Age-related uterine and ovarian hypertrophy in FSH receptor knockout and FSHbeta subunit knockout mice

Female mice in which the gene encoding the follicle-stimulating hormone FSH receptor (FSHR) knockout (KO) or its ligand (FSHbetaKO) have been disrupted were infertile. Ovaries of these mice were significantly smaller than those of heterozygous littermates but significantly larger than those of hypogonadal mice of the same age. Uterine masses in all three mutants were <6 mg, significantly reduced compared with heterozygous mice. At 1 year of age uterine mass had increased to >12 mg in 63% of FSHRKO females and 88% of FSHbetaKO females. Despite the increase in uterine size there was no evidence of contractility: uteri were flaccid and unresponsive to electrical or pharmacological stimulation. In most females in which uterine growth had occurred there was evidence of ovarian growth with hypertrophy of the interstitial tissue, occurrence of ovarian cysts and epithelial and tubular inclusions. There was no evidence of uterine or ovarian hypertrophy in hypogonadal (hpg) mice at any age or in 1 year old females in which the FSH mutations were bred onto the hpg background. There was an inverse correlation of plasma LH concentrations and uterine mass in 1 year old mutant females with uterine hypertrophy. Ovariectomy of both FSHRKO and FSHbetaKO females with large uteri resulted in decreased uterine mass and increased plasma concentration of LH. The number of mice with ovarian pathology, reminiscent of the serous ovarian adenocarcinomas found in humans, was significantly greater in the FSHbetaKO mice, indicating that the presence of an intact FSH receptor on ovarian cells of FSHbetaKO females may allow constitutive basal stimulation of the ovary, which is absent in mice lacking FSH receptors.

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Genetic and Biochemical Markers of Ovarian Function and Their Impact on Women Reproductive Status

Revista de Chimie ◽

10.37358/rc.20.10.8365 ◽

2020 ◽

Vol 71 (10) ◽

pp. 212-217

Author(s):

Adina-Elena Tanase ◽

Roxana Popescu ◽

Mircea Onofriescu ◽

Roxana Daniela Matasariu

Keyword(s):

Ovarian Function ◽

Rflp Analysis ◽

Fsh Receptor ◽

Gene Encoding ◽

Female Population ◽

Fshr Gene ◽

Pcr Rflp ◽

Regulation Mechanisms ◽

American Society ◽

Dependent Mechanism

Endometriosis is a disease very common nowadays affecting 1-2% of the female population, by estrogen-dependent mechanism. The identification of mutations in the gene encoding for the FSH receptor (FSHR) has been reported since 1995. Physiology teaches us that follicle-stimulating hormone (FSH) is a hormone that is vital in the steroidogenesis regulation mechanisms, while FSH receptor (FSHR) activation helps to promote folliculogenesis and estrogensynthesis. Therefore, studies to show if there are any correlations between endometriosis and FSHR are acquired. Genotyping of FSHR gene polymorphisms were performed using PCR - Restriction Fragment Length Polymorphism (PCR-RFLP) analysis. We analysed a total of 78 patients, 44 infertile patients with endometriosis and 34 controls (non-infertile, pregnant patients). The endometriosis group included women with diagnosis of endo-metriosis confirmed by laparoscopy and /or laparotomy and histological evidence of disease with the endometriosis staging according to American Society for Reproductive Medicine (ASRM). Corroborated with the severity of endometriosis, A919G and A2039G tests found that 71.4% of the M (GG) results were associated with primary infertility, not statistically significant (p=0.994) and 42.9% of the total M results had moderate or severe forms of endometriosis (p = 0.185). The genetic involvement in different pathologies such as endometriosis, has yet to be understood, but knowing more about its mechanism, will help physician target the disease at a more profound level.

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IκBα targeting promotes oxidative stress-dependent cell death

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-01921-x ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Giovanna Carrà ◽

Giuseppe Ermondi ◽

Chiara Riganti ◽

Luisella Righi ◽

Giulia Caron ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Fate ◽

Protein Interactions ◽

In Silico ◽

Inverse Correlation ◽

Ros Production ◽

Gene Encoding ◽

Specific Expression ◽

Novel Approach ◽

Stress Dependent

Abstract Background Oxidative stress is a hallmark of many cancers. The increment in reactive oxygen species (ROS), resulting from an increased mitochondrial respiration, is the major cause of oxidative stress. Cell fate is known to be intricately linked to the amount of ROS produced. The direct generation of ROS is also one of the mechanisms exploited by common anticancer therapies, such as chemotherapy. Methods We assessed the role of NFKBIA with various approaches, including in silico analyses, RNA-silencing and xenotransplantation. Western blot analyses, immunohistochemistry and RT-qPCR were used to detect the expression of specific proteins and genes. Immunoprecipitation and pull-down experiments were used to evaluate protein-protein interactions. Results Here, by using an in silico approach, following the identification of NFKBIA (the gene encoding IκBα) amplification in various cancers, we described an inverse correlation between IκBα, oxidative metabolism, and ROS production in lung cancer. Furthermore, we showed that novel IκBα targeting compounds combined with cisplatin treatment promote an increase in ROS beyond the tolerated threshold, thus causing death by oxytosis. Conclusions NFKBIA amplification and IκBα overexpression identify a unique cancer subtype associated with specific expression profile and metabolic signatures. Through p65-NFKB regulation, IκBα overexpression favors metabolic rewiring of cancer cells and distinct susceptibility to cisplatin. Lastly, we have developed a novel approach to disrupt IκBα/p65 interaction, restoring p65-mediated apoptotic responses to cisplatin due to mitochondria deregulation and ROS-production.

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Cortical Thinning Associated with Age and CSF Biomarkers in Early Parkinson’s Disease Is Modified by the SNCA rs356181 Polymorphism

Neurodegenerative Diseases ◽

10.1159/000493103 ◽

2018 ◽

Vol 18 (5-6) ◽

pp. 233-238

Author(s):

Frederic Sampedro ◽

Juan Marín-Lahoz ◽

Saul Martínez-Horta ◽

Javier Pagonabarraga ◽

Jaime Kulisevsky

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cognitive Decline ◽

De Novo ◽

Brain Regions ◽

Cortical Atrophy ◽

Csf Biomarkers ◽

Gene Encoding ◽

Cortical Thinning ◽

Age Related

The role of cerebrospinal fluid (CSF) biomarkers such as CSF α-synuclein and CSF tau in predicting cognitive decline in Parkinson’s disease (PD) continues to be inconsistent. Here, using a cohort of de novo PD patients with preserved cognition from the Parkinson’s Progression Markers Initiative (PPMI), we show that the SNCA rs356181 single nucleotide polymorphism (SNP) modulates the effect of these CSF biomarkers on cortical thinning. Depending on this SNP’s genotype, cortical atrophy was associated with either higher or lower CSF biomarker levels. Additionally, this SNP modified age-related atrophy. Importantly, the integrity of the brain regions where this phenomenon was observed correlated with cognitive measures. These results suggest that this genetic variation of the gene encoding the α-synuclein protein, known to be involved in the development of PD, also interferes in its subsequent neurodegeneration. Overall, our findings could shed light on the so far incongruent association of common CSF biomarkers with cognitive decline in PD.

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Inverse Correlation Between Alzheimer’s Disease and Cancer: Short Overview

Molecular Neurobiology ◽

10.1007/s12035-021-02544-1 ◽

2021 ◽

Author(s):

Agnieszka Zabłocka ◽

Wioletta Kazana ◽

Marta Sochocka ◽

Bartłomiej Stańczykiewicz ◽

Maria Janusz ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Kinase Inhibitor ◽

Fungal Infections ◽

Neurological Diseases ◽

Inverse Correlation ◽

Biological Mechanisms ◽

Age Related ◽

Common Risk Factors

AbstractThe negative association between Alzheimer’s disease (AD) and cancer suggests that susceptibility to one disease may protect against the other. When biological mechanisms of AD and cancer and relationship between them are understood, the unsolved problem of both diseases which still touches the growing human population could be overcome. Actual information about biological mechanisms and common risk factors such as chronic inflammation, age-related metabolic deregulation, and family history is presented here. Common signaling pathways, e.g., p53, Wnt, role of Pin1, and microRNA, are discussed as well. Much attention is also paid to the potential impact of chronic viral, bacterial, and fungal infections that are responsible for the inflammatory pathway in AD and also play a key role to cancer development. New data about common mechanisms in etiopathology of cancer and neurological diseases suggests new therapeutic strategies. Among them, the use of nilotinib, tyrosine kinase inhibitor, protein kinase C, and bexarotene is the most promising.

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A Novel Missense Mutation in the Gene Encoding Major Intrinsic Protein (MIP) in a Giant Panda with Unilateral Cataract Formation

10.21203/rs.3.rs-30524/v3 ◽

2020 ◽

Author(s):

Chao Bai ◽

Yuyan You ◽

Xuefeng Liu ◽

Maohua Xia ◽

Wei Wang ◽

...

Keyword(s):

Missense Mutation ◽

Conformational Changes ◽

Giant Panda ◽

Ailuropoda Melanoleuca ◽

Major Intrinsic Protein ◽

Gene Encoding ◽

Functional Candidate Gene ◽

Intrinsic Protein ◽

Age Related ◽

Unilateral Cataract

Abstract Background: Cataracts are defects of the lens that cause progressive visual impairment and ultimately blindness in many vertebrate species. Most cataracts are age-related, but up to one third have an underlying genetic cause. Cataracts are common in captive zoo animals, but it is often unclear whether these are congenital or acquired (age-related) lesions. Results: Here we used a functional candidate gene screening approach to identify mutations associated with cataracts in a captive giant panda (Ailuropoda melanoleuca). We screened 11 genes often associated with human cataracts and identified a novel missense mutation (c.686G>A) in the MIP gene encoding major intrinsic protein. This is expressed in the lens and normally accumulates in the plasma membrane of lens fiber cells, where it plays an important role in fluid transport and cell adhesion. The mutation causes the replacement of serine with asparagine (p.S229N) in the C-terminal tail of the protein, and modeling predicts that the mutation induces conformational changes that may interfere with lens permeability and cell–cell interactions.Conclusion: The c.686G>A mutation was found in a captive giant panda with a unilateral cataract but not in 18 controls from diverse regions in China, suggesting it is most likely a genuine disease-associated mutation rather than a single-nucleotide polymorphism. The mutation could therefore serve as a new genetic marker to predict the risk of congenital cataracts in captive giant pandas.

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Children with type 1 diabetes of early age at onset – immune and metabolic phenotypes

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2019-0103 ◽

2019 ◽

Vol 32 (9) ◽

pp. 935-941

Author(s):

Madalena Sales Luis ◽

Margarida Alcafache ◽

Sara Ferreira ◽

Ana Laura Fitas ◽

Joana Simões Pereira ◽

...

Keyword(s):

Type 1 Diabetes ◽

Age At Onset ◽

Disease Onset ◽

Inverse Correlation ◽

Early Age ◽

Insulin Requirements ◽

Age Related ◽

One Year ◽

Immune Imbalance

Abstract Objectives We aimed to evaluate children with type 1 diabetes (T1D) with early age at onset (EAO) for clinical, immune and metabolic features in order to identify age-related disease phenotypes. Methods Comparative study of two groups of T1D children: EAO (≤5 years) and later age at onset (LAO; >5 years), regarding the presence of other autoimmune (AI) diseases, diabetes ketoacidosis and immunologic profile at onset and metabolic data 1 year after diagnosis. Statistical analysis was performed with significance set for p < 0.05. Results The study included 137 children (EAO = 52, mean age 3.6 ± 1.5 [mean ± standard deviation (SD)] and LAO = 85, mean age 10.4 ± 2.9). EAO was more associated with concomitant AI diseases (p = 0.032). Despite no differences in disease onset, EAO presented with lower C-peptide levels (p = 0.01) and higher absolute lymphocyte number (p < 0.0001), with an inverse correlation between these two variables (p = 0.028). Additionally, the EAO group had a higher frequency of serum detection of three antibodies (Abs) (p = 0.0008), specifically insulin Abs (p = 0.0001). One year after diagnosis, EAO had higher total daily insulin (TDI) dose (p = 0.008), despite similar hemoglobin A1c (HbA1c). Conclusions Our data show an association of EAO T1D with more AI diseases, higher number of Abs, lower initial insulin reservoir and higher insulin requirements 1 year after diagnosis. In this group, immune imbalance seems more evident and disease progression faster, probably reflecting distinct “immune environment” with different ages at disease onset. Further studies in the field of immunogenetics and immune tolerance are required, to improve patient stratification and find novel targets for therapeutic intervention.

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Contributing Determinants to Hearing Loss in Elderly Men and Women: Results from the Population-Based Rotterdam Study

Audiology and Neurotology ◽

10.1159/000448348 ◽

2016 ◽

Vol 21 (Suppl. 1) ◽

pp. 10-15 ◽

Cited By ~ 11

Author(s):

Stephanie C. Rigters ◽

Mick Metselaar ◽

Marjan H. Wieringa ◽

Robert J. Baatenburg de Jong ◽

Albert Hofman ◽

...

Keyword(s):

Hearing Loss ◽

High Frequency ◽

Pure Tone Audiometry ◽

Inverse Correlation ◽

Population Based ◽

Rotterdam Study ◽

Cross Sectional ◽

Men And Women ◽

Age Related ◽

Age Related Hearing Loss

To contribute to a better understanding of the etiology in age-related hearing loss, we carried out a cross-sectional study of 3,315 participants (aged 52-99 years) in the Rotterdam Study, to analyze both low- and high-frequency hearing loss in men and women. Hearing thresholds with pure-tone audiometry were obtained, and other detailed information on a large number of possible determinants was collected. Hearing loss was associated with age, education, systolic blood pressure, diabetes mellitus, body mass index, smoking and alcohol consumption (inverse correlation). Remarkably, different associations were found for low- and high-frequency loss, as well as between men and women, suggesting that different mechanisms are involved in the etiology of age-related hearing loss.

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Differential impact of osteoporosis, sarcopenia and obesity on physical performance in aging men

Endocrine Connections ◽

10.1530/ec-20-0580 ◽

2021 ◽

Author(s):

Franca Genest ◽

Michael Schneider ◽

Andreas Zehnder ◽

Dominik Lieberoth-Leden ◽

Lothar Seefried

Keyword(s):

Physical Performance ◽

Descriptive Analysis ◽

Functional Decline ◽

Inverse Correlation ◽

Community Dwelling ◽

Cross Sectional ◽

Skeletal Muscle Index ◽

Age Related ◽

Aging Men ◽

Prevalence Of Osteoporosis

Purpose: Aging and concurrent constitutional changes as sarcopenia, osteoporosis and obesity are associated with progressive functional decline. Coincidence and mutual interference of this risk factors require further evaluation. Methods: Cross-sectional evaluation of musculoskeletal health in a community-dwelling cohort of men aged 65-90 years. Objectives included descriptive analysis of age-related decline in physical performance, prevalence of osteoporosis (FRAX-Score), sarcopenia (EWGSOP criteria) and obesity (BMI>30kg/m²) and their coincidence/interference. Results: Based on 507 participants assessed, aging was associated with progressive functional deterioration, regarding power (Chair Rise Test -1.54% per year), performance (Usual Gait Speed -1.38 % per year) and muscle force (Grip Strength -1.52 % per year) while muscle mass declined only marginally (Skeletal Muscle Index -0.29% per year). Prevalence of osteoporosis was 41.8% (n=212) while only 22.9% (n=116) of the participants met the criteria for sarcopenia and 23.7% (n=120) were obese. Osteosarcopenia was found in n=79 (15.6%), sarcopenic obesity was present in 14 men (2.8%). A combination of all three conditions could be confirmed in n=8 (1.6%). There was an inverse correlation of BMI with physical performance whereas osteoporosis and sarcopenia did not interfere with functional outcomes. Conclusion: Based on current definitions there is considerable overlap in the prevalence of osteoporosis and sarcopenia, while obesity appears to be a distinct problem. Functional decline appears to be associated with obesity rather than osteoporosis or sarcopenia. It remains to be determined to what extend obesity itself causes performance deficits or if obesity is merely an indicator of insufficient activity eventually predisposing to functional decline.

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Age-Decline in the Activity of the Plasma Membrane Ca2+ Pump (PMCA) of Normal Human Red Blood Cells (RBCs).

Blood ◽

10.1182/blood.v106.11.1670.1670 ◽

2005 ◽

Vol 106 (11) ◽

pp. 1670-1670

Author(s):

Robert M. Bookchin ◽

Nuala Daw ◽

Zipora Etzion ◽

Teresa Tiffert ◽

Virgilio L. Lew

Keyword(s):

Glycosylated Hemoglobin ◽

Inverse Correlation ◽

Population Variation ◽

Channel Activation ◽

Hb A1c ◽

Human Red Blood Cells ◽

Age Related ◽

Gardos Channel ◽

High K ◽

Almost All

Abstract We recently demonstrated that the activity of the PMCA varies greatly among the RBCs in a normal blood sample (Lew et al., Blood102:4206,2003). To test the possibility that these variations might be related to cell age, we designed a new experimental protocol to separate RBCs with different PMCA Vmax, which used glycosylated hemoglobin (Hb) A1c as an age marker for the normal RBCs, and avoided Co2+ (used in our usual PMCA activity assay) which we found to interfere with Hb A1c measurements: The ionophore A21837 was used to generate a high, rapid and uniform [CaT]i in RBCs, which were suspended in a 90mM-K+ buffer to prevent RBC dehydration by Gardos channel activation. These RBCs were then washed in high-K+ buffer (ice-cold to inhibit the Ca2+ pump) with 1% albumin to remove the ionophore. At t=0, the washed and packed ionophore-free cells were delivered into 20 volumes of high-K+ buffer at 37oC to initiate Ca2+ extrusion by the PMCA, and then sampled at 15 sec intervals into 25 vol of an ice-cold, K+-free, isotonic buffer containing 10 mM SCN−; these conditions were designed to trap un-extruded Ca2+ and to elicit rapid dehydration of those cells which had not yet pumped out all their Ca2+ load. After ~ 40 min at 0oC each sample was spun; the packed RBCs were resuspended in 10 vol of the same buffer and spun again through diethylphthalate oil (D=1.117 g/ml) to separate the dehydrated RBCs (pellets) from the non-dehydrated cells. The fraction of cells in pellets and on top of the oil was estimated in each sample from Hb measurements, and their Hb A1c content was measured by HPLC. Initially, almost all RBCs, except those with the most vigorous pumps, were recovered in the pellets, but with time, the fraction of cells which had fully extruded their Ca2+ load and were recovered on top of the oil approached 100%. The progressively smaller pellets contained RBCs with progressively weaker pumps; their Hb A1c fraction increased with decrease in the yield of RBCs in the pellet. This inverse correlation between yield and Hb A1c fraction in the pellets was observed in all six experiments performed with RBCs from four donors. Since the decline in PMCA activity correlated directly with an increase in Hb A1c, the observed population variation in PMCA activity reflects an age-related decline in PMCA activity. Whether this decline is due to progressive glycosylation of of a lysine residue near the catalytic ATP domain on the pump ATPase (Gonzalez Flecha et al., J Membr Biol171:25,1999) or to other mechanisms, remains to be determined. The age-decline in PMCA activity may be responsible for the increasing density of aging RBCs, by allowing intermittent episodes of [Ca2+]i elevations in the circulation, with transient Gardos channel activation and gradual dehydration by net KCl and water loss.

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Identification and validation of reference genes for real time PCR expression studies in heads of nurse honeybees

Biologia ◽

10.2478/s11756-013-0267-2 ◽

2013 ◽

Vol 68 (6) ◽

Cited By ~ 1

Author(s):

Lenka Kohútová ◽

Jaroslav Klaudiny ◽

Róbert Nádašdy ◽

Mária Šedivá ◽

Ján Kopernický ◽

...

Keyword(s):

Real Time ◽

Real Time Pcr ◽

Reference Genes ◽

Selection Process ◽

Constitutive Expression ◽

Larval Food ◽

Gene Encoding ◽

Age Related ◽

Expression Studies ◽

Suitable Reference

AbstractThe primary aim of this study was to identify reference genes and workers of particular role and ages that would be suitable for exploring genetic/epigenetic variations in constitutive expression of a gene encoding antimicrobial peptide defensin1 in worker heads using real-time PCR. This peptide is an integral component of larval food and honey and has potential to act against some brood pathogens. Expression levels of distinct genes may vary in worker heads due to genetic factors, age of bee, and particular role of a worker that depends on its age or colony needs. Prerequisite for exploring the variations in defensin1 expression was therefore to identify such workers in which correlated expression of defensin1 and suitable reference genes occurs. Selection process was done by carefully designed quantitative real-time PCR procedure in two colonies showing different age-related division of labor. Expression of ten candidate reference genes, defensin1 and amylase, as a marker of forager bees, was assessed in pooled head samples of workers aged 2 to 30 days. Correlated and moreover stable expression of defensin1 and six candidate genes was detected in nursing bees in both colonies. The suitable reference genes were therefore selected on the basis of their expression stability. This was evaluated by geNorm and NormFinder algorithms in pooled head samples and through plotted Cq data in head samples of individual nurse bees. As the best reference genes were selected: psa1, tctp1, cyclophilin, gapdh and mrjp4 (in this order). They are suitable for aforementioned defensin1 expression studies and also for studies of other genes expressed in heads of nurses. In addition, an amylase expression-based procedure for reliable distinguishing nurses from foragers was elaborated.

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