Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 1.372
Filter
1.
Rev. colomb. cir ; 37(3): 377-392, junio 14, 2022. tab, fig
Article in Spanish | LILACS | ID: biblio-1378692

ABSTRACT

Introducción. Debido a que el cáncer de seno es una enfermedad asociada a una significativa tasa de morbilidad y mortalidad cuando se diagnostica en el período sintomático, se han hecho enormes esfuerzos orientados hacia la prevención primaria de esta enfermedad. Métodos. Se realizó una búsqueda de todos los experimentos clínicos aleatorizados que evaluaran la eficacia de la terapia endocrina para la reducción del riesgo de desarrollar cáncer de seno. La calidad metodológica de los estudios seleccionados fue valorada utilizando la herramienta de la Colaboración Cochrane para medir el riesgo de sesgo en ensayos aleatorizados. Se evaluó la heterogeneidad de los estudios primarios elegibles utilizando los estadísticos T², I², H². El sesgo de publicación fue evaluado mediante el test de Harbord y mediante la gráfica de funnel plot. La medida de efecto utilizada en este metaanálisis fue el riesgo relativo (RR) con el cálculo de los intervalos de confianza (IC) del 95%. Resultados. Encontramos doce experimentos clínicos aleatorizados que reclutaron a 68.180 mujeres, las cuales fueron asignadas al azar para recibir algún tipo terapia endocrina para reducir el riesgo de desarrollar cáncer de seno o placebo. La terapia endocrina en conjunto redujo el riesgo proporcional de cáncer de seno (invasivo más in situ) en un 42 %, resultado estadísticamente significativo RR 0,58 (IC95% 0,50 ­ 0,69). Conclusiones. La terapia endocrina es el manejo estándar de prevención en mujeres sanas con riesgo de desarrollar cáncer de seno no hereditario.


Introduction. Because breast cancer is a disease associated with a significant morbidity and mortality rate when diagnosed in the symptomatic period, enormous efforts have been made towards the primary prevention of this disease. Methods. A search was conducted for all randomized clinical trials evaluating the efficacy of endocrine therapy in reducing the risk of developing breast cancer. The methodological quality of the selected studies was assessed using the Cochrane Collaboration tool to assess risk of bias in randomized trials. Heterogeneity of eligible primary studies was assessed using the T², I², H² statistics. Publication bias was evaluated using the Harbord test and the funnel plot. The effect measure used in this meta-analysis was the relative risk (RR) with the calculation of the 95% confidence intervals (CI).Results. We found twelve randomized clinical trials that recruited 68,180 women who were randomly assigned to receive some type of endocrine therapy to reduce the risk of developing breast cancer or placebo. Endocrine therapy as a whole reduced the proportional risk of breast cancer (invasive plus in situ) by 42%, a statistically significant result RR 0.58 (95% CI 0.50 - 0.69). Conclusions. Endocrine therapy is the standard preventive management in healthy women at risk of developing non-hereditary breast cancer.


Subject(s)
Humans , Primary Prevention , Breast Neoplasms , Meta-Analysis , Selective Estrogen Receptor Modulators , Aromatase Inhibitors
3.
Femina ; 50(2): 72-90, 20220228. ilus
Article in Portuguese | LILACS | ID: biblio-1366123

ABSTRACT

As diferenças ou distúrbios do desenvolvimento sexual (DDS) compreendem um grupo heterogêneo de condições congênitas que resultam na discordância entre os cromossomos sexuais, as gônadas e/ou o sexo anatômico de um indivíduo. A classificação desses distúrbios é baseada no cariótipo conforme o Consenso de Chicago de 2006 e substitui os termos pseudo-hermafroditismo, hermafroditismo e intersexo. O objetivo desta revisão é fornecer ao ginecologista conhecimentos básicos sobre a etiologia, fisiopatologia e orientações das principais anormalidades de DDS para uma avaliação diagnóstica e terapêutica no atendimento de mulheres na infância, adolescência e em idade adulta com cariótipo 46,XY. O diagnóstico deve ser realizado pela interação entre o exame clínico as dosagens hormonais, os exames de imagem e a análise genética, desde o cariótipo até o estudo de alterações dos genes por técnicas de biologia molecular. O tratamento é realizado de acordo com a etiologia e inclui intervenções cirúrgicas como a gonadectomia e plásticas sobre a genitália externa, terapia de reposição hormonal e apoio psicológico. São necessárias a individualização dos casos e uma equipe interdisciplinar, para um atendimento adequado às mulheres com cariótipo 46,XY.(AU)


Differences or disorders of sexual development (DSDs) comprise a heterogeneous group of congenital conditions that result in the disagreement between an individual's sex chromosomes, gonads and/or anatomic sex. The classification of these disorders is based on the karyotype according to the 2006 Chicago Consensus and replaces the terms pseudohermaphroditism, hermaphroditism and intersex. The aim of this review is to provide the gynecologist with basic knowledge about the etiology, pathophysiology and guidelines of the main abnormalities of DDS for a diagnostic and therapeutic evaluation in the care of women in childhood, adolescence and adulthood with a karyotype 46,XY. The diagnosis must be made by the interaction between clinical examination hormonal measurements, imaging and genetic analysis from the karyotype to the study of gene alterations by molecular biology techniques. Treatment is carried out according to the etiology and includes surgical interventions such as gonadectomy and plastic surgery on the external genitalia, hormone replacement therapy and psychological support. Individualization of cases and an interdisciplinary team are required to provide adequate care for women 46,XY karyotype.(AU)


Subject(s)
Humans , Female , Disorder of Sex Development, 46,XY/surgery , Disorder of Sex Development, 46,XY/diagnosis , Disorder of Sex Development, 46,XY/etiology , Disorder of Sex Development, 46,XY/physiopathology , Disorder of Sex Development, 46,XY/drug therapy , Disorder of Sex Development, 46,XY/diagnostic imaging , Androgen-Insensitivity Syndrome , Estrogen Replacement Therapy , Cholestenone 5 alpha-Reductase/deficiency , Ovotesticular Disorders of Sex Development
4.
Acta Pharmaceutica Sinica B ; (6): 511-531, 2022.
Article in English | WPRIM | ID: wpr-929312

ABSTRACT

Aging is by far the most prominent risk factor for Alzheimer's disease (AD), and both aging and AD are associated with apparent metabolic alterations. As developing effective therapeutic interventions to treat AD is clearly in urgent need, the impact of modulating whole-body and intracellular metabolism in preclinical models and in human patients, on disease pathogenesis, have been explored. There is also an increasing awareness of differential risk and potential targeting strategies related to biological sex, microbiome, and circadian regulation. As a major part of intracellular metabolism, mitochondrial bioenergetics, mitochondrial quality-control mechanisms, and mitochondria-linked inflammatory responses have been considered for AD therapeutic interventions. This review summarizes and highlights these efforts.

5.
Article in Chinese | WPRIM | ID: wpr-927921

ABSTRACT

The present study explored the effect and mechanism of repeatedly steamed and sundried Rehmanniae Radix Praeparata(RRP) in delaying brain aging in ovariectomized mice. After ovariectomy, the mice were randomly divided into a model group, an estradiol valerate group(0.3 mg·kg~(-1)), and low-(1.0 g·kg~(-1)), medium-(2.0 g·kg~(-1)), and high-dose(4.0 g·kg~(-1)) RRP groups, and a sham operation group was also set up, with 15 mice in each group. One week after the operation, intragastric administration was carried out for 15 consecutive weeks. The step-down test and Morris water maze test were used to detect the behavioral changes of mice. HE staining and Nissl staining were used to observe the morphological changes of mouse brain tissues. Immunohistochemistry was used to detect the expression of Aβ and ER_β in mouse brain tissues. The serum estrogen levels and cholinesterase and cholinesterase transferase levels in brain tissues of mice were detected by assay kits. The extracted hippocampal protein was detected by the Nano-ESI-LC-MS system, identified by the Protein Discovery, and analyzed quantitatively and qualitatively by the SIEVE. The PANTHER Classification System was used for GO analysis and KEGG pathway enrichment analysis of the differential proteins. Compared with the sham operation group, the model group showed decreased learning and memory ability, shortened step-down latency(P<0.05), prolonged escape latency(P<0.05), reduced platform crossings and residence time in the target quadrant, scattered nerve cells in the hippocampus with enlarged intercellular space, increased expression of Aβ-positive cells(P<0.05), declining expression of ER_β-positive cells and estrogen level(P<0.05), and weakened cholinergic function(P<0.05). Compared with the model group, the RRP groups showed improved learning and memory ability, prolonged step-down latency(P<0.05), increased estrogen level(P<0.05), neatly arranged nerve cells in the hippocampus with complete morphology, declining Aβ-positive cells, and elevated expression of ER_β-positive cells. A total of 146 differential proteins were screened out by proteomics, and KEGG pathway enrichment yielded 75 signaling pathways. The number of proteins involved in the dopaminergic synapse signaling pathway was the largest, with 13 proteins involved. In summary, RRP can delay brain aging presumedly by increasing the level of estrogen, mediating the dopaminergic synapse signaling pathway, and improving cholinergic function.


Subject(s)
Aging , Animals , Female , Hippocampus/metabolism , Learning , Mice , Plant Extracts , Proteomics , Rehmannia
6.
Journal of Preventive Medicine ; (12): 577-580, 2022.
Article in Chinese | WPRIM | ID: wpr-927241

ABSTRACT

Objective@#To examine the associations of arsenic and estrogen levels with the risk of papillary thyroid carcinoma, so as to provide insights into prevention of papillary thyroid carcinoma.@*Methods@#Totally 57 patients with papillary thyroid carcinoma admitted to two tertiary hospitals in Urumqi, Xinjiang Uygur Autonomous Region in 2018 were selected as the case group, while 57 subjects with normal thyroid functions during the same period were selected as the control group. Subjects' gender, age, ethnicity, occupation and medical history of thyroid disease were collected using questionnaire surveys. Serum dimethyl arsenic acid (DMA) and monomethyl arsenic acid (MMA) were determined using high-performance liquid chromatography (HPLC) coupled to hydride generation-atomic fluorescence spectrometry (HG-AFS), serum thyroid hormone (TSH) by radioimmunoassay, estradiol (E2) by enzyme-linked immunosorbent assay and estrogen receptor ERα and ERβ by western blotting. The associations of arsenic and estrogen levels with the risk of papillary thyroid carcinoma were evaluated using a multivariable logistic regression model.@*Results@#There were 16 males (28.07%) and 41 females (71.93%) in the case group, with a mean age of (42.63±11.01) years, and there were 21 males (36.84%) and 36 females (63.16%) in the control group, with a mean age of (40.89±11.30) years. There were no significant differences between the case and control groups in terms of age (χ2=0.373, P=0.542), gender (χ2=1.000, P=0.317) or ethnic composition (χ2=0.291, P=0.590). The serum levels of TSH [2.85 (1.61) vs. 2.45 (1.79) μmol/L], E2 [74.93 (120.44) vs. 61.60 (37.35) pmol/L], ERα [1.49 (1.13) vs. 0.70 (0.31)], ERβ [1.59 (0.55) vs. 0.72 (0.36)], DMA [116.02 (100.48) vs. 32.33 (56.06) μg/L] and MMA [56.92 (47.90) vs. 27.90 (24.99) μg/L] were all significantly higher in the case group than in the control group (Z=-2.414, -2.292, -4.923, -5.167, -5.448 and -4.019, all P<0.05). Multivariable logistic regression analysis showed DMA (OR=1.013, 95%CI: 1.003-1.024) and E2 levels (OR=1.020, 95%CI: 1.004-1.036) were associated with the risk of papillary thyroid carcinoma.@*Conclusion@#Increased arsenic load and elevated estradiol levels may be associated with the risk of papillary thyroid carcinoma.

7.
Säo Paulo med. j ; 139(6): 662-674, Nov.-Dec. 2021. tab, graf
Article in English | LILACS | ID: biblio-1352296

ABSTRACT

ABSTRACT BACKGROUND: This article systematically updates the literature on changes in visual functions during the phases of the normal menstrual cycle in women. OBJECTIVES: To update Guttridge's 1994 review of visual structures and functions associated with the menstrual cycle and broaden the search through psychophysical, neuroimaging and neurobehavioral measurements covering 1994-2020. DESIGN AND SETTING: Narrative review conducted in a neurosciences and behavior laboratory in Brazil. METHODS: The PubMed, Cochrane Clinical Answers and Google Scholar databases were searched. After screening and applying the eligibility criteria, 32 articles were examined. Through this analysis, the following information was extracted: (1) geographical distribution of the study; (2) sample size (according to age and phase of the menstrual cycle); (3) type of measurements according to psychophysical, neuroimaging and neurobehavioral instruments; (4) vision testing model; (5) visual subcategory evaluated; (6) categories of processed visual stimuli; and (7) main findings. RESULTS: The menstrual phases give rise to significant changes in visual functions, including in relation to orientation and spatial attention, visual campimetry and visual sensitivity. These relate specifically to the follicular and luteal phases. CONCLUSIONS: These findings theoretically expand the effects of menstrual cycles on visual functions found by Guttridge (1994). Despite some inconsistencies in the studies analyzed, it was found that visual processing during the follicular and luteal phases of the normal menstrual cycle of healthy women can explain physiological, cognitive, behavioral and social modulations.


Subject(s)
Humans , Female , Follicular Phase , Menstrual Cycle , Brazil , Luteal Phase
8.
Braz. dent. j ; 32(6): 107-114, Nov.-Dec. 2021. tab, graf
Article in English | LILACS-Express | LILACS, BBO | ID: biblio-1355836

ABSTRACT

Abstract The purpose of the study was to investigate the association between single nucleotide polymorphisms (SNPs) in genes encoding estrogen receptors (ESR1 and ESR2, respectively) and delayed tooth emergence (DTE). This cross-sectional study was composed of biological unrelated children of both sexes, age ranging from 11 to 13 years old. DTE was defined when the successor primary tooth was still present in the oral cavity after its exfoliation time or the absence of the permanent tooth emergence into the oral cavity. Children were diagnosed with DTE when they had at least one delayed permanent tooth, according to age of exfoliation of each tooth proposed by The American Dental Association. Genomic DNA from saliva was used to evaluate the SNPs in ESR1 (rs9340799 and rs2234693) and ESR2 (rs1256049 and rs4986938) using Real-Time PCR. Chi-square or Fisher exact tests and Logistic Regression adjusted by age and gender were performed. SNP-SNP interaction was accessed by multifactor dimensionality reduction (MDR) analysis also adjusted by gender and age. The established alpha of this study was 5%. Among 537 included children, 296 (55%) were in the "DTE" group and the 241 (45%) were in the "Control" group. Age and gender were not statistically different among the groups (p>0.05). Genotype distribution of the SNPs rs9340799, rs2234693, rs1256049 and rs4986938 were not associated with DTE (p> 0.05). The models elected by MDR were not statistically significant either. Conclusions: The studied SNPs in ESR1 and ESR2 were not associated with permanent DTE.


RESUMO O objetivo do presente estudo foi investigar a associação entre polimorfismos de nucleotídeo único (SNPs) em genes que codificam receptores de estrógeno (ESR1 e ESR2, respectivamente) e o retardo na emergência dentária (DTE). Este estudo transversal foi composto por crianças biológicas não relacionadas de ambos os sexos, com idades entre 11 e 13 anos. O DTE foi definido pela presença do dente decíduo na cavidade bucal após seu tempo e também, quando as crianças apresentaram pelo menos um dente permanente com atraso. O DNA genômico foi usado para avaliar os SNPs em ESR1 (rs9340799 e rs2234693) e ESR2 (rs1256049 e rs4986938) usando PCR em tempo real. Foram realizados testes Qui-quadrado ou exato de Fisher e Regressão Logística ajustados por idade e sexo. A interação SNP-SNP foi acessada pela análise de redução de dimensionalidade multifatorial (MDR), também ajustada por sexo e idade. O alfa de 5% foi estabelecido. Entre 537 crianças incluídas, 296 (55%) estavam no grupo "DTE" e 241 (45%) estavam no grupo "Controle". A idade e o sexo não foram estatisticamente diferentes entre os grupos (p> 0,05). A distribuição de genótipos dos SNPs rs9340799, rs2234693, rs1256049 e rs4986938 não foi associada ao DTE (p> 0,05). Os modelos eleitos pelo MDR também não foram estatisticamente significativos. Conclusões: Os SNPs estudados na ESR1 e ESR2 não foram associados ao DTE na dentição permanente.

9.
Int. j. cardiovasc. sci. (Impr.) ; 34(4): 486-489, July-Aug. 2021. tab, graf
Article in English | LILACS | ID: biblio-1286836

ABSTRACT

Abstract Swyer syndrome is one of the disorders of sexual differentiation. Previous studies have demonstrated increased sympathetic activity with heart rate variability (HRV) analysis with decreasing estradiol levels. One patient presented a pure 46, XY gonadal dysgenesis with female phenotype. Cardiac autonomic modulation was assessed through HRV analysis while at rest. This research analyzed linear and nonlinear indexes. HRV analysis showed reduced parasympathetic and global modulation with an apparent increase in sympathetic tone and a loss of HR fractal dynamics toward correlated behavior, characterized by low entropy and high determinism of time series.


Subject(s)
Humans , Female , Middle Aged , Cardiovascular Diseases/complications , Gonadal Dysgenesis, 46,XY/complications , Progestins/therapeutic use , Linear Models , Nonlinear Dynamics , Hormone Replacement Therapy , Estrogens/therapeutic use
10.
Int. j. morphol ; 39(4)ago. 2021.
Article in English | LILACS-Express | LILACS | ID: biblio-1385451

ABSTRACT

SUMMARY: Estrogen receptors (ER) have been identified in human nasal mucosa, but its physiologic and pathologic impacts are not totally established. ER have been demonstrated in nasal mucosa by several authors, mainly by immunohistochemical method in nasal mucosa samples surgically removed. The present study aimed to quantify ERα and ERβ mRNA concentration by using an absolute quantitative real-time PCR in cells from nasal mucosa smear of women under oral contraceptive therapy. Nasal epithelium smear samples were collected from 110 patients divided in two groups: 55 women who present regular menstrual cycle without using contraceptives and 55 women who present regular menstrual cycle and have been using oral contraceptives for more than 3 months. All the patients answered a rhinitis symptoms questionnaire. The current study showed the potential usefulness of nasal turbinate mucosa cell sourcing, collected through swab, for extracting useful RNA for gene expression. We have identified the predominant expression of ERα isoform in a ratio 10-15 times higher compared to ERβ isoform. There is a tendency for positive correlation between the ERb isoform and the rhinitis severity score.


RESUMEN: Se han identificado receptores de estrógeno (RE) en la mucosa nasal humana, sin embargo sus impactos fisiológicos y patológicos aún no están totalmente establecidos. Varios autores han demostrado RE en la mucosa nasal, principalmente por método inmunohistoquímico en muestras obtenidas quirúrgicamente. El presente estudio tuvo como objetivo cuantificar la concentración de ARNm de REa y REb mediante el uso de una PCR cuantitativa absoluta en tiempo real en células de frotis de mucosa nasal de mujeres bajo terapia anticonceptiva oral. Se recolectaron muestras de frotis de epitelio nasal de 110 pacientes divididas en dos grupos: 55 mujeres que presentan ciclo menstrual regular sin uso de anticonceptivos y 55 mujeres que presentan ciclo menstrual regular con uso de anticonceptivos orales durante más de 3 meses. Todas las pacientes respondieron un cuestionario de síntomas de rinitis. El estudio actual mostró la utilidad de la obtención de células de la mucosa de la concha nasal, recolectadas a través de un hisopo, para extraer ARN para la expresión génica. Hemos identificado la expresión predominante de la isoforma REμ en una proporción de 10 a 15 veces mayor en comparación con la isoforma REß. Hemos identificado la expresión predominante de la isoforma REα en una proporción de 10 a 15 veces mayor en comparación con la isoforma REß. Existe una tendencia a una correlación positiva entre la isoforma REß y la puntuación de gravedad de la rinitis.

11.
Rev. Assoc. Med. Bras. (1992) ; 67(2): 265-270, Feb. 2021. tab
Article in English | LILACS | ID: biblio-1287804

ABSTRACT

SUMMARY OBJECTIVE: Currently, there is an ongoing debate whether progesterone receptor positive and estrogen receptor negative breast carcinomas represent a true distinct subtype of tumor or a mere immunohistochemical artifact. In this study, we conducted an immunohistochemistry panel with the antibodies TFF1, EGFR, and CK5 to reclassify this phenotype in a luminal or basal-like subtype. METHODS: Tumors estrogen receptor -/progesterone receptor +, Her-2 - from a large population of breast cancer patients were selected to be studied. Immunohistochemistry with the antibodies TFF1, EGFR, and CK5 was performed. Tumors showing positivity for TFF1, regardless of EGFR and CK5 results, were classified as luminal-like carcinomas. Those lesions that were negative for TFF1, but were positive for EGFR and/or CK5, were classified as basal-like triple-negative carcinomas. When the three markers were negative, tumors were classified as undetermined. Clinical pathologic characteristics of patients and tumor recurrence were evaluated. RESULTS: Out of 1188 breast carcinomas investigated, 30 cases (2.5%) presented the estrogen receptor -/progesterone receptor +/HER2- phenotype. Of them, 27 tumors (90%) were classified as basal-like triple-negative carcinomas, one as luminal-like (3.3%), and two as undetermined tumors (6.7%). The mean follow-up for the study group was 27.7 (2.7 to 50) months. Out of the 26 patients, 6 had cancer recurrence: 2 local and 4 systemic recurrences. The average time for recurrence was 17 (8 to 38) months. CONCLUSION: Estrogen receptor -/progesterone receptor +/tumors exhibit aggressive behavior, similar to triple-negative tumors. An appropriate categorization of these tumors should be made to improve their therapeutic management.


Subject(s)
Humans , Female , Receptors, Progesterone , Biomarkers, Tumor , Breast Neoplasms , Receptors, Estrogen , Receptor, ErbB-2 , Neoplasm Recurrence, Local
12.
Clinics ; 76: e2380, 2021. tab, graf
Article in English | LILACS | ID: biblio-1153943

ABSTRACT

OBJECTIVES: To compare the effects of low-dose conjugated estrogen (CE), raloxifene, and the combination thereof on the endometrium of postmenopausal women. METHODS: Postmenopausal women between 45 and 60 years of age, with Gail score≥1.67 and no endometrial disorders, were randomly assigned to receive low-dose CE (0.3 mg), raloxifene (60 mg), or combined therapy for 1 year. Transvaginal ultrasound was performed at baseline and every 3 months; the Kupperman Index was assessed at baseline and every 6 months. Endometrial biopsies were performed if endometrial thickness (ET) was ≥5 mm or if vaginal bleeding occurred. The primary outcome was the occurrence of ET≥5 mm over the one-year period. RESULTS: Seventy-three women were randomly assigned and analyzed on an intent-to-treat basis. Eight, three, and four women in the CE, raloxifene, and combination groups, respectively, exhibited ET≥5 mm. No genital bleeding was reported in the combination group. Endometrial biopsy revealed atrophy or polyps in all groups, with one patient in the CE group exhibiting a proliferative endometrium without atypia. At 6 months, there was a progressive increase in mean ET in the CE group, but not in the other two groups, with statistically significant differences at 6, 9, and 12 months. Mean scores for vasomotor symptoms and Kupperman Index favored the CE and combination groups over raloxifene. CONCLUSION: Combined raloxifene and low-dose CE decreased the severity of menopausal symptoms to a similar extent as CE alone and had similar effects as raloxifene alone on the endometrium.


Subject(s)
Humans , Female , Breast Neoplasms , Raloxifene Hydrochloride , Menopause , Double-Blind Method , Estrogens, Conjugated (USP) , Selective Estrogen Receptor Modulators , Endometrium/diagnostic imaging
13.
Journal of Clinical Hepatology ; (12): 467-470, 2021.
Article in Chinese | WPRIM | ID: wpr-873424

ABSTRACT

The incidence rate of nonalcoholic fatty liver disease (NAFLD) has increased sharply, and there is still a lack of effective pharmacotherapy at present. Although great achievements have been made in the research on the pathogenesis of NAFLD, we still do not know enough about the gender differences of NAFLD. As an important sex hormone, estrogen affects the development and progression of NAFLD by regulating mood and energy homeostasis, adipose tissue function and distribution, inflammatory response, insulin resistance, liver fat accumulation, and liver immunity. An adequate understanding of the mechanism of action of estrogen and its receptor in NAFLD may provide new ideas for the treatment of NAFLD.

14.
Acta Pharmaceutica Sinica B ; (6): 340-354, 2021.
Article in English | WPRIM | ID: wpr-881140

ABSTRACT

Enormous studies have corroborated that long non-coding RNAs (lncRNAs) extensively participate in crucial physiological processes such as metabolism and immunity, and are closely related to the occurrence and development of tumors, cardiovascular diseases, nervous system disorders, nephropathy, and other diseases. The application of lncRNAs as biomarkers or intervention targets can provide new insights into the diagnosis and treatment of diseases. This paper has focused on the emerging research into lncRNAs as pharmacological targets and has reviewed the transition of lncRNAs from the role of disease coding to acting as drug candidates, including the current status and progress in preclinical research. Cutting-edge strategies for lncRNA modulation have been summarized, including the sources of lncRNA-related drugs, such as genetic technology and small-molecule compounds, and related delivery methods. The current progress of clinical trials of lncRNA-targeting drugs is also discussed. This information will form a latest updated reference for research and development of lncRNA-based drugs.

15.
Acta Pharmaceutica Sinica B ; (6): 156-180, 2021.
Article in English | WPRIM | ID: wpr-881131

ABSTRACT

@#This study was aimed to design the first dual-target small-molecule inhibitor co-targeting poly (ADP-ribose) polymerase-1 (PARP1) and bromodomain containing protein 4 (BRD4), which had important cross relation in the global network of breast cancer, reflecting the synthetic lethal effect. A series of new BRD4 and PARP1 dual-target inhibitors were discovered and synthesized by fragment-based combinatorial screening and activity assays that together led to the chemical optimization. Among these compounds, 19d was selected and exhibited micromole enzymatic potencies against BRD4 and PARP1, respectively. Compound 19d was further shown to efficiently modulate the expression of BRD4 and PARP1. Subsequently, compound 19d was found to induce breast cancer cell apoptosis and stimulate cell cycle arrest at G1 phase. Following pharmacokinetic studies, compound 19d showed its antitumor activity in breast cancer susceptibility gene 1/2 (BRCA1/2) wild-type MDA-MB-468 and MCF-7 xenograft models without apparent toxicity and loss of body weight. These results together demonstrated that a highly potent dual-targeted inhibitor was successfully synthesized and indicated that co-targeting of BRD4 and PARP1 based on the concept of synthetic lethality would be a promising therapeutic strategy for breast cancer.

16.
Acta Pharmaceutica Sinica B ; (6): 30-54, 2021.
Article in English | WPRIM | ID: wpr-881123

ABSTRACT

The sustained cell proliferation resulting from dysregulation of the cell cycle and activation of cyclin-dependent kinases (CDKs) is a hallmark of cancer. The inhibition of CDKs is a highly promising and attractive strategy for the development of anticancer drugs. In particular, third-generation CDK inhibitors can selectively inhibit CDK4/6 and regulate the cell cycle by suppressing the G1 to S phase transition, exhibiting a perfect balance between anticancer efficacy and general toxicity. To date, three selective CDK4/6 inhibitors have received approval from the U.S. Food and Drug Administration (FDA), and 15 CDK4/6 inhibitors are in clinical trials for the treatment of cancers. In this perspective, we discuss the crucial roles of CDK4/6 in regulating the cell cycle and cancer cells, analyze the rationale for selectively inhibiting CDK4/6 for cancer treatment, review the latest advances in highly selective CDK4/6 inhibitors with different chemical scaffolds, explain the mechanisms associated with CDK4/6 inhibitor resistance and describe solutions to overcome this issue, and briefly introduce proteolysis targeting chimera (PROTAC), a new and revolutionary technique used to degrade CDK4/6.

17.
Article in English | WPRIM | ID: wpr-922561

ABSTRACT

Apolipoprotein A-I (ApoA-I), the main protein component of high-density lipoprotein (HDL), plays a pivotal role in reverse cholesterol transport (RCT). Previous studies indicated a reduction of serum ApoA-I levels in various types of cancer, suggesting ApoA-I as a potential cancer biomarker. Herein, ectopically overexpressed ApoA-I in MDA-MB-231 breast cancer cells was observed to have antitumor effects, inhibiting cell proliferation and migration. Subsequent studies on the mechanism of expression regulation revealed that estradiol (E2)/estrogen receptor α (ERα) signaling activates

18.
Chinese Journal of Oncology ; (12): 405-413, 2021.
Article in Chinese | WPRIM | ID: wpr-877505

ABSTRACT

The introduction of cyclin-dependent kinase (CDK) 4/6 inhibitors has revolutionized the clinical management paradigm of hormone receptor (HR) positive/human epidermal growth factor receptor (HER) 2 negative breast cancer. As of today, CDK 4/6 inhibitors including Palbociclib, Ribociclib, and Abemaciclib have been widely approved by regulatory agencies. Randomized clinical trials demonstrated that CDK 4/6 inhibitors in combination with an aromatase inhibitor (AI) or fulvestrant in the first-, second- or later-line setting for HR positive/HER2 negative locally advanced or metastatic breast cancer led to substantial reduction in the risk of disease progression or death. Adverse effects of treatment were manageable and as or better than expected in terms of patient satisfaction. Considering CDK4/6 inhibitors in combination with endocrine therapy being a novel approach in China clinical practice, the panel developed the consensus comprehensively describing the pharmacology properties, monitoring strategy during treatment and adverse events management, to facilitate greater understanding in Chinese oncologists of a whole new therapeutic class of drug, promote accuracy of clinical decision and help reach the ultimate goal of improving survival and quality of life of the target patient population.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , China , Consensus , Cyclin-Dependent Kinase 4 , Cyclin-Dependent Kinase 6 , Humans , Protein Kinase Inhibitors/therapeutic use , Quality of Life , Receptor, ErbB-2
19.
Article in Chinese | WPRIM | ID: wpr-907821

ABSTRACT

Objective:To investigate the significance and regulatory mechanism of miR-142-3p and ER1 in serum and placenta of pregnant women with gestational diabetes mellitus (GDM) complicated with preeclampsia (PE) in the occurrence and development of disease.Methods:A total of 198 pregnant women admitted from Jun. 2019 to Jun. 2020 were selected as the study subjects, including 66 pregnant women with GDM (GDM group) , 60 pregnant women with GDM complicated with PE (GDM+PE group) and 72 normal pregnant women (control group) . Clinical indicators were detected and pregnancy outcome data were collected. The relative expression levels of miR-142 -3p and ER1 mRNA in serum and placental tissues of study subjects were determined by quantitative real-time polymerase link assay. The expression of ER1 protein in the placenta was detected by Western blot. Human choriotrophoblast cells HTR-8/SVneo were treated with miR-142-3p.Results:The expression levels of miR-142-3p in serum and placenta tissues in GDM+PE group were significantly lower than those in GDM+PE group and control group ( P<0.05) . The mRNA expression of ER1 in serum and placenta in GDM+PE group was significantly higher than that in GDM+PE group and control group ( P<0.05) . There was a significant negative correlation between the relative expression levels of miR-142-3p and ER1 mRNA in serum and placental tissues of pregnant women in the GDM+PE group ( r=-0.589 and -0.643, P=0.006 and < 0.001) .After transfection of HTR-8/SVneo cells with miR-142-3p, ER1 mRNA expression in the mimic group was 1.09±0.14,significantly lower than that of NC group (2.14±0.52) , inhibitor group (3.69±0.88) and inhibitor NC group (2.26±0.43) ( P<0.001) . The expression of DNMT1 in inhibitor group was significantly higher than that in the other three groups ( P<0.001) . Conclusion:In patients with GDM complicated with PE, miR-142-3p levels are reduced and ER1 levels are increased, which may be involved in the occurrence and progression of the disease.

20.
Article in Chinese | WPRIM | ID: wpr-907769

ABSTRACT

Objective:To explore the effect of estrogen-related receptor α (ERRα) on lipopolysaccharide (LPS)-induced vascular endothelial cell apoptosis and tight junction protein degradation.Methods:RPMVECs transfected with shERRα were cultured in vitro and divided into four groups: Normal control group (Ctr group); shERRα knockdown group (shERRα group); normal cells + LPS treated group (LPS group): The cells in the six-well plates were cultured in serum-free medium for 12 h, and then treated with 20 μg/mL LPS for 12 h; and shERRα+LPS group: ERRα knockdown cells were treated as the LPS group. ROS fluorescence kit was used to detect the intracellular ROS levels . Apoptosis ratio was detected by TUNEL staining, AnnexinV-FITC and PI. Cell membrane ZO-1 expression was detected by cellular immunofluorescence, and the levels of apoptosis-related proteins Bcl-2, Bax, Smac, Cytochrome c, and tight junction protein ZO-1, as well as the expression of Occludin, JAM-A and E-Ca at molecular level were detected by Western blot.Results:Compared with the Ctr group and the shERRα group, the ROS level, apoptosis rate (TUNEL test: 16.44 ± 2.55; and flow cytometry test: 23.56 ± 2.22), the expression of pro-apoptotic proteins Bax, Smac and Cytochrome c were increased in the LPS group, while the expression of anti-apoptotic proteins Bcl-2 and tight junction protein were decreased. In the LPS group. Cellular immunofluorescence results showed that the ZO-1 was degraded in the cell membrane and the network structure was broken. Compared with the LPS group, inhibition of ERRα in the shERRα+LPS group increased cell damage.Conclusions:ERRα can negatively regulate the apoptosis and affect the function of pulmonary microvascular endothelial cells, thereby regulating sepsis-induced acute lung injury.

SELECTION OF CITATIONS
SEARCH DETAIL