Alpha-lipoic acid is a natural molecule, which directly or by means of its reduced form, dihydrolipoic acid, exerts antioxidant, anti-inflammatory and immunomodulatory activities, very helpful also ...in preventing miscarriage and preterm delivery. Used as dietary supplement alpha-lipoic acid was demonstrated to be safe for living organisms even when administered at high doses. However, no study was made so far to verify the safety of its continuous administration on a substantial number of pregnant women. The present investigation was performed to answer this issue.
An observational retrospective study was carried out analyzing 610 expectant mothers. They had been treated daily by oral route with 600 mg alpha-lipoic acid, for at least 7 weeks during gestation. The primary outcome was to verify alpha-lipoic acid safety in the mother and infant. Maternal safety was assessed by monitoring for adverse reactions, physical and clinical examination, including a morbidity assessment. Laboratory and clinical examinations were performed monthly. Neonatal safety was assessed by the evaluation of birth weight, gestational age, Apgar scores, neonatal death with the related cause of death. Data collected from the Birth Registry of Campania Region were used as control.
This study provided a very clear and reassuring picture about the safety of alpha-lipoic acid oral treatment during pregnancy. No adverse effect was noticed in mothers or newborns. The two sets of monitored data, from treated and controls, were completely superimposable or, in some cases, better in alpha-lipoic acid group.
Our results open a reassuring scenario regarding the administration of alpha-lipoic acid during pregnancy.
The antioxidants role in cell response regulation attracted great interest in the last decades and it is undergoing to a profound reconsideration. The mere concept of “biological antioxidant” has ...been frequently misconceived or misused, possibly leading to the misinterpretation of some experimental observation. Organosulfur compounds in general and α-lipoic acid, a dithiol molecule, can be considered a typical example of the kind. Reduced α-lipoic acid, dehydrolipoic acid has been in fact originally considered a bona fide, reducing, electron donor molecule. A more recent approach, according to stoichiometric and thermodynamic evidences, lead to a reinterpretation of the biochemical role of “antioxidants”. The electrophilic nature of oxidized nucleophilic molecules, including α-lipoic acid, renders more plausible a mechanism based on the ability to activate Nrf2/EpRE mediated hormetic response.
In this study, we demonstrate that nmolar concentrations of oxidized α-lipoic acid, but not dehydrolipoic acid, protect human umbilical primary endothelial cells (HUVEC) from TNF-α induced dysfunction, inhibit NF-κB activation and block apoptosis following the activation of Nrf2 transcription factor. Our observations corroborate the concept that the major, if not the unique, mechanism by which α-lipoic acid can non-enzymatically exert its reducing activity is related to the electrophilic nature of the oxidized form.
This study aims to characterize in vitro D-chiro-inositol intestinal absorption and identify factors able to improve its bioavailability. D-chiro-inositol, one of the natural occurring stereoisomer ...of myo-inositol, acts as a second messenger in insulin-regulated glucose metabolism in complementary mode with myo-inositol. Because of their insulin-mimetic activities and safety, both myo-inositol and D-chiro-inositol are often employed as supplements in insulin-resistance treatment.
Trans-epithelial passage of D-chiro-inositol was evaluated in the human intestinal Caco-2 cell line differentiated on filter, a widely established in vitro model to study intestinal absorption. D-chiro-inositol transport was assayed in a concentration range corresponding to an estimated in vivo concentration following oral supplementation. α-Lactalbumin peptides, obtained by in vitro simulated gastrointestinal digestion, were tested as possible modulators of the intestinal permeability of D-chiro-inositol.
The absorption of this stereoisomer was relatively low and presumably due to passive diffusion, while it was greatly enhanced by the presence of α-Lactalbumin digest. α-Lactalbumin peptides induced an increase in paracellular permeability that was completely reversible, indicating lack of cytotoxicity. This effect involved temporary rearrangement of F-actin apical cytoskeleton and of the tight junction protein ZO-1.
Although further studies are required to identify and characterize the most effective peptides, the ability of α-Lactalbumin digest to act as absorption enhancers may have very interesting and promising applications in the fields of nutritional supplements and pharmacology.
The effects of different dietary amounts of organic and inorganic Zn were studied in male White Pekin ducks (WPD) from 1 to 56 days of age. The control diet (26 ppm of Zn from raw ingredients) was ...supplemented with 30, 60 and 120 ppm of Zn from both inorganic and organic sources, for a total of seven treatment groups, each containing five replicates of nine 1-day-old ducklings each. BW, feed intake and feed conversion ratio (FCR) were recorded at 1, 28 and 56 days of age. At 56 days of age, five birds per group were used in a digestibility trial to measure Zn retention and excretion. At the end of the trial, five birds per treatment were slaughtered and carcass traits as well as Zn content in tibia and liver were measured. Samples of blood from five birds per treatment were used to measure plasma concentration of Zn and Cu. BW gain during the entire period of the trial increased (P < 0.001) by 30 and 60 ppm of Zn. Increasing Zn contents progressively increased (P < 0.001) the tibia and the liver Zn contents as well as the plasma Zn and Cu contents. The concentration of 120 ppm of Zn increased (P < 0.001) tibia ash and decreased (P < 0.001) abdominal fat in the carcasses. In the period 1 to 56 days, Zn oxide increased (P < 0.001) growth rate and improved (P < 0.03) FCR compared with organic Zn, whereas organic Zn increased (P < 0.003) the dressed carcass percentage. Organic Zinc increased (P < 0.001) Zn and Cu concentration in the plasma. A level of 30 ppm of Zn from an inorganic source was adequate for male WPD during 1 to 56 days of age, based on positive effects of growth rate and Zn excretion.
The aim of the article was to study the effect of different growth promoters on growth performance, carcass quality, biochemical and haematological traits and immune response of growing rabbits. A ...total number of 105 male growing NZW rabbits during 35–91 days of age were randomly distributed among 7 groups fed the same basal diet and submitted to different dietary treatments: the first group was unsupplemented and used as control; the other groups were supplemented respectively with bee pollen and/or propolis at 200 mg/kg BW of each and inulin and/or mannanoligosaccharides (MOS) at 35 mg/kg BW of each. Body weight gain, daily feed intake, feed conversion ratio (FCR), biochemical and haematological blood parameters, carcass characteristics, histological studies of ileum and spleen and economical efficiency were measured. Bee pollen administered alone or with propolis significantly (p < 0.01) the body weight gain and improved FCR in respect of the control group. Inulin with MOS significantly improved just FCR than the control group. Bee pollen with propolis and MOS supplemented‐groups resulted in significantly higher (7.96 and 8.41% respectively) white blood cells compared to the control group. Plasma total cholesterol was significantly higher for the MOS group in respect of the control, bee pollen, inulin and inulin with MOS supplemented‐groups. Propolis resulted in significantly higher dressed carcass percentage than the control group and higher carcass index than only bee pollen with propolis supplemented‐group. Bee pollen, in particular if in combination with propolis, could be used as a supplement in the growing rabbits during days 35–91 of age with positive effects on growth rate and feed conversion ratio.
Abstract
Study question
Low doses of D-Chiro-Inositol are beneficial in the treatment of a PCOS mouse model. However, high doses are detrimental for ovarian histology/function. Is D-Chiro-Inositol ...toxic for the mammalian ovary?
Summary answer
Five mg/day D-Chiro-Inositol for 21 days produced PCOS-like histological/hormonal features. Ten/20 mg/day for 21 days induced ovarian/hormonal states resembling those typical of aged mice.
What is known already
Administration of Myo-Inositol and D-Chiro-Inositol combined according to their plasma molar ratio of 40:1 has beneficial effects in the management of human PCOS. We confirmed the efficacy of this formulation, containing 0.2 mg/day D-Chiro-Inositol, in a mouse model of PCOS. However, formulations containing higher amounts of DCIns had negative effects on ovarian histology and mouse fertility. We investigated possible ovarian toxicity of D-Chiro-Inositol, studying its effects after administration to 30-day-old female mice for 21 days. Young adult mice reproduced the condition of young women possibly facing reproductive/metabolic problems, such as PCOS.
Study design, size, duration
The effects of various doses of D-Chiro-Inositol were analysed on mouse ovarian histology, serum testosterone levels and expression of the ovarian enzyme aromatase. The 21-day period follows normal protocols of pharmacologic PCOS induction in the mouse and spans five ovulatory cycles. Doses employed, 5, 10, 20 mg/day, correspond to doses of 1200, 2400, 4800 mg/day in humans. The first dose is in the range of 1000–1500 mg/day currently prescribed to PCOS patients in clinical practice.
Participants/materials, setting, methods
Five mice/treatment were provided with water administering various doses of D-Chiro-Inositol or 0,5 mg/day letrozole as PCOS-positive controls, for 21 days. At the end of the period, ovulatory cycles were analysed by observations of vaginal cells after vaginal smears; ovarian histology was evaluated by sectioning, hematoxylin-eosin staining and light-transmission microscopy; serum testosterone levels were measured by ELISA; and expression of the ovarian enzyme aromatase was assayed by Western Blots.
Main results and the role of chance
The estrus cycle progressed normally in negative control mice, but was arrested at day 8–10 in the majority of mice under all pharmacologic treatments. Uteri of negative control mice displayed the typical aspect of mature and cycling animals. Uteri of all other mice had an immature/metestrus-diestrus-like aspect, typical of non-cycling animals.
Ovaries of negative control mice showed a normal presence of primary, secondary and tertiary follicles containing a growing oocyte, and of corpora lutea. Ovaries from mice treated with 5 mg/day D-Chiro-Inositol or 0,5 mg/day letrozole had apparently normal primary and secondary follicles but also cystic tertiary follicles resembling those found in human PCOS.
Ovaries from mice treated with 10 or 20 mg/day D-Chiro-Inositol had scarce primary and secondary follicles, a very limited number of tertiary follicles and no cystic follicles, but large follicles/areas with diffused cell proliferation. The typical ovarian structure was lost, especially in the highest dosage.
Treatments with 5 mg/day D-Chiro-Inositol and 0,5 mg/day letrozole increased serum testosterone levels above those of negative control mice, but the former reduced, while the latter increased aromatase levels relative to negative controls. Other treatments had no apparent effects on either testosterone or aromatase levels.
Our experimental paradigm makes the role of chance highly improbable.
Limitations, reasons for caution
The strength of our study relies on the use of an animal model representative of general human tissue organisation and physiological pathways. One weakness consists in the lack of data on serum estrogen levels, due to the paucity of blood provided by a single mouse and the ELISA sensitivity.
Wider implications of the findings: Under all experimental conditions, D-Chiro-Inositol negatively affected ovarian histology and function. Notwithstanding physiological/biochemical differences between mice and humans, caution is therefore recommended when administering D-Chiro-Inositol to PCOS patients at doses corresponding to those we employed in the mouse and/or for long periods, since it may result ineffective or even toxic.
Trial registration number
Not applicable
This review aims at presenting an overview on metformin effects in diabetic and pre-diabetic states as well as in Polycystic Ovary Syndrome. The molecular mechanisms in which metformin is involved ...are discussed in depth. Particular attention is paid to the metabolic alterations and infertility which are important aspects characterizing PCOS. The part devoted to the molecular mechanisms underlying the metformin activity is a necessary introduction to the following sections and helps explaining its therapeutic activity in disorders where the common denominator is insulin resistance. The review also compares the effects of metformin with those of other therapeutic molecules. An important part is also dedicated to the side effects and limitations in the use of this drug, with a particular attention to the long-term effects. Metformin exerts multiple activities at the molecular level, still partly to be clarified, and induces a number of side effects. For these reasons, it should be administered with caution and always under careful control to patients suffering from diabetic and pre-diabetic states, and from PCOS. Furthermore, wherever possible it would be necessary to prefer the use of safer molecules.
We calculate the thermal conductance of a structured silicon nanocrystal with a hole of different sizes. The numerical study is based on non-equilibrium molecular dynamics simulations using two ...potential models for the interatomic interactions: (i) an empirical Tersoff-Brenner (Tersoff) potential; (ii) a semi-empirical tight binding (TB) potential. TB potential model predicts a similar thermal conductance for the nanocrystal with no hole and with a small size hole, which contrasts with the monotonic decrease predicted by Tersoff potential model. In addition, thermal conductance decreasing is higher for TB potential model when the surface-to-volume ratio increases. This points out that to study thermal properties of nanostructures with high surface-to-volume ratio is mandatory the use of potential models with high transferability to take adequately into account the relevant quantum physical effects due to boundaries and surfaces.
We investigate the role that nonlinearity in the interatomic potential has on the thermal conductance of a suspended nanoribbon when it is subjected to a longitudinal strain. To focus on the first ...cubic and quartic nonlinear terms of a general potential, we propose an atomic system based on an α-β Fermi-Pasta-Ulam nearest neighbor interaction. We perform classical molecular dynamics simulations to investigate the contribution of longitudinal, transversal and flexural modes to the thermal conductance as a function of the α-β parameters and the applied strain. We compare the cases where atoms are allowed to vibrate only in plane (2D) with the case of vibrations in and out of plane (3D). We find that the dependence of conductance on α and β relies on a crossover phenomenon between linear/nonlinear delocalized/localized flexural and transversal modes, driven by an on/off switch of the strain.
We present a theory that accurately describes the counting of excited states of a noninteracting fermionic gas. At high excitation energies the results reproduce Bethe's theory. At low energies ...oscillatory corrections to the many-body density of states, related to shell effects, are obtained. The fluctuations depend nontrivially on energy and particle number. Universality and connections with Poisson statistics and random matrix theory are established for regular and chaotic single-particle motion.
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