Oestrogen treatment restores dentate gyrus development in premature newborns by IGF1 regulation.

Prematurely-born infants cared for in the neonatal units suffer from memory and learning deficits. Prematurity diminishes neurogenesis and synaptogenesis in the hippocampal dentate gyrus (DG). This dysmaturation of neurons is attributed to elevated PSD95, NMDR2A, and IGF1 levels. Since oestrogen treatment plays key roles in the development and plasticity of DG, we hypothesized that 17ß-estradiol (E2) treatment would ameliorate neurogenesis and synaptogenesis in the DG, reversing cognitive deficits in premature newborns. Additionally, E2-induced recovery would be mediated by IGF1 signalling. These hypotheses were tested in a rabbit model of prematurity and nonmaternal care, in which premature kits were gavage-fed and reared by laboratory personnel. We compared E2- and vehicle-treated preterm kits for morphological, molecular, and behavioural parameters. We also treated kits with oestrogen degrader, RAD1901, and assessed IGF1 signalling. We found that E2 treatment increased the number of Tbr2+ and DCX+ neuronal progenitors and increased the density of glutamatergic synapses in the DG. E2 treatment restored PSD95 and NMDAR2A levels and cognitive function in preterm kits. Transcriptomic analyses showed that E2 treatment contributed to recovery by influencing interactions between IGF1R and neurodegenerative, as well as glutamatergic genes. ERα expression was reduced on completion of E2 treatment at D7, followed by D30 elevation. E2-induced fluctuation in ERα levels was associated with a reciprocal elevation in IGF1/2 expression at D7 and reduction at D30. ERα degradation by RAD1901 treatment enhanced IGF1 levels, suggesting ERα inhibits IGF1 expression. E2 treatment alleviates the prematurity-induced maldevelopment of DG and cognitive dysfunctions by regulating ERα and IGF1 levels.

Effects of myo-inositol plus folic acid on ovarian morphology and oocyte quality in PCOS mouse model.

Although the role of myo-inositol (MYO) in promoting the oocyte quality of PCOS patients has been documented in human studies; the cellular effects of this supplement on oocytes have not been directly examined due to ethical limitations. In the first phase of this study, MYO dosimetry was carried out simultaneously with the PCOS model development. An effective dose was obtained following the assessment of fasting insulin and testosterone levels using ELISA and ovarian morphology appraisal by histopathology. In the second phase, following the continuous administration of the effective dose of MYO and dehydroepiandrosterone (DHEA), cellular evaluation was performed. The quality of oocytes from superovulation was analyzed by examining maturity and normal morphology percentage using a stereomicroscope, intracellular reactive oxygen species (ROS) and glutathione (GSH) levels using fluorometry, and ATP count evaluation using ELISA. The results revealed that, among the four different MYO concentrations, the 0.36 mg/g dose compared with the DHEA group reduced testosterone levels and large atretic antral follicles (LAtAnF) diameter. This dose also increased the corpus luteum count and the granulosa:theca (G/T)layer thickness ratio in antral follicles. Furthermore, this dose increased mature oocytes and normal morphology percentage, ATP count, and GSH levels; however, it decreased ROS levels in mature oocytes. Our findings provide the grounds for further cellular and molecular studies on the PCOS mouse model, suggesting that the improvement in mitochondrial function and its antioxidant properties is probably one of the mechanisms by which MYO increases oocyte quality.

Does Gold-Silver Core-Shell Nanostructure with Alginate Coating Induce Apoptosis in Human Lymphoblastic Tumoral (Jurkat) Cell Line?

Background: T-cell acute lymphoblastic leukemia (T-ALL) is known as an aggressive malignant disease resulting from the neoplastic alteration of T precursor cells. Although treatment with stringent chemotherapy regimens has achieved an 80% cure rate in children, it has been associated with lower success rates in adult treatment. Silver nanoparticles (Ag-NPs) have a toxic effect on human breast cancer cells, human glioblastoma U251 cells, and chronic myeloid leukemia cells in vitro. This study aimed to investigate the effect of Ag nanostructures (Ag-NSs) on Jurkat cells' viability and apoptosis. Methods: The Jurkat cell line was acquired. Following the synthesis Ag-NSs and their characterization, they were incubated with Jurkat cells at different doses for 24, 48, and 72 hours to determine the optimal time and dose. Two groups were examined: a control group with Jurkat cells without nanostructure maintained in the same medium as the cells in the treatment group without changing the medium, and a treatment group with cells treated with the Ag nanostructure solution at a dose of 75 µg/ml for 48 hours according to the MTT results. After 48 hours, the cells from the two groups were used for the q RT-PCR of the apoptotic genes (BAX, BCL-2, and CASPASE-3). Results: According to our results, the rod-shaped silver nanostructures had a size of about 50 nm, increased apoptotic markers, including BAX and CASPASE-3, and induced cell death. Conclusions: Ag-NSs have anticancer properties and can induce apoptosis of cells; therefore, they may be a potential candidate for the treatment of T-cell acute lymphoblastic leukemia.

Demographic and socioeconomic disparities of pituitary adenomas and carcinomas in the United States.

INTRODUCTION: Growth of some pituitary tumors is driven by hormones which vary in concentration along the lines of patient socioeconomic status. Thus, pituitary tumors may exhibit disparities in incidence upon stratification by socioeconomic variables. Exploring for these disparities could provide direction in tumor etiology elucidation and identification of healthcare inequalities. METHODS: To investigate pituitary adenoma and carcinoma incidence (per 100,000) with respect to sex, age, income, residence, and race/ethnicity, we searched the largest American administrative dataset (1997-2016), the National (Nationwide) Inpatient Sample (NIS), which surveys 20% of United States (US) discharges. RESULTS: Annual national incidence was 2.80 for adenomas and 0.046 for carcinomas. For adenomas, males had an incidence of 2.63, similar (p = 0.17) to females at 2.78; likewise, for carcinomas, males had a statistically equivalent (p = 0.24) incidence at 0.051 to females at 0.041. Amongst age groups, for adenomas incidence progressively rose, peaking 65-84 years old (6.12), before declining. For adenomas and carcinomas respectively, patients with low income had an incidence of 2.66 and 0.044, similar (p = 0.11; p = 0.72) to the 3.01 and 0.041 of middle/high income patients. Incidence was greatest for adenomas amongst urban centers (3.47), followed by rural (3.16) and suburban (3.01) communities. Examining race/ethnicity (p = 0.0000016), for adenomas, incidences amongst Blacks, Asian/Pacific Islanders, Hispanics, and Whites were as follows, respectively: 3.64, 2.57, 2.54, 2.44. Annually, incidence for adenomas was increasing (τ = 0.63, p = 0.00021), but decreasing (τ = -0.60, p = 0.00085) for carcinomas. Specifically, for carcinomas incidence was only decreasing for females and the middle/high income. CONCLUSION: In the US, time-enduring healthcare disparities were identified for pituitary adenomas and carcinomas, against the background of sociodemographic strata. For carcinomas, annual incidence was declining only for middle/high income patients and females, which supporting prior investigations that low income patients and males are experiencing barriers to definitive treatment for pituitary adenomas. Incidence was also found to be greatest Blacks and urban residents.

Demographic and socioeconomic disparities of benign cerebral meningiomas in the United States.

Epidemiology provides an avenue for deciphering disease pathogenesis. By determining incidence across socioeconomic and demographic variables in the context of benign cerebral meningiomas (BCM), epidemiologic data may aid in elucidating and addressing healthcare inequalities. To investigate BCM incidence (per 100,000) with respect to sex, age, income, residence, and race/ethnicity, we queried the largest United States (US) administrative dataset (1997-2016), the National (Nationwide) Inpatient Sample (NIS), which surveys 20% of US discharges. Annual national BCM incidence was 5.01. Females had an incidence of 6.78, higher (p = 0.0000038) than males at 3.14. Amongst age groups incidence varied (p = 1.65 × 10-11) and was highest amongst those 65-84 (16.71) and 85+ (18.32). Individuals with middle/high income had an incidence of 5.27, higher (p = 0.024) than the 4.91 of low income patients. Depending on whether patients lived in urban, suburban, or rural communities, incidence varied (χ2 = 8.22, p = 0.016) as follows, respectively: 5.23; 4.96; 5.51. Amongst race/ethnicity (p = 8.15 × 10-14), incidence for Whites, Blacks, Asian/Pacific Islanders, Hispanics, and Native Americans were as follows, respectively: 5.05; 4.59; 4.22; 2.99; 0.55. In the US, BCM annual incidence exhibited disparities amongst socioeconomic and demographic subsets. Disproportionately, incidence was greatest for patients who were White, Black, female, 65 and older, and middle/high income.

Demographic and socioeconomic disparities of benign and malignant spinal meningiomas in the United States.

INTRODUCTION: Spinal meningiomas constitute the majority of primary spinal neoplasms, yet their pathogenesis remains elusive. By investigating the distribution of these tumors across sociodemographic variables can provide direction in etiology elucidation and healthcare disparity identification. METHODS: To investigate benign and malignant spinal meningioma incidences (per 100,000) with respect to sex, age, income, residence, and race/ethnicity, we queried the largest American administrative dataset (1997-2016), the National (Nationwide) Inpatient Sample (NIS), which surveys 20% of United States (US) discharges. RESULTS: Annual national incidence was 0.62 for benign tumors and 0.056 for malignant. For benign meningiomas, females had an incidence of 0.81, larger (P=0.000004) than males at 0.40; yet for malignant meningiomas, males had a larger (P=0.006) incidence at 0.062 than females at 0.053. Amongst age groups, peak incidence was largest for those 65-84 years old (2.03) in the benign group, but 45-64 years old (0.083) for the malignant group. For benign and malignant meningiomas respectively, individuals with middle/high income had an incidence of 0.67 and 0.060, larger (P=0.000008; P=0.04) than the 0.48 and 0.046 of low income patients. Incidences were statistically similar (P=0.2) across patient residence communities. Examining race/ethnicity (P=0.000003) for benign meningiomas, incidences for Whites, Asian/Pacific Islanders, Hispanics, and Blacks were as follows, respectively: 0.83, 0.42, 0.28, 0.15. CONCLUSIONS: Across sociodemographic strata, healthcare inequalities were identified with regards to spinal meningiomas. For benign spinal meningiomas, incidence was greatest for patients who were female, 65-84 years old, middle/high income, living in rural communities, White, and Asian/Pacific Islander. Meanwhile, for malignant spinal meningiomas incidence was greatest for males, those 45-65 years old, and middle/high income.

Estrogen Treatment Reverses Prematurity-Induced Disruption in Cortical Interneuron Population.

Development of cortical interneurons continues until the end of human pregnancy. Premature birth deprives the newborns from the supply of maternal estrogen and a secure intrauterine environment. Indeed, preterm infants suffer from neurobehavioral disorders. This can result from both preterm birth and associated postnatal complications, which might disrupt recruitment and maturation of cortical interneurons. We hypothesized that interneuron subtypes, including parvalbumin-positive (PV+), somatostatin-positive (SST+), calretinin-positive (CalR+), and neuropeptide Y-positive (NPY+) interneurons, were recruited in the upper and lower cortical layers in a distinct manner with advancing gestational age. In addition, preterm birth would disrupt the heterogeneity of cortical interneurons, which might be reversed by estrogen treatment. These hypotheses were tested by analyzing autopsy samples from premature infants and evaluating the effect of estrogen supplementation in prematurely delivered rabbits. The PV+ and CalR+ neurons were abundant, whereas SST+ and NPY+ neurons were few in cortical layers of preterm human infants. Premature birth of infants reduced the density of PV+ or GAD67+ neurons and increased SST+ interneurons in the upper cortical layers. Importantly, 17 ß-estradiol treatment in preterm rabbits increased the number of PV+ neurons in the upper cortical layers relative to controls at postnatal day 14 (P14) and P21 and transiently reduced SST population at P14. Moreover, protein and mRNA levels of Arx, a key regulator of cortical interneuron maturation and migration, were higher in estrogen-treated rabbits relative to controls. Therefore, deficits in PV+ and excess of SST+ neurons in premature newborns are ameliorated by estrogen replacement, which can be attributed to elevated Arx levels. Estrogen replacement might enhance neurodevelopmental outcomes in extremely preterm infants.SIGNIFICANCE STATEMENT Premature birth often leads to neurodevelopmental delays and behavioral disorders, which may be ascribed to disturbances in the development and maturation of cortical interneurons. Here, we show that preterm birth in humans is associated with reduced population of parvalbumin-positive (PV+) neurons and an excess of somatostatin-expressing interneurons in the cerebral cortex. More importantly, 17 ß-estradiol treatment increased the number of PV+ neurons in preterm-born rabbits, which appears to be mediated by an elevation in the expression of Arx transcription factor. Hence the present study highlights prematurity-induced reduction in PV+ neurons in human infants and reversal in their population by estrogen replacement in preterm rabbits. Because preterm birth drops plasma estrogen level 100-fold, estrogen replacement in extremely preterm infants might improve their developmental outcome and minimize neurobehavioral disorders.

Disruption of Interneuron Neurogenesis in Premature Newborns and Reversal with Estrogen Treatment.

Many Preterm-born children suffer from neurobehavioral disorders. Premature birth terminates the hypoxic in utero environment and supply of maternal hormones. As the production of interneurons continues until the end of pregnancy, we hypothesized that premature birth would disrupt interneuron production and that restoration of the hypoxic milieu or estrogen treatment might reverse interneuron generation. To test these hypotheses, we compared interneuronal progenitors in the medial ganglionic eminences (MGEs), lateral ganglionic eminences (LGEs), and caudal ganglionic eminences (CGEs) between preterm-born [born on embryonic day (E) 29; examined on postnatal day (D) 3 and D7] and term-born (born on E32; examined on D0 and D4) rabbits at equivalent postconceptional ages. We found that both total and cycling Nkx2.1+, Dlx2+, and Sox2+ cells were more abundant in the MGEs of preterm rabbits at D3 compared with term rabbits at D0, but not in D7 preterm relative to D4 term pups. Total Nkx2.1+ progenitors were also more numerous in the LGEs of preterm pups at D3 compared with term rabbits at D0. Dlx2+ cells in CGEs were comparable between preterm and term pups. Simulation of hypoxia by dimethyloxalylglycine treatment did not affect the number of interneuronal progenitors. However, estrogen treatment reduced the density of total and proliferating Nkx2.1+ and Dlx2+ cells in the MGEs and enhanced Ascl1 transcription factor. Estrogen treatment also reduced Ki67, c-Myc, and phosphorylation of retinoblastoma protein, suggesting inhibition of the G1-to-S phase transition. Hence, preterm birth disrupts interneuron neurogenesis in the MGE and estrogen treatment reverses interneuron neurogenesis in preterm newborns by cell-cycle inhibition and elevation of Ascl1. We speculate that estrogen replacement might partially restore neurogenesis in human premature infants.SIGNIFICANCE STATEMENT Prematurity results in developmental delays and neurobehavioral disorders, which might be ascribed to disturbances in the development of cortical interneurons. Here, we show that preterm birth disrupts interneuron neurogenesis in the medial ganglionic eminence (MGE) and, more importantly, that estrogen treatment reverses this perturbation in the population of interneuron progenitors in the MGE. The estrogen seems to restore neurogenesis by inhibiting the cell cycle and elevating Ascl1 expression. As preterm birth causes plasma estrogen level to drop 100-fold, the estrogen replacement in preterm infants is physiological. We speculate that estrogen replacement might ameliorate disruption in production of interneurons in human premature infants.