Aromatase Activity and Bone Loss in Men

Aromatase is a specific component of the cytochrome P450 enzyme system responsible for the transformation of androgen precursors into estrogens. This enzyme is encoded by the CYP19A1 gene located at chromosome 15q21.2, that is, expressed in ovary and testis, but also in many extraglandular sites such as the placenta, brain, adipose tissue, and bone. The activity of aromatase regulates the concentrations of estrogens with endocrine, paracrine, and autocrine effects on target issues including bone. Importantly, extraglandular aromatization of circulating androgen precursors is the major source of estrogen in men. Clinical and experimental evidences clearly indicate that aromatase activity and estrogen production are necessary for longitudinal bone growth, the attainment of peak bone mass, pubertal growth spurt, epiphyseal closure, and normal bone remodeling in young individuals. Moreover, with aging, individual differences in aromatase activity may significantly affect bone loss and fracture risk in men

The influence of vitamins B12 and D3 on balance and falls: results from the study of a geriatric sample of patients at the Clinic for the Prevention of Falls, Osteoporosis and Sarcopenia (I.P.P.O.S) of the rehabilitation clinic of the University General Hospital of Patras (U.G.H.P.)

Balance disorders and falls are common in the elderly and have a multifactorial etiology. In the geriatric population, it is common to develop various nutritional deficiencies that manifest themselves in different ways at the clinical level. Among the deficiencies in question, the most frequent are those of vitamins B12 and D3. Both of these seem to play an important role in the regular functioning of the musculoskeletal and nervous system and, consequently, their lack plays a pathophysiological role in balance disorders and is a predisposing risk factor for falls. However, the research results and data to date are often conflicting, and especially in the case of vitamin B12, there is little on the Greek population, which presents its own particularities. The purpose of the present cross-sectional study is to evaluate for the first time in a sample of the Greek population, a possible association of vitamins B12 and D3 with balance disorders and falls and to verify the hypothesis that their lower levels are associated with worse balance and increased frequency of falls. More specifically, ninety patients, females and males, were evaluated, from December 2019 to December 2020 during their first ambulatory visit at the Prevention of Falls Clinic of the General University Hospital of Patras. Vitamins B12 and D3 levels were measured. The number of falls during the last 12 months was recorded and patients were assessed using Mini-Balance Evaluation Systems Test (Mini-BESTest), Fried Phenotype, Walking Speed, Hand Grip Strength, Short Physical Performance Battery (SPPB), Mini Mental State Examination (MMSE), Geriatric Depression Scale (GDS).It was worth to report that the levels of vitamins B12 and D3 were statistically significantly lower in participants who reported at least one fall in the previous 12 months (for B12: M=346.9, SD=128.5 and for D3: M=24 .3, SD=8.9) than participants who reported no having falls for B12 (M=452.3, SD=176.0), t(88) =3.235, p=0.002 and for D3 : (M=30.6, SD=9.3), t(88) =3.285, p=0.001 respectively). A statistically significant positive correlation was found between vitamin B12 levels and Mini-BESTest, r(90)=0.816, p<0.001. Likewise, there is a statistically significant positive correlation between vitamin D3 levels and Mini-BESTest, r(90)=0.785, p<0.001. Higher Mini-BESTest scores correspond to higher vitamin B12 and D3 values. A multiple linear regression analysis showed that Mini-BESTest, is statistically significantly predicted, F(10,79)=18.734, p<0.001, adj. R2=0.70 by Vit-B12 and FRIED Phenotype (pre-frail vs non frail). Similarly, in multiple binary logistic regression analysis, falls were statistically significantly predicted by FRIED Phenotype (pre -frail vs non-frail) χ2(5)=63.918, p<0.001, Nagelkerke R Squared=0.68. Summarizing, higher levels of vitamin B12, but not of D3, are associated with better balance but not with fewer falls in a Greek sample of community-dwelling elderly.Οι διαταραχές ισορροπίας και οι πτώσεις είναι συχνές στους ηλικιωμένους και έχουν πολυπαραγοντική αιτιολογία. Στον γηριατρικό πληθυσμό είναι σύνηθες φαινόμενο να αναπτύσσονται διάφορες διατροφικές ελλείψεις που εκδηλώνονται ποικιλοτρόπως σε κλινικό επίπεδο. Ανάμεσα στις εν λόγω ελλείψεις συχνότερες είναι αυτές των βιταμινών Β12 και D3. Και οι δύο αυτές φαίνεται να παίζουν σημαντικό ρόλο στην ομαλή λειτουργία του μϋοσκελετικού και νευρικού συστήματος και κατ’ επέκταση, η έλλειψή τους να διαδραματίζει έναν φυσιοπαθολογία ρόλο στις διαταραχές της ισορροπίας και να αποτελεί προδιαθεσικό παράγοντα για πτώσεις. Ωστόσο, τα μέχρι σήμερα ερευνητικά αποτελέσματα και δεδομένα, αρκετές φορές είναι αντικρουόμενα και ειδικά στην περίπτωση της βιταμίνης Β12 είναι ελάχιστα επί του ελληνικού πληθυσμού ο οποίος, παρουσιάζει τις δικές του ιδιαιτερότητες. Ο σκοπός της παρούσας συγχρονικής μελέτης είναι να αξιολογήσει για πρώτη φορά σε ένα δείγμα του ελληνικού πληθυσμού, μια πιθανή συσχέτιση των βιταμινών B12 και D3 με διαταραχές της ισορροπίας και τις πτώσεις και να επαληθεύσει την υπόθεση, πως χαμηλότερα επίπεδά τους σχετίζονται με χειρότερη ισορροπία και αυξημένη συχνότητα πτώσεων. Πιο συγκεκριμένα, ενενήντα ασθενείς, γυναίκες και άνδρες, αξιολογήθηκαν, από τον Δεκέμβριο 2019 έως τον Δεκέμβριο 2020 κατά τη διάρκεια της πρώτης τους περιπατητικής επίσκεψης στην Κλινική Πρόληψης Πτώσεων του Γενικού Πανεπιστημιακού Νοσοκομείου Πατρών, μετρήθηκαν τα επίπεδα των Βιταμινών Β12 και τα D3, καταγράφηκε αριθμός των πτώσεων κατά τους τελευταίους 12 μήνες και οι ασθενείς αξιολογήθηκαν χρησιμοποιώντας το Mini-Balance Evaluation Systems Test (Mini-BESTest) για την ισορροπία, τα Fried Phenotype κριτήρια για την Ευπάθεια, το Short Physical Performance Battery (SPPB) για την φυσική απόδοση και μετρήθηκαν η ταχύτητα βάδισης (Walking Speed) και η δύναμη δραγμού (Hand Grip Strength), Mini Mental State Examination (MMSE), Geriatric Depression Scale (GDS).Αξίζει να σημειωθεί ότι τα επίπεδα των βιταμινών Β12 και D3 ήταν στατιστικά σημαντικά χαμηλότερα στους συμμετέχοντες που ανέφεραν ότι είχαν τουλάχιστον μία πτώση τους προηγούμενους 12 μήνες (για την Β12: M=346,9, SD=128,5 και για την D3: M=24,3, SD=8,9) από τους συμμετέχοντες που ανέφεραν ότι δεν είχαν πτώσεις (για την Β12 (M=452,3, SD=176,0), t(88) =3,235, p=0,002 και για την D3: M=30,6, SD=9,3), t(88) =3,285, p=0,001 αντίστοιχα). Βρέθηκε μία στατιστικά σημαντική θετική συσχέτιση μεταξύ των επιπέδων της βιταμίνης Β12 και του Mini-BESTest, r(90)=0,816, p<0,001. Ομοίως, υπάρχει στατιστικά σημαντική θετική συσχέτιση μεταξύ των επιπέδων της βιταμίνης D3 και του Mini-BESTest, r(90)=0,785, p<0,001. Οι υψηλότερες βαθμολογίες στο Mini-BESTest αντιστοιχούν σε υψηλότερες τιμές βιταμίνης B12 και D3.Μια ανάλυση πολλαπλής γραμμικής παλινδρόμησης έδειξε ότι τo Mini-BESTest είναι στατιστικώς σημαντικά προβλεπόμενο, F(10,79)=18.734, p<0.001, adj. R2=0,70 από την Vit-B12 και τον Φαινότυπο Ευπάθειας της FRIED (FRIED Phenotype (pre-frail vs non frail). Ομοίως, στην ανάλυση πολλαπλής δυαδικής λογιστικής παλινδρόμησης, οι πτώσεις προβλέφθηκαν στατιστικώς σημαντικά από τον Φαινότυπο Ευπάθειας της FRIED (pre-frail vs non-frail) χ2(5)=63,918, p<0,001, Nagelkerke R Squared=0,68. Συμπερασματικά, υψηλότερα επίπεδα της βιταμίνης Β12 αλλά όχι και της D3, συνδέονται με καλύτερη ισορροπία αλλά όχι με λιγότερες πτώσεις σε ένα δείγμα ελλήνων ηλικιωμένων που διαβιούν στην κοινότητα

The regulatory role of neurotensin on the hypothalamic-anterior pituitary axons: emphasis on the control of thyroid-related functions

Neurotensin (NT) is a 13 amino acid neurohormone and/or neuromodulator, located in the synaptic vesicles and released from the neuronal terminals in a calcium-dependent manner. This peptide is present among mammalian and nonmammalian species, mainly in the central nervous system and the gastrointestinal tract. Due to its neuroendocrine activity, NT has been related to the pathophysiology of a series of disorders, such as schizophrenia, drug-abuse, Parkinson's disease, cancer, stroke, eating disorders and other neurodegenerative conditions. Moreover, NT participates in the physiology of pain-induction, central blood pressure control and inflammation. NT also plays an important interactive role in all components of the hypothalamic-anterior pituitary circuit, which is mediated by an endocrine, paracrine or/and autocrine manner, towards most of the anatomical regions that define this circuit. A considerable amount of data implicates NT in thyroid-related regulation through this circuit, the exact mechanisms of which should be further investigated for the potential development of more targeted approaches towards the treatment of thyroid-related endocrine diseases. The aim of this study was to provide an up-to-date review of the literature concerning the regulatory role of NT on the hypothalamic-anterior pituitary axons, with an emphasis on the control of thyroid-related functions

Postnuclear supernatants of rat brain regions as substrates for the in vitro assessment of cadmium-induced neurotoxicity on acetylcholinesterase activity

Acetylcholinesterase (AChE) activity is thought to be a major neurotoxicity biomarker. Considering the recently highlighted controversy over the use of AChE activity as a biomarker for the neurotoxicity induced by cadmium (Cd; a major environmental contaminant), we have evaluated the in vitro effects of different concentrations of Cd on AChE activity in postnuclear supernatants of brain regions of newborn, 21-day-old, and adult male Wistar rats. Our findings demonstrate that Cd is a consistent inhibitor of AChE activity at concentrations higher than 10(-3) M as well as that, at a concentration of 10(-2) M, Cd induces an almost absolute inhibition of this crucial enzyme in the examined postnuclear supernatants. These findings confirm previous in vitro experiments of ours, but are not in full agreement with the available in vivo findings; in fact, they underline that this in vitro approach to Cd-induced neurotoxicity does not produce the distinctive brain region-specific responses in terms of AChE activity that we have recently observed in vivo. Our study does not support the use of AChE activity as a biomarker for the assessment of Cd-induced neurotoxicity in rat brain-derived postnuclear supernatants, at least under the examined in vitro experimental conditions

Activation of acetylcholinesterase after U-74389G administration in a porcine model of intracerebral hemorrhage

Spontaneous intracerebral hemorrhage (ICH) accounts for 10-15% of all strokes. Despite high incidence, morbidity and mortality, the precise pathophysiology of spontaneous ICH is not fully understood, while there is little data concerning the mechanisms that follow the primary insult of the hematoma formation. The cholinergic system, apart from its colossal importance as a neurotransmission system, seems to also play an important role in brain injury recovery. It has been recently suggested that the brain possesses a cholinergic anti-inflammatory pathway that counteracts the inflammatory responses after ICH, thereby limiting damage to the brain itself. We, herein, report the findings of our study concerning the role of acetylcholinesterase (AChE; a crucial membrane-bound enzyme involved in cholinergic neurotransmission) in a porcine model of spontaneous ICH, with a focus on the first 4 and 24 h following the lesion's induction, in combination with a study of the effectiveness of the lazaroid antioxidant U-74389G administration. Our study demonstrates the activation of AChE activity following U-74389G administration. The lazaroid U-74389G seems to be an established neuroprotectant and this is the first report of its supporting role in the enhancement of cholinergic response to the induction of ICH

Developmental neurotoxicity of cadmium on enzyme activities of crucial offspring rat brain regions

Cadmium (Cd) is an environmental contaminant known to exert significant neurotoxic effects on both humans and experimental animals. The aim of this study was to shed more light on the effects of gestational (in utero) and lactational maternal exposure to Cd (50 ppm of Cd as Cd-chloride in the drinking water) on crucial brain enzyme activities in important rat offspring brain regions (frontal cortex, hippocampus, hypothalamus, pons and cerebellum). Our study provides a brain region-specific view of the changes in the activities of three crucial brain enzymes as a result of the developmental neurotoxicity of Cd. Maternal exposure to Cd during both gestation and lactation results into significant changes in the activities of acetylcholinesterase and Na(+),K(+)-ATPase in the frontal cortex and the cerebellum of the offspring rats, as well as in a significant increase in the hippocampal Mg(2+)-ATPase activity. These brain-region-specific findings underline the need for further research in the field of Cd-induced developmental neurotoxicity. Deeper understanding of the mechanisms underlying the neurodevelopmental deficits taking place due to in utero and early age exposure to Cd could shed more light on the causes of its well-established cognitive implications

Gestational exposure to cadmium alters crucial offspring rat brain enzyme activities: the role of cadmium-free lactation

The present study aimed to shed more light on the effects of gestational (in utero) exposure to cadmium (Cd) on crucial brain enzyme activities of Wistar rat offspring, as well as to assess the potential protective/restorative role that a Cd-free lactation might have on these effects. In contrast to earlier findings of ours regarding the pattern of effects that adult-onset exposure to Cd has on brain AChE, Na(+),K(+)- and Mg(2+)-ATPase activities, as well as in contrast to similar experimental approaches implementing the sacrificing mode of anaesthesia, in utero exposure to Cd-chloride results in increased AChE and Na(+),K(+)-ATPase activities in the newborn rat brain homogenates that were ameliorated through a Cd-free lactation (as assessed in the brain of 21-day-old offspring). Mg(2+)-ATPase activity was not found to be significantly modified under the examined experimental conditions. These findings could provide the basis for a further evaluation of the herein discussed neurotoxic effects of in utero exposure to Cd, in a brain region-specific manner

Experimentally-induced Wernicke's encephalopathy modifies crucial rat brain parameters: the importance of Na+,K+-ATPase and a potentially neuroprotective role for antioxidant supplementation

Wernicke's encephalopathy (WE) is a serious neuropsychiatric syndrome caused by chronic alcoholism and thiamine (T) deficiency. Our aim was to shed more light on the pathophysiology of WE, by introducing a modified in vivo experimental model of WE and by focusing on changes provoked in the total antioxidant status (TAS) and three crucial brain enzyme activities in adult rats. Rats were placed on ethanol (EtOH) consumption (20 % v/v) for a total of 5 weeks. By the end of the third week, rats were fed a T-deficient diet (TDD) and were treated with pyrithiamine (PT; 0.25 mg/kg) for the remaining 2 weeks. Following the induction of WE symptomatology, rats were treated with three consecutive (every 8 h) injections of saline or T (100 mg/kg) and were sacrificed. Brain homogenates were generated and used for spectrophotometrical evaluation of TAS and enzymatic activities. Additionally, in vitro experiments were conducted on brain homogenates or pure enzymes incubated with T or neuromodulatory antioxidants. Pre-exposure to EtOH provided a successful protocol modification that did not affect the expected time of WE symptomatology onset. Administration of T ameliorated this symptomatology. WE provoked oxidative stress that was partially limited by T administration, while T itself also caused oxidative stress to a smaller extent. Brain acetylcholinesterase (AChE) was found inhibited by WE and was further inhibited by T administration. In vitro experiments demonstrated a potential neuroprotective role for L-carnitine (Carn). Brain sodium-potassium adenosine triphosphatase (Na(+),K(+)-ATPase) activity was found increased in WE and was reduced to control levels by in vivo T administration; this increase was also evident in groups exposed to PT or to TDD, but not to EtOH. In vitro experiments demonstrated a potential neuroprotective role for this Na(+),K(+)-ATPase stimulation through T or L-cysteine (Cys) administration. Brain magnesium adenosine triphosphatase (Mg(2+)-ATPase) activity was found decreased by prolonged exposure to EtOH, but was not affected by the experimental induction of WE. Our data suggest that T administration inhibits AChE, which is also found inhibited in WE. Moreover, increased brain Na(+),K(+)-ATPase activity could be a marker of T deficiency in WE, while combined T and antioxidant co-supplementation of Cys and/or Carn could be neuroprotective in terms of restoring the examined crucial brain enzyme activities to control levels

Experimentally-induced maternal hypothyroidism alters crucial enzyme activities in the frontal cortex and hippocampus of the offspring rat.

Thyroid hormone insufficiency during neurodevelopment can result into significant structural and functional changes within the developing central nervous system (CNS), and is associated with the establishment of serious cognitive impairment and neuropsychiatric symptomatology. The aim of the present study was to shed more light on the effects of gestational and/or lactational maternal exposure to propylthiouracil (PTU)-induced hypothyroidism as a multilevel experimental approach to the study of hypothyroidism-induced changes on crucial brain enzyme activities of 21-day-old Wistar rat offspring in a brain region-specific manner. This experimental approach has been recently developed and characterized by the authors based on neurochemical analyses performed on newborn and 21-day-old rat offspring whole brain homogenates; as a continuum to this effort, the current study focused on two CNS regions of major significance for cognitive development: the frontal cortex and the hippocampus. Maternal exposure to PTU in the drinking water during gestation and/or lactation resulted into changes in the activities of acetylcholinesterase and two important adenosinetriphosphatases (Na(+),K(+)- and Mg(2+)-ATPase), that seemed to take place in a CNS-region-specific manner and that were dependent upon the PTU-exposure timeframe followed. As these findings are analyzed and compared to the available literature, they: (i) highlight the variability involved in the changes of the aforementioned enzymatic parameters in the studied CNS regions (attributed to both the different neuroanatomical composition and the thyroid-hormone-dependent neurodevelopmental growth/differentiation patterns of the latter), (ii) reveal important information with regards to the neurochemical mechanisms that could be involved in the way clinical hypothyroidism could affect optimal neurodevelopment and, ultimately, cognitive function, as well as (iii) underline the need for the adoption of more consistent approaches towards the experimental simulation of congenital and early-age-occurring hypothyroidism