RESUMO
OBJECTIVES: To determine how age affects insulin resistance during the menstrual cycle and insulin resistance-associated indices: the Triglyceride-glucose and Triglyceride-glucose-BMI indexes. METHODS: This prospective observational study used fasting plasma glucose, fasting insulin, triglycerides, body mass index (BMI), and days since the start of the menstrual period collected from the NHANES dataset (1999-2006). Insulin resistance was determined using the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR). The participants were categorized as young (16-34 years) or older (>35 years). Rhythmicity during the menstrual cycle was analyzed using the Cosinor and Cosinor2 packages for R. MAIN OUTCOME MEASURES: Cosine fit curves for insulin resistance during the menstrual cycle and age-associated effects on rhythmicity. RESULTS: Using 1256 participants, rhythmicity was observed for fasting insulin and HOMA-IR (p < 0.05) but not for fasting plasma glucose, the Triglyceride-glucose index, or the Triglyceride-glucose-BMI index. Significant amplitudes for fasting insulin and HOMA-IR were observed when age was considered. Acrophases for fasting insulin and HOMA-IR were significant only for the younger group, and the differences between these groups were significant, suggesting that the changes in scores for insulin resistance for the younger and older groups occur at different times of their menstrual cycle. CONCLUSIONS: Insulin resistance does fluctuate during the menstrual cycle, and it is at a maximum at different times for younger and older women. Since these results are unadjusted, this study is preliminary and further investigation is required.
RESUMO
OBJECTIVE: To assess how obesity, normal weight (NW) versus overweight/obese (OW/OB), impacts platelet-rich plasma's (PRP) effectiveness during in vitro fertilization and how obesity affects platelets during the menstrual cycle. METHODS: Endometrial mean thickness (EMT), embryo implantation, and clinical pregnancy were assessed using a self-controlled retrospective study that enrolled 59 patients with two failed cycles and treated with autologous PRP (three-dose scheme). The NHANES dataset was used to assess platelet changes during the menstrual cycle, using the mean platelet volume to platelet count ratio (MPR) index. The COSINOR packages for R were used to determine rhythmicity. RESULTS: PRP treatments significantly improved the EMT (2.5 ± 1.4 mm, P<0.001), unaffected by obesity. After the PRP treatment, one patient spontaneously became pregnant; therefore, 58 patients underwent embryo transfer (62 cycles), of which in 39 cycles the embryos implanted (63.9%). This was a significant improvement from their previous cycle (vs. 22.6%, P<0.001). Clinical pregnancy also improved with the PRP treatment over the previous cycle (57.4% vs. 16.1%, P<0.001). When stratified by obesity, there was an appreciable decrease in embryo implantation and clinical pregnancy rates for the OW/OB group; nevertheless, the PRP treatment significantly improved embryo implantation and clinical pregnancy (P<0.05). A rhythm was observed with the MPR index (P<0.05) only for the NW group, suggesting that the platelets normally fluctuate during the menstrual cycle. CONCLUSION: PRP improved embryo implantation and clinical pregnancy rates; however, these beneficial effects were attenuated by obesity. PRP presumptively promoted a change in the uterine environment to mimic the normal findings associated with normal-weight women.
RESUMO
Glutamate, the major excitatory neurotransmitter in the vertebrate brain, exerts its functions through the activation of specific plasma membrane receptors and transporters. Overstimulation of glutamate receptors results in neuronal cell death through a process known as excitotoxicity. A family of sodium-dependent glutamate plasma membrane transporters is responsible for the removal of glutamate from the synaptic cleft, preventing an excitotoxic insult. Glial glutamate transporters carry out more than 90% of the brain glutamate uptake activity and are responsible for glutamate recycling through the GABA/Glutamate/Glutamine shuttle. The aryl hydrocarbon receptor is a ligand-dependent transcription factor that integrates environmental clues through its ability to heterodimerize with different transcription factors. Taking into consideration the fundamental role of glial glutamate transporters in glutamatergic synapses and that these transporters are regulated at the transcriptional, translational, and localization levels in an activity-dependent fashion, in this contribution, we explored the involvement of the aryl hydrocarbon receptor, as a model of environmental integrator, in the regulation of the glial sodium-dependent glutamate/aspartate transporter. Using the model of chick cerebellar Bergmann glia cells, we report herein that the aryl hydrocarbon receptors exert a time-dependent decrease in the transporter mRNA levels and a diminution of its uptake activity. The nuclear factor kappa light chain enhancer of the activated B cell signaling pathway is involved in this regulation. Our results favor the notion of an environmentally dependent regulation of glutamate removal in glial cells and therefore strengthen the notion of the involvement of glial cells in xenobiotic neurotoxic effects.
Assuntos
Ácido Aspártico , Receptores de Hidrocarboneto Arílico , Ácido Aspártico/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Proteínas de Transporte de Glutamato da Membrana Plasmática/metabolismo , Sistema X-AG de Transporte de Aminoácidos/metabolismo , Sódio/metabolismo , Neuroglia/metabolismo , Ácido Glutâmico/metabolismo , Células CultivadasRESUMO
BACKGROUND: The aim was to evaluate the effect different types of abdominal fat have on NAFLD development and the effects of abdominal fat has on the association between Metabolic Syndrome (MetS) and NALFD. METHODS: Data was collected from the cross-sectional NHANES dataset (2017-2018 cycle). Using the controlled attenuation parameter (USG CAP, dB/m), which measures the level of steatosis, the cohort was stratified into two groups: NAFLD(+) (≥274 dB/m) and NAFLD(-). Using complex samples analyses, associations between liver steatosis or NAFLD and types of abdominal fat area [Total abdominal (TAFA), subcutaneous (SAT), and visceral (VAT)] were determined. Pearson's correlation coefficient (r) was calculated to evaluate the associations between adipose tissues and NAFLD. Logistic regression was used to determine the risk [odds ratio (OR) and 95% confidence interval (95%CI)]. Participants were also classified by MetS, using the Harmonizing Definition criteria. RESULTS: Using 1,980 participants (96,282,896 weighted), there was a significant (p<0.001) correlation between USG CAP and TAFA (r = 0.569), VAT (r = 0.645), and SAT (r = 0.479). Additionally, the risk of developing NAFLD was observed for total abdominal obesity (OR = 19.9, 95%CI: 5.1-77.8, p<0.001), visceral obesity (OR = 9.1, 95%CI: 6.2-13.5, p<0.001) and subcutaneous obesity (OR = 4.8, 95%CI: 3.2-6.9, p<0.001). Using 866 participants (44,399,696 weighted), for visceral obesity, participants with MetS and visceral obesity (OR = 18.1, 95%CI: 8.0-41.3, p<0.001) were shown to have a greater risk than participants with MetS only (OR = 6.3, 95%CI: 2.6-15.2, p<0.001). For subcutaneous obesity, again, participants with MetS and subcutaneous obesity (OR = 18.3, 95%CI: 8.0-41.9, p<0.001) were shown to have a greater risk than the MetS-only group (OR = 10.3, 95%CI: 4.8-22.4, p<0.001). CONCLUSION: TAFA, VAT, and SAT were positively associated with USG CAP values and increased the risk of developing NAFLD. Also, the type of abdominal fat depots did affect the association between MetS and NAFLD.
Assuntos
Síndrome Metabólica , Hepatopatia Gordurosa não Alcoólica , Humanos , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Síndrome Metabólica/complicações , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/metabolismo , Estudos Transversais , Obesidade Abdominal/complicações , Obesidade Abdominal/epidemiologia , Obesidade Abdominal/metabolismo , Inquéritos Nutricionais , Obesidade/complicações , Gordura Abdominal/metabolismo , Gordura Intra-Abdominal/metabolismoRESUMO
Rotenone is a pesticide commonly used in agriculture that is associated with the risk of developing Parkinson's disease (PD) by inducing mitochondrial damage. As a protective cell response to different challenges, they activate mitophagy, which involves parkin activity. Parkin is an E3 ubiquitin ligase necessary in the initial steps of mitophagy, and its overexpression protects against parkinsonian effects in different models. Recent studies have reported that the aryl hydrocarbon receptor (AHR), a ligand-dependent transcription factor, induces parkin expression. Kynurenine, an endogenous AHR ligand, promotes neuroprotection in chronic neurodegenerative disorders, such as PD, although its neuroprotective mechanism needs to be fully understood. Therefore, we evaluated whether the overexpression of parkin by AHR activation with kynurenine promotes autophagy and reduces the neurotoxicity induced by rotenone in SH-SY5Y cells differentiated to dopaminergic neurons. SH-SY5Y neurons were treated with rotenone or pretreated with kynurenine or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and parkin levels, apoptosis, mitochondrial potential membrane, and autophagy were determined. The results showed that kynurenine and TCDD treatments induced parkin expression in an AHR-dependent manner. Kynurenine pretreatment inhibited rotenone-induced neuronal apoptosis in 17%, and the loss of mitochondrial membrane potential in 30% when compare to rotenone alone, together with a decrease in autophagy. By contrast, although TCDD treatment increased parkin levels, non-neuroprotective effects were observed. The kynurenine protective activity was AHR independent, suggesting that parkin induction might not be related to this effect. On the other hand, kynurenine treatment inhibited alpha amine-3-hydroxy-5-methyl-4-isoxazol propionic acid and N-methyl-D-aspartate receptors, which are well-known excitotoxicity mediators activated by rotenone exposure.
Assuntos
Neuroblastoma , Fármacos Neuroprotetores , Doença de Parkinson , Dibenzodioxinas Policloradas , Humanos , Rotenona , Cinurenina/farmacologia , Receptores de Hidrocarboneto Arílico , Ligantes , Morte Celular , Apoptose , Ubiquitina-Proteína Ligases/metabolismo , Linhagem Celular Tumoral , Fármacos Neuroprotetores/farmacologiaRESUMO
BACKGROUND AND AIMS: Hyperinsulinemia and hyperuricemia are known to increase the risk of mortality due to certain complications, such as Type 2 Diabetes and cardiovascular disease. However, despite their common comorbidities, their combined effect has not been evaluated. The study's aim was to evaluate the combine effect of hyperinsulinemia and hyperuricemia on all-cause mortality. METHODS AND RESULTS: NHANES datasets (cycles 2003-2018) were examined. Differences between groups were evaluated using Rao-Scott Chi-square and General Linear Model for categorical and continuous data, respectively. Hazard Ratios (HR) were calculated using Cox regression with 95% confidence intervals (95%CI). There was significant difference (p < 0.05) in the mortality rate between the control group (2.3 ± 0.2%), the hyperinsulinemia only group (3.1 ± 0.3%), the hyperuricemia only group (4.0 ± 0.8%), and both conditions (5.1 ± 0.8%). Individually, when compared to the control group, there was a significant increase in mortality risk for hyperinsulinemia (HR: 1.50, 95%CI: 1.12-2.01, p = 0.007) and hyperuricemia (HR: 1.80, 95%CI:1.18-2.75, p = 0.006). However, when both conditions were present, there appeared an additive effect in the mortality risk (HR: 2.32, 95%CI: 1.66-3.25, p < 0.001). When stratified by BMI class, only normal weight participants presented with a significant risk (HR: 7.00, 95%CI: 2.50-20.30, p < 0.001). Also, when stratified by age, only participants older than 40 years presented a risk (HR: 2.22, 95%CI: 1.56-3.16, p < 0.001). CONCLUSION: Alone, hyperuricemia and hyperinsulinemia significantly increased the mortality rate; however, the combined presence of both pathologies was associated with a significantly augmented mortality rate. Normal weight participant or that were >40 years old had a greater risk for mortality.
Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Hiperinsulinismo , Hiperuricemia , Humanos , Adulto , Hiperuricemia/diagnóstico , Hiperuricemia/complicações , Diabetes Mellitus Tipo 2/complicações , Inquéritos Nutricionais , Hiperinsulinismo/diagnóstico , Fatores de RiscoRESUMO
Patients with polycystic ovary syndrome (PCOS) on a high-carbohydrate diet intrinsically suffer from exacerbated glucotoxicity, insulin resistance (IR), and infertility. Lowering the carbohydrate content has improved fertility in patients with IR and PCOS; however, the effects of a well-controlled ketogenic diet on IR and fertility in PCOS patients undergoing in vitro fertilization (IVF) have not been reported. Twelve PCOS patients with a previous failed IVF cycle and positive for IR (HOMA1-IR>1.96) were retrospectively evaluated. Patients followed a ketogenic diet (50 g of total carbohydrates/1800 calories/day). Ketosis was considered when urinary concentrations were > 40 mg/dL. Once ketosis was achieved, and IR diminished, patients underwent another IVF cycle. The nutritional intervention lasted for 14 ± 11 weeks. Carbohydrate consumption decreased from 208 ± 50.5 g/day to 41.71 ± 10.1 g/day, which resulted in significant weight loss (-7.9 ± 1.1 kg). Urine ketones appeared in most patients within 13.4 ± 8.1 days. In addition, there was a decrease in fasting glucose (-11.4 ± 3.5 mg/dl), triglycerides (-43.8 ± 11.6 mg/dl), fasting insulin (-11.6 ± 3.7 mIU/mL), and HOMA-IR (-3.28 ± 1.27). All patients underwent ovarian stimulation, and compared to the previous cycle, there was no difference in oocyte number, fertilization rate, and viable embryos produced. However, there was a significant improvement in the implantation (83.3 vs. 8.3 %), clinical pregnancy (66.7 vs. 0 %), and ongoing pregnancy/live birth rates (66.7 vs. 0 %). Here, restriction in carbohydrate consumption in PCOS patients induced ketosis, improved key metabolic parameters, and decreased IR. Even though this did not affect oocyte or embryo quality or quantity, the subsequent IVF cycle significantly improved embryo implantation and pregnancy rates.
Assuntos
Infertilidade Feminina , Resistência à Insulina , Cetose , Síndrome do Ovário Policístico , Gravidez , Humanos , Feminino , Síndrome do Ovário Policístico/tratamento farmacológico , Estudos Retrospectivos , Implantação do Embrião , Fertilização in vitro , Carboidratos/uso terapêutico , Infertilidade Feminina/terapiaRESUMO
Limited options are available for infertility associated with damaged or suboptimal tissues, typically the endometrium or ovaries. The goal of regenerative medicine is to restore function to specific tissues. Here, a 35-year-old female patient underwent two interventions of regenerative medicine: (i) autologous mesenchymal stem cells (MSCs) were applied in the myometrium, and (ii) intraovarian infusion of platelet-rich plasma (PRP). After two failed in vitro fertilization cycles (IVF), in which the endometrium was <5 mm, MSCs were applied, achieving a 7 mm trilaminar lining; however, the embryo quality remained poor. Therefore, intraovarian PRP was utilized for the next IVF cycle; the patient's response improved, and a euploid embryo developed. After the embryo transfer and a normal 38 weeks of pregnancy, a baby girl was born. Here, we demonstrate two forms of regenerative medicine that can be utilized to improve IVF.
RESUMO
BACKGROUND: Polycystic ovary syndrome (PCOS) is an endocrine disease that combines metabolic, reproductive, and psychological dysfunctions. Ovulation disorders and impaired endometrial receptivity in PCOS can cause infertility. Insulin resistance (IR) is a pathological state of inadequate response to insulin that affects reproduction in PCOS, as damage caused by IR at the endometrial level becomes an obstacle for embryo implantation. Reversing IR resulted in spontaneous pregnancies in PCOS patients, indicating that metabolic corrections improve endometrial dysfunctions. Mesenchymal stem-cell treatment has also corrected endometrial quality and lead to pregnancies in patients with Asherman's syndrome. We propose a combination of nutritional intervention with the surgical placement of stem cells to improve endometrial quality to achieve pregnancy in a PCOS patient undergoing in vitro fertilization (IVF) treatment. CASE SUMMARY: After two failed IVF cycles, a metabolic intervention, consisting of a ketogenic diet with daily consumption of 50 g of carbohydrates (CH), was indicated until pregnancy. Metabolic Syndrome was assessed using the Harmonizing Definition (3 of 5 pathologies: Central obesity, hypertension, hyperglycemia, hypertriglyceridemia, and dyslipidemia), and the Homeostatic Model Assessment of IR (HOMA-IR) was used to measure the level of IR. Once IR improved, endometrial quality improved. However, two day 5-thawed embryos (euploid, donated oocyte-partner's sperm) failed to implant, suggesting endometrial quality improvement was insufficient. Therefore, transmyometrial implantation of mesenchymal stem cells from the stromal vascular fraction of adipose tissue was performed to enrich the endometrial stem cell niche. Minimal endometrial mean thickness for embryo transfer (6.9 mm) was achieved three months after stem cell treatment and continuous dietary control of IR. Two euploid-day 5-thawed embryos (donated oocyte-partner's sperm) were transferred, and embryo implantation was confirmed on day 14 by ß-hCG serum levels. Currently, a 37 wk baby girl is born. CONCLUSION: In PCOS, endometrial quality can be improved by combining nutrient-based metabolic correction with endometrial stem cell niche enrichment.
RESUMO
SUMMARY STATEMENT: EAAT1/GLAST down-regulates its expression and function at the transcriptional level by activating a signaling pathway that includes PI3K, PKC and NF-κB, favoring the notion of an activity-dependent fine-tuning of glutamate recycling and its synaptic transactions through glial cells.
Assuntos
Transportador 1 de Aminoácido Excitatório , Regulação da Expressão Gênica , Células Cultivadas , Transportador 1 de Aminoácido Excitatório/genética , Transportador 1 de Aminoácido Excitatório/metabolismo , Regulação da Expressão Gênica/genética , Ácido Glutâmico/metabolismo , Neuroglia/metabolismoRESUMO
BACKGROUND: Down syndrome (DS) is the most common chromosomal survival aneuploidy. The increase in DS life expectancy further heightens the risk of dementia, principally early-onset Alzheimer's disease (AD). AD risk in DS is higher, considering that this population may also develop metabolic diseases such as obesity, dyslipidemias, and diabetes mellitus. The extra genetic material that characterizes DS causes an imbalance in the genetic dosage, including over-expression of AD's key pathophysiological molecules and the gene expression regulators, the microRNAs (miRNAs). Two miRNAs, chromosome 21-encoded, miR-155, and let-7c, are associated with cognitive impairment and dementia in adults; but, expression dynamics and relationship with clinical variables during the DS's lifespan had remained hitherto unexplored. METHODS: The anthropometric, clinical, biochemical, and profile expression of circulating miR-155 and let-7c were analyzed in a population of 52 control and 50 DS subjects divided into the young group (Aged ≤20 years) and the adult group (Aged ≥21 years). RESULTS: The expression changes for miR-155 were not significant; nevertheless, a negative correlation with HDL-Cholesterol concentrations was observed. Notably, let-7c was over-expressed in DS from young and old ages. CONCLUSION: Overall, our results suggest that let-7c plays a role from the early stages of DS's cognitive impairment while overexpression of miR-155 may be related to lipid metabolism changes. Further studies of both miRNAs will shed light on their potential as therapeutic targets to prevent or delay DS's cognitive impairment.
Assuntos
Doença de Alzheimer , MicroRNA Circulante , Síndrome de Down , MicroRNAs , Adulto , Doença de Alzheimer/genética , Cromossomos Humanos Par 21/genética , Síndrome de Down/genética , Humanos , MicroRNAs/genética , MicroRNAs/metabolismoRESUMO
ZO-2 is a peripheral tight junction (TJ) protein whose silencing in renal epithelia induces cell hypertrophy. Here, we found that in ZO-2 KD MDCK cells, in compensatory renal hypertrophy triggered in rats by a unilateral nephrectomy and in liver steatosis of obese Zucker (OZ) rats, ZO-2 silencing is accompanied by the diminished activity of LATS, a kinase of the Hippo pathway, and the nuclear concentration of YAP, the final effector of this signaling route. ZO-2 appears to function as a scaffold for the Hippo pathway as it associates to LATS1. ZO-2 silencing in hypertrophic tissue is due to a diminished abundance of ZO-2 mRNA, and the Sp1 transcription factor is critical for ZO-2 transcription in renal cells. Treatment of OZ rats with metformin, an activator of AMPK that blocks JNK activity, augments ZO-2 and claudin-1 expression in the liver, reduces the paracellular permeability of hepatocytes, and serum bile acid content. Our results suggest that ZO-2 silencing is a common feature of hypertrophy, and that ZO-2 is a positive regulator of the Hippo pathway that regulates cell size. Moreover, our observations highlight the importance of AMPK, JNK, and ZO-2 as therapeutic targets for blood-bile barrier dysfunction.
Assuntos
Proteínas Quinases Ativadas por AMP , Fígado Gorduroso , Proteína da Zônula de Oclusão-2/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Via de Sinalização Hippo , Hipertrofia , Ratos , Ratos Zucker , Proteínas de Junções ÍntimasRESUMO
Stem cell technology is a powerful tool ready to respond to the needs of modern medicine that is experiencing rapid technological development. Given its potential in therapeutic applications, intellectual property rights (IPR) as a protection resource of knowledge are a relevant topic. Patent eligibility of stem cells has been controversial as restrictions to access the fundamental technologies open a gap between research and clinic. Therefore, we depicted the current patent landscape in the field to discuss if this approach moves forward in closing this breach by examining patent activity over the last decade from a transdisciplinary perspective. Stem cell therapeutic applications is an area of continuous growth where patent filing through the PCT is the preferred strategy. Patenting activity is concentrated in the USA, European Union, and Australia; this accumulation in a few key players leads to governance, regulation, and inequality concerns. To boost wealthiness and welfare in society - stem cell therapies' ultimate goal - while at post-pandemic recovery, critical elements in the field of IPR rise to overcome current limitations: to promote bridge builders able to connect the research and business worlds, regulatory updates, novel financing models, new vehicles (startups, spinouts, and spin-offs), and alternative figures of intellectual property.
Assuntos
Propriedade Intelectual , Células-Tronco , Comércio , Tecnologia , Terapia Baseada em Transplante de Células e TecidosRESUMO
BACKGROUND: Identifying a potential single monogenetic disorder in healthy couples is costly due to the Assisted Reproduction facilities' current methodology for screening, which focuses on the detecting multiple genetic disorders at once. Here, we report the successful application of a low-cost and fast preimplantation genetic testing for monogenic/single gene defects (PGT-M) approach for detecting propionic acidemia (PA) in embryos obtained from a confirmed heterozygous propionyl-CoA carboxylase alpha subunit (PCCA) couple. CASE SUMMARY: A fertile 32-years old Mexican couple with denied consanguinity sought antenatal genetic counseling. They were suspected obligate PA carriers due to a previous deceased PA male newborn with an unknown PCCA/propionyl-CoA carboxylase beta subunit (PCCB) genotype. Next-Generation Sequencing revealed a heterozygous genotype for a pathogenic PCCA variant (c.2041-1G>T, ClinVar:RCV000802701.1; dbSNP:rs1367867218) in both parents. The couple requested in vitro fertilization (IVF) and PGT-M for PA. From IVF, 12 oocytes were collected and fertilized, of which two resulted in high-quality embryos. Trophectoderm biopsies and Whole Genome Amplification by a fragmentation/amplification-based method were performed and revealed that the two embryos were euploid. End-point polymerase chain reaction and further Sanger sequencing of the exon-intron borders revealed a wild-type PCCA male embryo and a heterozygous c.2041-1G>T female embryo. Both embryos were transferred, resulting in a clinical pregnancy and the delivery of a healthy male newborn (38 wk, weight: 4080 g, length: 49 cm, APGAR 9/9). The absence of PA was confirmed by expanded newborn screening. CONCLUSION: We show that using PGT-M with Whole Genome Amplification templates, coupled with IVF, can reduce the transmission of a pathogenic variant of the PCCA gene.
RESUMO
The presence of tight junction protein zonula occludens 2 (ZO-2) at the nucleus inhibits the transcription of genes regulated by TEAD transcription factor. Here, we analyzed whether the movement of ZO-2 into the nucleus modulates the nuclear concentration of TEAD. In sparse cultures of ZO-2 knockdown Madin-Darby canine kidney cells, nuclear TEAD was diminished, as in parental cells transfected with a ZO-2 construct without nuclear localization signals, indicating that ZO-2 facilitates the entry of TEAD into the nucleus. Inhibition of nPKCδ in parental cells triggers the interaction between ZO-2 and TEAD at the cytoplasm and facilitates TEAD/ZO-2 complex nuclear importation. Using proximity ligation, immunoprecipitation, and pull-down assays, TEAD/ZO-2 interaction was confirmed. Nuclear TEAD is phosphorylated, and its exit in parental cells is enhanced by activation of a ZO-2 nuclear exportation signal by nPKCε, while the nuclear accumulation of ZO-2 triggered by the mutation of ZO-2 nuclear export signals induces no change in TEAD nuclear concentration. In summary, our results indicate that the movements of ZO-2 in and out of the nucleus modulate the intracellular traffic of TEAD through a process regulated by nPKCδ and ε and provide a novel role of ZO-2 as a nuclear translocator of TEAD.
Assuntos
Núcleo Celular/metabolismo , Células Epiteliais/metabolismo , Fatores de Transcrição de Domínio TEA/metabolismo , Proteína da Zônula de Oclusão-2/metabolismo , Animais , Linhagem Celular , Cães , Células HEK293 , Humanos , Sinais de Localização Nuclear , Fosforilação , Ligação Proteica , Proteína Quinase C-épsilon/metabolismo , Processamento de Proteína Pós-Traducional , Transporte Proteico , Ratos , Transdução de SinaisRESUMO
If methotrexate (MTX) fails to resolve cervical ectopic pregnancies (CEP), the remaining surgical options result in the potential loss of the patient's fertility. Therefore, we examined if the embryo reduction technique can resolve the CEP without any complications while conserving the patient's fertility. We report three cases in which CEP didn't respond to MTX but was successfully solved by embryo reduction. Each patient underwent a standard in vitro fertilization (IVF) protocol. Once CEP was confirmed, the pregnancy's location, the fetus's size and gestational sac and heartbeat were determined. Afterward, embryo reduction was performed under general anesthesia (operative time: ~30 min). All patients had successful procedures without any postoperative complications. Since the procedure, one woman was pregnant and delivered, the second has registered a positive ß-human chorionic gonadotropin test and the last is waiting for IVF preparation. In summary, embryo reduction is a feasible approach in the management of CEP with favorable fertility outcomes.
RESUMO
OBJECTIVE: To improve insulin action, most clinicians prescribe Metformin in patients with insulin resistance (IR). Women with polycystic ovary syndrome (PCOS), in which IR is an important physiopathological mechanism, treatment with Metformin and specialized diets have been suggested to reduce the patient's IR. However, numerous studies have demonstrated conflicting results with respect to supplementing a diet with Metformin. Therefore, we conducted a meta-analysis to determine if Metformin provides a benefit in conjunction with hypocaloric diets to improve insulin sensitivity in PCOS women. METHODS: PubMed, SCOPUS, LILACS, and EBSCO databases and retrieved studies' bibliographies were searched for prospective studies that investigated the effect between Metformin and hypocaloric diets in PCOS women until April 2020. Pre- and post-intervention values for fasting plasma glucose (FPG), fasting plasma insulin (FPI), and IR indices (HOMA1-IR, ISI, and QUICKI) were extracted. Using Comprehensive Meta-Analysis software, the pooled standard difference in the means (SDM) and 95%CIs were calculated. RESULTS: 11 publications (12 studies) were selected. There was not a benefit of adding Metformin to a hypocaloric diet with respect to FPG (SDM= -0.17; 95%CI: -0.48-0.14, p = .28) and FPI (SDM = 0.16; 95%CI: -0.24-0.55, p = .45). None of the IR indices also demonstrated any benefit of using Metformin when a diet intervention was implemented (HOMA1-IR: SDM = 0.28; 95%CI: -0.27-0.84, p = .315; ISI: SDM = 0.344; 95%CI: -0.17-0.85, p = .186; QUICKI: SDM= -0.01; 95%CI: -0.42-0.41, p = .968). CONCLUSION: Here, we determined that adding Metformin to hypocaloric diets did not improve serum glucose or insulin concentrations as well as IR in PCOS women.
Assuntos
Restrição Calórica , Hipoglicemiantes/uso terapêutico , Resistência à Insulina , Metformina/uso terapêutico , Síndrome do Ovário Policístico/tratamento farmacológico , Glicemia , Feminino , Humanos , Insulina/sangue , Síndrome do Ovário Policístico/sangue , Síndrome do Ovário Policístico/dietoterapiaRESUMO
Recurrent implantation failure (RIF), defined as ≥3 failed in vitro fertilization (IVF) cycles with the accumulated transfer of at least five embryos, plague many infertile women. The exact cause is unknown; however, evidence supports the immune system, specifically the Tumor Necrosis Factor (TNF) pathway. Etanercept (a TNFα antagonist) has been shown to improve pregnancy rates in women with rheumatoid arthritis or endometriomas; therefore, this study aimed to determine the effectiveness of etanercept for IVF in RIF women. Eighty-three RIF women were recruited from the Ingenes Institute in Mexico City for this single-arm, prospective study. All patients underwent a similar IVF protocol and received etanercept (4 × 25 mg every 72 h) after endometrial preparation, if applicable, and at embryo transfer. IVF endpoints assessed were embryo implantation (h-ßCG >10 mg/dL at Day 14), the presence of a gestational sac, live birth, and birth weight. All women reported no side-effects associated with the etanercept treatment. 75.9 % of the cohort achieved embryo implantation, 74.7 % developed gestational sacs, and the ongoing pregnancy/live birth rate was at 62.7 %. However, 56.7 % of the live births were preterm (<37 weeks) and 60.5 % of the births were underweight (<2500 g). When stratified by fresh or frozen cycles or by the ova source (patient versus donor), the results were not significantly different with respect to the implantation rate, formation of gestational sacs, and the live birth rate. Here, we showed that using etanercept during endometrial preparation improves IVF outcomes in RIF women.
Assuntos
Implantação do Embrião/efeitos dos fármacos , Endométrio/efeitos dos fármacos , Endométrio/fisiologia , Etanercepte/farmacologia , Fertilização in vitro , Adulto , Anti-Inflamatórios não Esteroides/farmacologia , Implantação do Embrião/fisiologia , Feminino , Humanos , Infertilidade Feminina , Nascido Vivo , Gravidez , Taxa de Gravidez , Estudos ProspectivosRESUMO
BACKGROUND: To determine if a modified ovarian sensitivity index (MOSI), based on initial follicular measurements and the initial follicle-stimulating hormone (FSH) dose, can predict the production of high-quality embryos for successful implantation during in vitro fertilization (IVF). METHODS: This study consisted of two phases: 1) a retrospective study and 2) a prospective observational study. For the first phase, 363 patients charts were reviewed, of which 283 had embryos transferred. All women underwent a standardized antagonist-based IVF protocol. At the first follow-up (Day 3/4), the number and size of the follicles were determined. MOSI was calculated as ln (number follicles (≥6 mm) × 1000 / FSH initial dose). Afterward, the number and quality of the ova, embryo development, and the number and quality of the blastocysts were determined. Embryo implantation was confirmed by ß-hCG. For the second phase, 337 IVF cycles were followed to determine MOSI's accuracy. RESULTS: MOSI could predict the production of ≥4 high-quality embryos by Day 2 (AUC = 0.69, 95%CI:0.63-0.75), ≥2 blastocysts (AUC = 0.74, 95%CI:0.68-0.79), and ≥ 35% rate of blastocyst formation (AUC = 0.65, 95%CI:0.58-0.72). Using linear regression, MOSI was highly associated with the number of ova captured (ß = 5.15), MII oocytes (ß = 4.31), embryos produced (ß = 2.90), high-quality embryos (ß = 0.98), and the blastocyst formation rate (ß = 0.06, p < 0.01). Using logistic regression, MOSI was highly associated with achieving ≥4 high-quality embryos (odds ratio = 2.80, 95%CI:1.90-4.13), ≥2 blastocysts (odds ratio = 3.40, 95%CI:2.33-4.95), and ≥ 35% blastocysts formation rate (odds ratio = 1.96, 95%CI:1.31-2.92). This effect was independent of age, BMI, and antral follicle count. For implantation, MOSI was significantly associated with successful implantation (odds ratio = 1.79, 95%CI:1.25-2.57). For the prospective study, MOSI was highly accurate at predicting ≥6 high-quality embryos on Day 2 (accuracy = 68.5%), ≥6 blastocysts (accuracy = 68.0%), and a blastocyst formation rate of ≥35% (accuracy = 61.4%). CONCLUSION: MOSI was highly correlated with key IVF parameters that are associated with achieved pregnancy. Using this index with antagonist cycles, clinicians may opt to stop an IVF cycle, under the assumption that the cycle will fail to produce good blastocysts, preventing wasting the patient's resources and time.
Assuntos
Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Ovário/fisiologia , Indução da Ovulação/métodos , Adulto , Implantação do Embrião , Feminino , Fertilização in vitro , Humanos , Ovário/efeitos dos fármacos , Gravidez , Taxa de Gravidez , Estudos Prospectivos , Estudos Retrospectivos , Adulto JovemRESUMO
OBJECTIVE: Our objective was to determine whether estradiol (E2) levels (Day 3 and fold change to Day 10), antral follicle count (AFC), and number of ova collected could predict ovarian hyperstimulation syndrome (OHSS) and culdocentesis intervention. METHODS: We conducted a retrospective review of patient charts between January 2008 and December 2017. OHSS was defined using American Society for Reproductive Medicine criteria. Predictability was evaluated by measuring the area under the receiver operating characteristic curve (AUC). RESULTS: The cohort included 319 women (166 controls, 153 OHSS, of whom 54 had severe OHSS). The OHSS group had higher E2Day 3 (249 ± 177 vs. 150 ± 230 ng/L), E2FoldChange (32.2 ± 29.1 vs. 20.1 ± 23.8), AFC (18.2 ± 9.1 vs. 11.6 ± 8.3), and number of ova collected (21.1 ± 9.0 vs. 10.1 ± 6.5). E2Day 3 (AUC = 0.76, 95%CI: 0.71-0.82), E2FoldChange (AUC = 0.71, 95%CI: 0.65-0.77), AFC (AUC = 0.75, 95%CI: 0.70-0.81), and number of ova collected (AUC = 0.85, 95%CI: 0.81-0.89) were predictive for OHSS. All variables were predictive for culdocentesis intervention (E2Day 3: AUC = 0.63, 95%CI: 0.55-0.70; E2FoldChange: AUC = 0.63, 95%CI: 0.55-0.71; AFC: AUC = 0.74, 95%CI: 0.68-0.80; number of ova collected: AUC = 0.80, 95%CI: 0.75-0.85). CONCLUSIONS: Day 3 E2 levels and number of ova collected predict patients who could develop OHSS and may require culdocentesis.