analyses were used for the evaluation of the studied variables. Haplotype analysis was used to evaluate the linkage disequilibrium (LD) between the variants (p<0.05). Results An association of NPY c.20T>C variant was found with the ACS group when compared to the healthy group. In the analysis between variants and risk factors in the ACS group, NPY c.84G>A was associated with hypertension. The analysis between TIMI risk showed a significance for NPY c.20T>C between the low and intermediate/high TIMI risk groups. In the haplotype analysis, strong linkage disequilibrium (LD) was found between the variants NPY c.150G>A and NPY c.-485T>C. Conclusion The NPY c.20T>C variant appears to contribute to the development of ACS. The NPY2R c.-1116A>G variant may contribute to the early development of ACS and the NPY c.84G>A variant appears to contribute to the development of hypertension. In addition, the NPY c.20T>C is associated with a protective effect in ACS severity.


Subject(s)
Humans , Male , Female , Adult , Middle Aged , Aged , Aged, 80 and over , Young Adult , Neuropeptide Y , Acute Coronary Syndrome/etiology , Receptors, Neuropeptide Y , Polymorphism, Single Nucleotide , Heart Disease Risk Factors , Hypertension
4.
J. bras. nefrol ; 44(2): 147-154, June 2022. tab, graf
Article in English | LILACS-Express | LILACS | ID: biblio-1386022

ABSTRACT

Abstract Introduction: Diabetes mellitus (DM) is a chronic disease characterized by hyperglycemia that leads to diabetic nephropathy (DN). We showed that P2X7, a purinergic receptor, was highly expressed in DM; however, when oxidative stress was controlled, renal NO recovered, and the activation of this receptor remained significantly reduced. The aim of this study was to assess the influence of NO on the P2X7 and apoptosis in mouse immortalized mesangial cells (MiMC) cultured in high glucose (HG) medium. Methods: MiMCs were cultured with DMEM and exposed to normal glucose (NG), mannitol (MA), or HG. Cell viability was assessed by an automated counter. Supernatants were collected for NO quantification, and proteins were extracted for analysis of NO synthases (iNOS and eNOS), caspase-3, and P2X7. Results: Cell viability remained above 90% in all groups. There was a significant increase in the proliferation of cells in HG compared to MA and NG. NO, iNOS, caspase-3, and P2X7 were significantly increased in HG compared to NG and MA, with no changes in eNOS. We observed that there was a strong and significant correlation between P2X7 and NO. Discussion: The main finding was that the production of NO by iNOS was positively correlated with the increase of P2X7 in MCs under HG conditions, showing that there is a common stimulus between them and that NO interacts with the P2X7 pathway, contributing to apoptosis in experimental DM. These findings could be relevant to studies of therapeutic targets for the prevention and/or treatment of hyperglycemia-induced kidney damage to delay DN progression.


Resumo Introdução: Diabetes mellitus (DM) é uma doença crônica caracterizada por hiperglicemia levando à nefropatia diabética (ND). Mostramos que P2X7, um receptor purinérgico, foi altamente expresso na DM; entretanto, quando o estresse oxidativo foi controlado, o NO renal recuperou-se, e a ativação deste receptor permaneceu significativamente reduzida. Este estudo objetivou avaliar a influência do NO no P2X7 e a apoptose em células mesangiais imortalizadas de camundongos (CMiC) cultivadas em meio de glicose elevada (GE). Métodos: CMiCs foram cultivadas em meio DMEM e expostas à glicose normal (GN), manitol (MA), ou GE. A viabilidade celular foi avaliada por contador automático. Sobrenadantes foram coletados para quantificação de NO, e foram extraídas proteínas para análise de NO sintases (iNOS e eNOS), caspase-3, e P2X7. Resultados: A viabilidade celular permaneceu acima de 90% em todos os grupos. Houve aumento significativo na proliferação de células na GE comparado com MA e GN. NO, iNOS, caspase-3 e P2X7 foram significativamente aumentados na GE comparados com GN e MA, sem alterações na eNOS. Observamos que houve correlação forte e significativa entre P2X7 e NO. Discussão: O principal achado foi que a produção de NO pela iNOS foi positivamente correlacionada com aumento de P2X7 em CMs sob condições de GE, mostrando que existe um estímulo comum entre eles e que o NO interage com a via do P2X7, contribuindo para apoptose na DM experimental. Estes achados podem ser relevantes para estudos de alvos terapêuticos para a prevenção e/ou tratamento de danos renais induzidos por hiperglicemia para retardar a progressão da ND.

5.
Gac. méd. Méx ; 158(2): 101-107, mar.-abr. 2022. graf
Article in Spanish | LILACS-Express | LILACS | ID: biblio-1375535

ABSTRACT

Resumen Los receptores son proteínas codificadas por el ADN, algunos de los cuales ya han sido cristalizados, lo que permite conocer los detalles de su estructura a nivel atómico y algunos aspectos de su función. Esta revisión se enfoca en los más diversos y abundantes, los receptores acoplados a la proteína G. Esta familia de receptores reconoce y media la acción de varios ligandos endógenos (hormonas, neurotransmisores, factores de crecimiento y hormonas locales) y también interviene en la patogenia de diversas enfermedades, por lo que son el blanco terapéutico de aproximadamente 30 a 40 % de los medicamentos que se emplean en la práctica clínica cotidiana y de diversas drogas ilegales. La cristalografía de rayos X es una de las herramientas clave que ha permitido observar la estructura de estos receptores en los aminoácidos que participan en esta interacción, lo que posibilita conocer el sitio de unión del ligando endógeno y de moléculas sintéticas que actúan sobre ellos para modular su acción. El modelado molecular es también una herramienta bioinformática computacional que apoya la investigación sobre la unión receptor-ligando, que hace posible el diseño y desarrollo de fármacos cada vez más específicos. A estos desarrollos se suman importantes cambios en los conceptos farmacodinámicos fundamentales.


Abstract Receptors are proteins coded by DNA, some of which have already been crystalized, thus allowing the details of their structure at the atomic level and some aspects of their function to be known. This review focuses on the most diverse and abundant family of receptors, G protein-coupled receptors. This family of receptors recognizes and mediates the action of several endogenous ligands (hormones, neurotransmitters, growth factors and local hormones) and also intervenes in the pathogenesis of various diseases, which is why they are targeted by approximately 30 to 40% of medications that are used in daily clinical practice and of various illegal drugs as well. X-ray crystallography is one of the essential tools that has allowed to observe the structure of these receptors in the amino acids that participate in this interaction, which allows to know the binding site of the endogenous ligand and of synthetic molecules that act on them to modulate their action. Molecular modeling or "docking" is also a computational bioinformatics tool that supports research on receptor-ligand binding, which allows the design and development of increasingly specific drugs. These developments have brought along significant changes in fundamental pharmacodynamic concepts.

6.
Arch. argent. pediatr ; 120(2): e98-e101, abril 2022. tab
Article in English, Spanish | LILACS, BINACIS | ID: biblio-1363992

ABSTRACT

La prucaloprida acelera el vaciamiento gástrico en adultos con gastroparesia. No existen estudios con este medicamento en niños con gastroparesia. Se presenta un niño de 8 años que consultó por síntomas posprandiales de un mes de duración, con diagnóstico de gastroparesia por gammagrafía de vaciamiento gástrico. No mejoró con metoclopramida, domperidona, eritromicina y esomeprazol. Recibió prucaloprida durante dos períodos (durante 178 y 376 días) a dosis de 0,03-0,04 mg/kg/día. Presentó mejoría en el seguimiento con el índice cardinal de síntomas de gastroparesia y gammagrafías de vaciamiento gástrico. Por la buena respuesta, la prucaloprida podría ser una opción terapéutica en la gastroparesia pediátrica.


Prucalopride has been used in adults with gastroparesis, accelerating gastric emptying. There are no studies with this drug in gastroparetic children. An 8-year-old boy is presented who consulted for a month of postprandial symptoms, with a diagnosis of gastroparesis by gastric emptying scintigraphy. He did not improve with metoclopramide, domperidone, erythromycin, and esomeprazole. He received prucalopride for two periods (for 178 and 376 days) at doses: 0.03 - 0.04 mg/kg/day, presenting improvement in the follow-up with the cardinal gastroparesis symptom index and gastric emptying scintigraphy. Due to the good response, prucalopride may be a therapeutic option in pediatric gastroparesis.


Subject(s)
Humans , Male , Child , Benzofurans/therapeutic use , Gastroparesis/diagnosis , Gastroparesis/drug therapy , Domperidone/therapeutic use , Gastric Emptying
7.
Biota Neotrop. (Online, Ed. ingl.) ; 22(2): e20211292, Mar 31, 2022. tab, graf
Article in English | LILACS-Express | LILACS | ID: biblio-1383931

ABSTRACT

Abstract: Adults of the beetle Cyclocephala literata Burmeister, 1847 are important pollinators to some Magnoliaceae. Is known that insects could find host plants by detecting volatiles through antennal sensilla. Cyclocephala has its three distal antennomeres lamellate, and the surface of each lamella has sensilla trichodea, chaetica, placodea, coeloconica, basiconica and ampullacea. Three kinds of sensilla placodea were found (type I, II and III), and two kinds of sensilla coeloconica were observed (type I and II). Females have on average 10,776 sensilla, of which 10,214 are sensilla placodea, 536 are sensilla coeloconica, and 26 are sensilla basiconica. Males have on average 10,386 sensilla, of which 9,873 are sensilla placodea, 464 are sensilla coeloconica, and 49 are sensilla basiconica. Males and females have similar quantities of sensilla, and sensilla placodea are predominant. The differences observed in the number of sensilla of males and females were found in other beetles and were attributed to the detection of cospecific sexual pheromones by one of the sexes, or to the detection of plant volatiles. The antennal sensilla of C. literata is described and quantified in present study, and some perspectives about the differences kind of chemical communication, pollination, and antennae dimorphism is discussed.


Resumo: Adultos do besouro Cyclocephala literata Burmeister, 1847 desempenham importantes funções de polinização em plantas da família Magnoliaceae. É conhecido que muitos insetos encontram plantas hospedeiras pela detecção de voláteis pelas sensilas antenais. Cyclocephala possui os três antenômeros distais lamelados e na superfície de cada lamela possuem sensila trichodea, caética, placódea, coelocônica, basicônica e ampulacea. Foram encontrados três tipos de sensilas placódeas (tipo I, II e III), e dois tipos de sensilas coelocônicas (tipo I e II). Fêmeas apresentam em média 10.776 sensilas, das quais 10.214 são sensilas placódeas, 536 são sensilas coelocônicas e 26 são sensilas basicônicas. Os machos apresentaram em média 10.386 sensilas, das quais 9.873 são sensilas placódeas, 464 são sensilas coelocônicas e 49 são sensilas basicônicas. Machos e fêmeas apresentam quantidades semelhantes de sensilas e as sensilas placódeas são predominantes. As diferenças encontradas nas quantidades de sensilas em machos e fêmeas também foram encontradas em outros besouros e foram atribuídas a detecção de feromônios coespecíficos por um dos sexos, ou para detecção de voláteis de plantas. A sensila antenal de C. literata é descrita e quantificada no presente estudo, e algumas perspectivas sobre as diferenças entre os tipos de comunicação química, polinização e dimorfismo antenal é discutido.

8.
Horiz. meÌüd. (Impresa) ; 22(1): e1355, ene.-mar. 2022. graf
Article in Spanish | LILACS-Express | LILACS | ID: biblio-1375619

ABSTRACT

RESUMEN El lactato es un metabolito altamente dinámico que, en condiciones anaerobias, es producido por hipoxia o isquemia; y en condiciones aerobias, es sintetizado por un mecanismo impulsado por la estimulación adrenérgica, a través del receptor β2, que potencia la acción de la bomba sodio-potasio, y por un estado de glicólisis aerobia acelerada. Este metabolito es capaz de intercambiarse entre diferentes células productoras y consumidoras, con lo que asegura la materia prima para obtener energía. El sistema nervioso simpático responde a los estímulos de estrés con la liberación de catecolaminas, que actúan como hormonas y como neurotransmisores en varios tejidos del cuerpo y permiten un aumento del metabolismo que eleva los valores de glucosa y el oxígeno disponible. Existe una relación fisiológica de dependencia entre las catecolaminas y la producción de lactato que predispone al organismo para responder de forma efectiva ante una situación de estrés. Sin embargo, en tejidos sensibles, la respuesta adrenérgica exacerbada puede ocasionar efectos exagerados que pueden incrementar la probabilidad de fallo. En base al conocimiento de estos mecanismos, se plantean estrategias terapéuticas enfocadas en regular la actividad simpática.


ABSTRACT Lactate is a highly dynamic metabolite that is produced, under anaerobic conditions, due to hypoxia or ischemia. Under aerobic conditions, it is synthesized by a mechanism driven by the stimulation of the β2 adrenergic receptor, which increases the activity of the sodium-potassium pump, and by a state of accelerated aerobic glycolysis. This metabolite is capable of being exchanged between different producing and consuming cells, ensuring the raw material for energy production. The sympathetic nervous system responds to stress stimuli through the release of catecholamines, which act as hormones and neurotransmitters in various tissues of the body, allowing an increase in metabolism that raises glucose and available oxygen levels. There is a physiological dependence between catecholamine levels and lactate production, predisposing the body to respond effectively to a stressful situation. However, an exacerbated adrenergic response may cause exaggerated effects on sensitive tissues that increase the probability of failure. Based on the knowledge of these mechanisms, therapeutic strategies focused on regulating the sympathetic activity are proposed.

9.
Article in Chinese | WPRIM | ID: wpr-940797

ABSTRACT

ObjectiveTo investigate the medicinal effect of total flavonoids of mulberry leaves on regulating liver lipid metabolism disorder in diabetes mellitus type 2 (T2DM) rats, and the mechanism based on liver peroxidase proliferators activate receptors-α (PPAR-α) and carnitine palmityl transferase-1 (CPT-1) proteins. MethodTotal flavonoids of mulberry leaves were extracted and purified by ethanol extraction + macroporous resin purification and then identified. T2DM rat model was induced by high fat diet (HFD) + streptozocin(STZ)method. Rats with blood glucose ≥ 11.1 mmol·L-1 were divided into three administration groups with the high dose (300 mg·kg-1), medium dose (150 mg·kg-1), and low dose (75 mg·kg-1) of total flavonoids of mulberry leaves for 8 weeks, respectively, to observe the weight and blood glucose of the rats. The pathological changes of rat livers were observed by hematoxylin-eosin (HE) staining. Biochemical method was used to detect the levels of total cholesterol (TC), triglyceride (TG), low density lipoprotein-cholesterol (LDL-C), and high density lipoprotein-cholesterol (HDL-C) of blood lipid metabolism in rats. The messenger ribonucleic acid (mRNA) and protein expressions of PPAR-α and CPT-1 were determined by real-time quantitative polymerase chain reaction (Real-time PCR) and Western blot. ResultAfter 8 weeks of intervention of total flavonoids of mulberry leaves, compared with the control group, the food intake, liver index, and fasting blood glucose of rats in the model group increased significantly (P<0.01). Compared with the model group, the food intake, fasting blood glucose, and liver index of rats in the administration groups decreased significantly (P<0.01). The results of HE staining showed that the liver tissue structure of rats in the control group was complete and there was no obvious abnormality. The model group showed vacuolar degeneration and inflammatory infiltration of hepatocytes of rats. There was no obvious abnormality in the liver structure of rats in the administration groups. The results of blood lipid showed that compared with the control group, the levels of TC, TG, and LDL-C increased significantly (P<0.01), but the level of HDL-C decreased significantly (P<0.01) in the model group. Compared with the model group, the levels of TC, TG, and LDL-C decreased significantly (P<0.05, P<0.01), whereas the level of HDL-C increased significantly (P<0.01) in the administration groups. The results of Real-time PCR showed that compared with the control group, the mRNA expression of PPAR-α and CPT-1 of rats in the model group decreased significantly (P<0.01). Compared with the model group, the mRNA expressions of PPAR-α and CPT-1 of rats in the high-dose group increased significantly (P<0.01). The results of Western blot showed that compared with the control group, the protein expressions of PPAR-α and CPT-1 of rats in the model group decreased significantly (P<0.01). Compared with the model group, the protein expressions of PPAR-α and CPT-1 of rats in the high-dose group increased significantly (P<0.05, P<0.01). ConclusionTotal flavonoids of mulberry leaves can effectively reduce blood glucose and improve liver lipid metabolism disorder in T2DM rats. The total flavonoids of mulberry leaves could regulate lipid metabolism and play a hypoglycemic role by activating and regulating PPAR-α and CPT-1 proteins and promoting oxidative decomposition of fatty acids.

10.
Article in Chinese | WPRIM | ID: wpr-940715

ABSTRACT

Bronchial asthma, a chronic inflammatory airway disease, belongs to the category of wheezing disease in the system of traditional Chinese medicine (TCM). The wheezing symptom of this disease is mainly caused by the imbalance of lung Qi. According to the theory of five flavor compatibility, the Chinese medicinal materials with five different flavors (pungent, bitter, sour, sweet, and salty) can be combined to produce new functions. The pungent medicinal materials have dispersing effect and the bitter medicinal materials have discharging effect, which are important components in the theory of five flavor compatibility. Pungent herbs and bitter herbs can relieve the adverse lung Qi, occupying an important position in the current medication for the treatment of asthma. However, there is still a lack of in-depth analysis of the TCM theory and mechanism of the compatibility of pungent herbs and bitter herbs in the treatment of asthma. The molecular mechanisms of action of pungent herbs and bitter herbs are closely related to transient receptor potential (TRP) channels and bitter taste receptors (TAS2Rs), respectively. Ca2+ signaling has been recognized in the process of asthma and is involved in the development of multiple symptoms of asthma. The TRP channels and TAS2Rs located on the cell membrane have been proved to directly regulate the intracellular Ca2+ signal and play a role in the treatment of asthma. Therefore, the dispersing effect of pungent herbs and the discharging effect of bitter herbs may be realized through the Ca2+ signaling pathway mediated by TRPs/TAS2Rs. We summarized the theoretical understanding and modern studies of pungent herbs dispersing lung Qi and bitter herbs discharging lung Qi, aiming to explain the internal relationship and mechanism of the compatibility of pungent herbs and bitter herbs in the treatment of asthma from the perspective of TCM theory and modern medicine. The compatibility of pungent herbs and bitter herbs based on the theory of five flavor compatibility for the treatment of asthma has a solid theoretical basis of TCM, and its mechanism can be verified by modern research. Therefore, it may be a main research direction in the treatment of asthma by Chinese medicinal herbs in the future.

11.
Cancer Research and Clinic ; (6): 227-230, 2022.
Article in Chinese | WPRIM | ID: wpr-934661

ABSTRACT

As one of the common benign gynecological diseases, endometriosis (EM) can have a serious impact on the physical and mental health and quality of life of women of childbearing age. Studies have shown that the risk of ovarian cancer in patients with EM is significantly higher than that in the general population. EM is closely related to the occurrence of some types of ovarian cancer, and this kind of ovarian cancer is named endometriosis-related ovarian cancer (EAOC). The incidence rate, pathogenesis, treatment and prognosis of EAOC are summarized in order to better understand it.

12.
Article in Chinese | WPRIM | ID: wpr-934403

ABSTRACT

Objective:To detect the expression of receptor tyrosine kinase-like orphan receptor 1 (ROR1) antigen in chronic lymphocytic leukemia (CLL) and evaluate its diagnostic value and explore its correlation with the abnormalities of genetics and molecular biology.Methods:All of 209 newly diagnosed B-cell chronic lymphoproliferative disorders (B-CLPD) patients who were admitted to the First Affiliated Hospital of Nanjing Medical University (Jiangsu Provincial People′s Hospital) from November 2020 to November 2021 were collected retrospectively, including 70 cases of CLL with typical phenotype, 16 cases of CLL with atypical phenotype, 14 cases of MCL, and 109 cases of other types of B-CLPD. Multi-parameter flow cytometry (FCM) was used to detect the expression levels of ROR1 in tumor cells of 209 patients. And then the diagnostic value of ROR1 in CLL patients and its correlation with the genetic and molecular biological abnormalities were analyzed by c2 test and fourfold table assessment.Results:The positive expression rate of ROR1 in CLL patients was significantly higher than that in non-CLL patients (78%>11%, P<0.001); there was no significant difference of ROR1 expression between typical phenotype CLL and atypical phenotype CLL (81%>63%, P>0.05). The positive expression rate of ROR1 in atypical phenotype CLL was significantly higher than that in MCL (63%>21%, P<0.05). Additionally, there was significant difference in detection rate of chromosomal abnormalities between ROR1 +CLL group and ROR1 -CLL group. The detection rate of complex karyotype in ROR1 +CLL group was higher than that in ROR1 -CLL group (34%>14%, P<0.05). The CLL patients over 60 years old had higher ROR1 positive rate ( P<0.05). Conclusions:ROR1 can be helpful in the diagnosis of CLL, especially in the differential diagnosis of atypical phenotype CLL, MCL and other types of B-CLPD. Patients with ROR1 positive expression were older and more likely to detect complex chromosomal karyotypes.

13.
Article in Chinese | WPRIM | ID: wpr-934323

ABSTRACT

Objective:To investigate the effect of interleukin (IL)-23 receptor (IL-23R) overexpression on the balance of T helper 17 (Th17 cells)/regulatory T cells (Treg cells) in experimental autoimmune uveitis (EAU) mice.Methods:Twelve 8-week-old female C57BL/6J mice were randomly divided into LV-Ctrl group and LV-IL-23R group, with 6 mice in each group. Two groups of mice were injected with LV-Ctrl and LV-IL-23R lentiviruses through the tail vein, respectively; 7 days after injection, the EAU mouse model was established by active immunization with vitamin A-binding protein 1-20 between photoreceptors. Starting from 13 days after immunization, the fundus of the mice was observed by indirect ophthalmoscopy every 2 days and clinical scores were performed; 30 days after immunization, hematoxylin-eosin staining was used to observe the histopathological changes of mouse retina. The levels of IL-17 in serum of the two groups of mice were detected by enzyme-linked immunosorbent assay; the proportion of Th17 cells and Treg cells was detected by flow cytometry. The relative mRNA expression of IL-23R, IL-17, retinoic acid-related orphan receptor γt (RORγt), IL-10 and forkhead transcripyion factor p3 (Foxp3) were detected by real-time quantitative polymerase chain reaction. Comparisons between groups were performed using repeated measures analysis of variance, independent samples Mann-Whitney U test, and independent samples t test. Results:Compared with the LV-Ctrl group, the retinal inflammatory reaction of the LV-IL-23R group was more severe. At 13 days after immunization, there was no significant difference in fundus inflammation scores between LV-IL-23R group and LV-Ctrl group ( t=-2.001, P=0.058); 15-29 days after immunization. The fundus inflammation scores of LV-IL-23R group were higher than those of LV-Ctrl group, and the difference was statistically significant ( t=-4.429,-6.578, -7.768, -10.183, -6.325, -7.304, -4.841, -6.872; P<0.001). Histopathological examination showed that the infiltration of inflammatory cells in the fundus increased, the retinal structure was damaged more seriously, and the histopathological score was significantly increased, and the difference was statistically significant ( t=-4.339, P=0.001). Compared with the LV-Ctrl group, the relative expression of IL-23R mRNA in the spleen of the LV-IL-23R group was significantly increased, and the difference was statistically significant ( Z=2.087, P=0.037). The relative expression of IL-17 and RORγt mRNA increased, while the relative expression of IL-10 and Foxp3 mRNA decreased, and the differences were statistically significant ( t=-6.313,-5.922, 4.844, 7.572; P=0.003, 0.004, 0.008, 0.002). Compared with the LV-Ctrl group, the level of IL-17 in the serum of the mice in the LV-IL-23R group was significantly increased, and the difference was statistically significant ( t=-5.423, P=0.002); the proportion of Th17 cells in the spleen and lymph nodes was significantly increased, whereas, the proportion of Treg cells was significantly reduced, and the difference was statistically significant ( t=-4.290, 3.700; P=0.002, 0.006). Conclusion:IL-23R overexpression can promote Th17/Treg imbalance in EAU mice, and aggravate the clinical and pathological manifestations of EAU.

14.
Article in Chinese | WPRIM | ID: wpr-933956

ABSTRACT

Objective:To explore the effect of combining repetitive transcranial magnetic stimulation (rTMS) with treadmill training in treating spinal cord injury (SCI).Methods:Fifty female Sprague-Dawley rats were randomly divided into a sham-operation (C) group, an SCI group, a treadmill training (TT) group, a treadmill training followed by rTMS (TR) group and an rTMS followed by treadmill training (RT) group. The C group only underwent laminectomy without spinal cord injury, while the model of T9 incomplete spinal cord injury was established in the other groups using the Louisville Injury System Apparatus impactor. One week after the operation the TT began. The TR group received rTMS immediately after the treadmill training and the RT group received it before. The treadmill′s speed started at 3.6m/min and gradually increased to 6m/min within 1 week. There was one 15min session a day, 5 days a week, for 8 weeks in total. The rTMS intensity was 30% of the maximum output intensity at 10Hz in 5s bursts with an interval of 25s. It lasted 10min, for a total of 1000 pulses. Hind limb motor functioning was evaluated using the Basso, Beattie & Bresnahan (BBB) locomotor rating scale and a grid walking test. The H max/M max ratio was used to quantify the excitability of the motor neurons. Immunohistochemistry was employed to detect the expression of 5-hydroxytryptamine (5-HT), 5-hydroxytryptamine 1A receptor (5-HT 1AR) and 5-hydroxytryptamine 2A receptor (5-HT 2AR). Results:The average BBB scores of the RT group were significantly higher than the SCI group′s averages from the 7th to 9th week after the injury. At the ninth week the average BBB score of the RT group was significantly higher than the TT group′s average. At the eighth and ninth week the average BBB scores of the TR group were significantly higher than in the SCI group. The number of drops in the RT group was significantly lower than in the SCI group at the seventh and ninth week. At the ninth week, the number of drops of the TR group was significantly lower compared with the SCI group. The H max/M max ratio of the SCI group was significantly higher than in the C and TR groups at the fifth and ninth week, while that of the TR group was significantly lower than the SCI group′s ratio at the ninth week. The expression of 5-HT, 5-HT 1AR and 5-HT 2AR in the RT and TR groups was significantly higher than in the SCI group, and the relative 5-HT 1AR density of the RT and TR groups was significantly higher than in the SCI and TT groups. Compared with the other 4 groups, the expression of 5-HT 2AR in the SCI group had increased significantly. Conclusions:Combining rTMS with treadmill training can significantly promote the recovery of locomotor function after incomplete spinal cord injury.

15.
Chinese Journal of Nephrology ; (12): 420-427, 2022.
Article in Chinese | WPRIM | ID: wpr-933873

ABSTRACT

Objective:To investigate whether it is by regulating interleukin 1β ( IL-1β) gene expression that androgen receptor (AR) in macrophages affects hyperphosphate-induced vascular smooth muscle cell calcification. Methods:The chromatin immunoprecipitation (ChIP) experiment was used to determine whether AR was bound to the androgen receptor element (ARE) sequence of IL-1β promoter in THP-1 cells. Whether the AR regulated IL-1β gene expression was detected by luciferase assay experiments. AR of THP-1 cells was silenced and transfected by lentivirus with vector or shRNA. Flow cytometry was used to select positive transfected cells THP-1ARsc (control) and THP-1ARsi (AR silencing) with fluorescent markers. Western blotting was used to detect AR protein levels of THP-1ARsc (control) and THP-1ARsi cells (AR silencing in monocytes). Macrophages MФARsc (control) or MФARsi (AR silencing) were induced by 50 ng/ml phorbol ester. Enzyme-linked immunosorbent assay was used to detect IL-1β expression levels of MФARsc or MФARsi conditioned medium. The human aortic smooth muscle cells (HASMC) were cultured in MФARsc or MФARsi conditioned medium with phosphate (2.5 mmol/L final concentration of sodium dihydrogen phosphate), and Alizarin red S staining was used to analyze HASMC calcification degree. Western blotting was used to detect the expression levels of RUNX2 (osteoblast marker) and SM22α (HASMC marker), and neutralization assay was performed to test IL-1β-mediating effect of macrophages AR on HASMC calcification. Results:AR was bound to ARE sequence of IL-1β promoter and regulated IL-1β gene expression. The expression level of IL-1β protein in conditioned medium of MФARsi cells decreased significantly compared to MФARsc cells ( P<0.001). Compared with MФARsc conditioned medium group, HASMC calcium deposition in MФARsi conditioned medium group decreased significantly, RUNX2 protein decreased and SM22α protein increased (all P<0.05). The degree of HASMC calcification in the MФARsi conditioned medium+IgG antibody group decreased than that in the MФARsc conditioned medium+IgG antibody group significantly, and the degree of HASMC calcification in the MФARsc conditioned medium+IL-1β antibody group decreased significantly than that in the MФARsc conditioned medium+IgG antibody group; while the degree of HASMC calcification in the MФARsi conditioned medium+IgG antibody group and MФARsi conditioned medium+IL-1β antibody group decreased than that in the MФARsc conditioned medium+IL-1β antibody group (all P<0.05). Conclusions:Macrophage AR regulates IL-1β expression by binding to ARE sequence within IL-1β promoter, and IL-1β mediates the effect of macrophage AR on hyperphosphate-induced HASMC calcification.

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Chinese Journal of Nephrology ; (12): 387-396, 2022.
Article in Chinese | WPRIM | ID: wpr-933869

ABSTRACT

Objective:To analyze the clinicopathological characteristics, treatment responses and kidney outcomes of patients with atypical membranous nephropathy (MN), and to provide information for the clinical practice.Methods:The clinical data of patients with atypical MN and synchronous primary MN who were diagnosed, treated and followed up in Peking University First Hospital from January 2008 to June 2020 were retrospectively collected and analyzed. Clinicopathological features, treatment responses and kidney prognosis were compared between the two groups. The expression of phospholipase A2 receptor (PLA2R) in kidney tissues was detected by immunofluorescence. Serum anti-PLA2R antibody was detected by enzyme-linked immunosorbent assay. Clinicopathological indexes were compared between PLA2R-related MN group and non-PLA2R-related MN group. Kaplan-Meier (Log-rank test) survival curve and multivariate Cox regression analysis methods were used to analyze the influencing factors of kidney prognosis in patients with atypical MN. The primary endpoint of renal adverse outcome was renal insufficiency, defined as end-stage renal disease or estimated glomerular filtration rate (eGFR) decline>30% baseline and<60 ml·min -1·(1.73 m 2) -1. Results:A total of 65 atypical MN patients were enrolled in this study. Compared with primary MN ( n=324), patients with atypical MN had younger age ( Z=-4.229, P<0.001), higher proportion of hematuria ( χ2=5.555, P=0.018), higher level of urinary protein ( Z=2.228, P=0.026) and lower level of eGFR ( t=-5.108, P<0.001); the proportion of IgG4 deposition in kidneys was lower ( χ2=8.081, P=0.004), and the proportions of IgA ( χ2=16.969, P<0.001) and IgM ( χ2=9.281, P=0.002) deposition were higher. There was no significant difference on gender, serum albumin, positive proportion of anti-PLA2R antibody, anti-PLA2R antibody level and kidney C3/C1q deposition between the two groups (all P>0.05). The proportions of atypical MN patients receiving renin-angiotensin aldosterone system inhibitors (49.3% vs 57.1%), calcineurin inhibitors (27.7% vs 19.1%) and cyclophosphamide (21.5% vs 23.8%) were comparable to those of primary MN patients (all P>0.05). The rates of clinical remission (80.0% vs 77.2%), partial remission (44.6% vs 44.1%), complete remission (35.4% vs 33.1%), spontaneous remission (36.9% vs 42.6%), response to cyclophosphamide (85.7% vs 81.8%), response to calcineurin inhibitor (88.9% vs 79.0%), and relapse (30.8% vs 26.8%) in atypical MN patients were comparable to those in primary MN patients (all P>0.05). During the follow-up 30.0(21.5, 61.5) months, 15 atypical MN patients (23.1%) had eGFR reduction>30%, among whom 7 patients (10.8%) had eGFR reduction>50% and 3 patients (4.6%) had end-stage kidney disease. There was no significant difference on poor kidney prognosis between the two groups (all P>0.05). Kaplan-Meier survival curve showed that patients with age>39 years old ( χ2=10.092, P=0.001), eGFR≤100 ml·min -1·(1.73 m 2) -1( χ2=5.491, P=0.019), tubular interstitial lesion ( χ2=6.999, P=0.008) and no nephropathy remission ( χ2=22.952, P<0.001) had earlier poor renal prognosis. Multivariate Cox regression analysis showed that no nephropathy remission ( HR=12.604, 95% CI 2.691-59.037, P=0.001) was an independent influencing factor for poor renal prognosis in atypical MN patients. Conclusion:No significant difference is found between atypical MN and primary MN on treatment responses and kidney prognosis, which implies that clinical practice of atypical MN can be performed by referring to the guidelines and experience of primary MN.

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Chinese Journal of Dermatology ; (12): 102-109, 2022.
Article in Chinese | WPRIM | ID: wpr-933519

ABSTRACT

Objective:To determine lysophosphatidic acid receptor 6 (LPAR6) expression in patients with mycosis fungoides (MF) , a variant of cutaneous T-cell lymphoma (CTCL) , and to investigate its role and mechanism of action in the development and prognosis of CTCL.Methods:A total of 110 patients with confirmed MF were collected from Department of Dermatology, Peking University First Hospital from 2011 to 2020, including 24 with large-cell transformation (LCT) and 25 with non-large cell transformation (NLCT) in the discovery cohort, and 24 with LCT and 37 with NLCT in the validation cohort. RNA sequencing and RT-PCR were conducted to determine the LPAR6 expression in patients in the discovery cohort and validation cohort respectively. LPAR6 expression was compared between patients with LCT and those with NLCT, and its effect on the prognosis of patients was evaluated. Two LPAR6-overexpressing CTCL cell lines MyLa and Sz4 were constructed to evaluate the effect of LPAR6 overexpression on proliferative activity of MyLa and Sz4 cells, with the cells normally expressing LPAR6 as the control group; after the treatment with LPAR6-related ligand lysophosphatidic acid (LPA) , 2S-OMPT, adenosine triphosphate (ATP) or adenosine (ADO) , the effects of LPAR6 activation on the proliferative activity and apoptosis of LPAR6-overexpressing MyLa and Sz4 cells were evaluated by the MTS method and flow cytometry respectively. Log-rank test was used for prognostic analysis, and t test or Mann-Whitney U test was used for comparisons between two groups. Results:As RNA sequencing showed, LPAR6 was one of the significantly underexpressed genes in the LCT group in the discovery cohort; in the validation cohort, LPAR6 expression (median[ Q1, Q3]) was significantly lower in the LCT group (204.90[81.90, 512.70]) than in the NLCT group (809.40[417.50, 1 829.20], U= 242.00, P= 0.002) ; in the two cohorts, the underexpression of LPAR6 was significantly associated with increased risk of poor prognosis (both P < 0.01) . Cell proliferation assay showed no significant difference in the proliferative activity of MyLa or Sz4 cells between the LPAR6 overexpression group and control group at 0, 24, 48 and 72 hours during the experiment (all P > 0.05) ; 48 hours after activation of LPAR6 by LPA, 2S-OMPT, ATP and ADO in MyLa cells, the LPAR6 overexpression group showed significantly decreased cellular proliferative activity (1.38 ± 0.01, 1.04 ± 0.01, 1.09 ± 0.03, 1.23 ± 0.01, respectively) compared the control group (1.73 ± 0.04, 1.23 ± 0.01, 1.24 ± 0.01, 1.42 ± 0.03, t= 30.33, 18.38, 4.78, 5.75, respectively, all P < 0.05) , but significantly increased cell apoptosis rate (17.93% ± 0.88%, 17.75% ± 0.35%, 23.97% ± 0.57%, 31.44% ± 0.34%, respectively) compared the control group (3.98% ± 0.03%, 7.81% ± 0.59%, 11.95% ± 0.85%, 12.02% ± 0.48%, t= 15.93, 14.49, 11.74, 33.01, respectively, all P < 0.05) ; 48 hours after activation of LPAR6 by 2S-OMPT and ADO in Sz4 cells, compared with the control group, the LPAR6 overexpression group also showed significantly decreased cellular proliferative activity (2S-OMPT: 1.29 ± 0.04 vs. 1.48 ± 0.01; ADO: 1.27 ± 0.01 vs. 1.51 ± 0.02; both P < 0.05) , but significantly increased cell apoptosis rate (2S-OMPT: 41.70% ± 0.70% vs. 29.35% ± 0.55%; ADO: 37.05% ± 0.15% vs. 24.60% ± 1.00%; both P < 0.05) . Conclusions:LPAR6 was underexpressed in the patients with LCT, and its underexpression was significantly associated with increased risk of poor prognosis. In vitro activation of LPAR6 could inhibit the proliferation of CTCL cells and promote their apoptosis, suggesting that the decrease of LPAR6 expression may be one of the important mechanisms underlying disease progression in patients with LCT.

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Article in Chinese | WPRIM | ID: wpr-933329

ABSTRACT

Objective:To evaluate the role of glutamate receptor 2 (GluR2) in cognitive dysfunction induced by chronic neuroinflammation in mice.Methods:Sixty adult male C57BL/6 mice, aged 8-10 weeks, weighing 18-25 g, were divided into 4 groups ( n=15 each) using a random number table method: control + dimethyl sulfoxide (DMSO) group (group C+ DMSO), control + AMPA receptor selective non-competitive antagonist CFM-2 group (group C+ CFM-2), lipopolysaccharide (LPS)+ DMSO group and LPS + CFM-2 group.In C+ DMSO group and C+ CFM-2 group, normal saline 0.2 ml was intraperitoneally injected every day for 10 consecutive days, and 10% DMSO 0.165 ml and CFM-2 33 μmol/kg (diluted to 0.165 ml with 10% DMSO) were intraperitoneally injected, respectively, on the 10th day after injection of normal saline.In LPS + DMSO group and LPS + CFM-2 group, LPS 0.5 mg/kg (diluted to 0.2 ml with normal saline) was intraperitoneally injected every day for 10 consecutive days, and 10% DMSO 0.165 ml and CFM-2 33 μmol/kg (diluted to 0.165 ml with 10% DMSO) were intraperitoneally injected, respectively, after LPS injection on the 10th day.The Y-maze test was performed at 48 h after the end of administration, then the animals were sacrificed, and the hippocampal tissues were taken for determination of the expression of GluR2, ionized calcium binding adapter molecule 1 (Iba1), tumor necrosis factor-α (TNF-α) (by Western blot) and the number of microglia in hippocampal CA1 area (by immunofluorescence). Results:Compared with group C + DMSO, the percentage of spontaneous alternation was significantly decreased, the expression of GluR2, Iba1 and TNF-α in hippocampus was up-regulated, the number of microglia in hippocampal CA1 area was increased ( P<0.05), and no significant change was found in the parameters mentioned above in group LPS + DMSO ( P>0.05). Compared with group LPS + DMSO, the percentage of spontaneous alternation was significantly increased, the expression of GluR2, Iba1 and TNF-α in hippocampus was down-regulated, and the number of microglia in hippocampal CA1 area was decreased in group LPS+ CFM-2 ( P<0.05). Conclusions:GluR2 is involved in chronic neuroinflammation-induced cognitive dysfunction through activation of microglia in mice.

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Article in Chinese | WPRIM | ID: wpr-933296

ABSTRACT

Objective:To evaluate the role of N-methyl-D-aspartate receptors (NMDA receptors) in sevoflurane anesthesia-caused necroptosis in hippocampal neurons of aged mice.Methods:Ninety clean-grade healthy male C57BL/6 mice, aged 18 months, weighing 27-30 g, were divided into 3 groups ( n=30 each) using a random number table method: control group (group C), sevoflurane anesthesia group (group S) and sevoflurane anesthesia plus NMDA receptor antagonist memantine hydrochloride group (group S+ M). Mice inhaled 3% sevoflurane for 2 h for 3 consecutive days in S group and S+ M group, and memantine hydrochloride 20 mg/kg was intraperitoneally injected at 1 h before each inhalation of sevoflurane in S+ M group.Mice only inhaled pure oxygen for 2 h in group C. Ten mice of each group were selected on 1 day before anesthesia and 3 and 7 days after anesthesia to perform Morris water maze test.The mice were sacrificed immediately after Morris water maze test, and hippocampus was removed for microscopic examination of pathological changes (with a light microscope) and for determination of the necroptosis rate of neurons and cytoplasmic free calcium concentration([Ca 2+ ] i)(by flow cytometry), and expression of NMDA receptor subtypes GluN2A, GluN2B and receptor-interacting protein kinase 1 (RIP1) (by Western blot). Results:Compared with group C, the escape latency was significantly prolonged, and the frequency of crossing the original platform was decreased, and the [Ca 2+ ] i and neuronal necroptosis rate in the hippocampus were increased at each time point after anesthesia, and the expression of GluN2A, GluN2B and RIP1 was up-regulated( P<0.05), and the pathologic changes were accentuated in S group and S+ M group.Compared with group S, the escape latency was significantly shortened, and the frequency of crossing the original platform was increased, and the [Ca 2+ ] i and neuronal necroptosis rate in the hippocampus were decreased at each time point after anesthesia, and the expression of GluN2A, GluN2B and RIP1 was down-regulated ( P<0.05), and the pathologic changes were attenuated in group S+ M. Conclusions:NMDA receptors are involved in the process of cognitive dysfunction induced by sevoflurane anesthesia in aged mice, and the mechanism may be related to the promotion of necrptosis in hippocampal neurons.

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Chinese Journal of Geriatrics ; (12): 586-590, 2022.
Article in Chinese | WPRIM | ID: wpr-933127

ABSTRACT

Objective:To investigate the effects and significance of α-synuclein(α-syn)on the expression level of β-arrestin 2 in Parkinson's disease(PD)in a mouse model.Methods:Twenty-eight C57BL/6J mice with similar motor skills were randomly divided into a model group and a control group, with 14 mice in each group.A PD model was established by injecting preformed fibrils of α-syn into the striatum of the brain, and behavioral changes were monitored after 4 weeks.The expression levels of α-syn, the dopamine receptor(DR), tyrosine hydroxylase(TH), inflammatory factors, β-arrestin 2 and the nuclear transcription factor-κB(NF-κB)signaling pathway-related proteins were determined by Western blotting.The interaction between α-syn and β-arrestin 2 was detected by fluorescence resonance energy transfer(FRET), and the regulation of α-syn on β-arrestin 2 transcriptional activation was detected by the dual luciferase report assay.Results:After 4 weeks of modeling, compared with the control group, the average movement speed of mice in the model group was significantly reduced( t=9.415, P<0.001), the movement track was sparse and concentrated around the open field, and the time needed to climb the pole was significantly prolonged( t=16.412, P<0.001). Compared with the control group, the relative expression of α-synin in astrocytes in the model group increased significantly, the relative expressions of D1DR and TH decreased significantly[(1.14±0.18) vs.(0.53±0.16), (0.67±0.13) vs.(1.15±0.11), (0.46±0.05) vs.(0.81±0.06)]( t=9.810, 10.917 and 17.356, all P<0.001), the relative expression of tumor necrosis factor-α, interleukin-1β, interleukin-6 and NF-κB signaling pathway-related proteins increased significantly( t=3.583, 4.284, 5.396, 11.747, 16.375 and 18.294, all P<0.001), and the relative expression of β-arrestin 2 protein[(0.42±0.11) vs.(1.33±0.14)]in astrocytes decreased significantly( t=19.795, P<0.001). The FRET results suggested a possible direct interaction between α-syn and β-arrestin 2.The results of the dual luciferase report assay showed that the transcription activity of β-arrestin 2 was significantly increased after α-syn gene knockout. Conclusions:The α-syn may induce inflammation in astrocytes by activating the NF-κB signaling pathway and participate in the pathogenesis of PD by reducing dopamine biosynthesis and inhibiting its physiological function through negative regulation of β-arrestin 2.

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