67 research outputs found
Effect of activin-A on progesterone synthesis in human luteal cells
No full textOBJECTIVE: To examine the effect of activin-A on basal and hCG-stimulated P production by human luteal cells.
DESIGN: Mixed luteal cell cultures and distinct cultures of two luteal cell types: small and large luteal cells from early and midluteal phase.
SETTING: Corpora lutea (CL) were obtained from the Obstetrics and Gynecology Department of the Catholic University, Rome, Italy.
PATIENTS: Fifteen nonpregnant women between 30 and 45 years of age underwent surgery for nonendocrine gynecological diseases.
INTERVENTIONS: Corpora lutea were obtained at the time of hysterectomy. The luteal cells were dispersed in Ham's F-12 medium containing collagenase at 37 degrees C in shaking water bath for 2 hours, filtered, centrifuged, and resuspended in fresh medium.
MAIN OUTCOME MEASURES: The cells diluted to a final concentration of 60,000 to 100,000 cells/mL of medium. After 24 hours, the cells attached to the wells and were incubated with or without hCG and/or activin-A at different concentrations.
RESULTS: Activin-A starting from 25 micrograms/L significantly decreased basal and hCG (250 mIU/mL [conversion to SI unit, 1.00])-induced P production by mixed luteal cells. The small luteal cells responded to hCG (250 mIU/mL), and the treatment with activin-A (from 25 to 100 micrograms/L) reduced their basal and hCG-induced P production. Activin-A addition did not change the amount of P release by large luteal cells at any concentration.
CONCLUSIONS: These results imply that activin-A plays a role in the local regulation of human CL
Molecular Dynamics as a Precision Therapy: A Perspective on Epileptic Encephalopathies
No full textNo abstract availabl
In silico modeling of the immune system: cellular and molecular scale approaches
No full textThe revolutions in biotechnology and information technology have produced clinical data, which complement biological data. These data enable detailed descriptions of various healthy and diseased states and responses to therapies. For the investigation of the physiology and pathology of the immune responses, computer and mathematical models have been used in the last decades, enabling the representation of biological processes. In this modeling effort, a major issue is represented by the communication between models that work at cellular and molecular level, that is, multiscale representation. Here we sketch some attempts to model immune system dynamics at both level
Novel potent and selective θ ligands: Evaluation of their agonist and antagonist properties
No full textTB62, A POTENT 5-HT1A SEROTONERGIC FULL AGONIST, ENDOWED WITH DUAL ANTINOCICEPTIVE AND ANXIOLITIC/ANTIDEPRESSANT ACTIVITY
No full textPain is a physiological experience crucial for self-preservation. It is estimated that more than 30% of the adult population suffers from chronic pain worldwide, generating a huge burden on national and world health services and economies.1 Despite recent advances in pain research, the development of new therapies is challenging, and opioids are still a “gold standard”. Over 15 million people worldwide misuse prescription opioids, therefore, non-addictive treatments for chronic pain are highly needed. Chronic pain can lead to distress, frustration which can contribute to the development or exacerbation of anxiety and depression.2 Conversely, anxiety and depression can lower pain thresholds, intensify pain perception, and increase the risk of developing chronic pain conditions.
The serotonergic system (5-HT) plays a critical role in mood state control and endogenous analgesia. Therefore, it represents an excellent target to control both the perceptive and affective components of chronic pain.3
Within a drug discovery project on 5-HT1A ligands, our research group prepared and tested a new series of rigid analogues of a previously identified aralkyl-phenoxyethylammine partial agonist.4 The new compounds were obtained by incorporating the basic nitrogen into a pyrrolidine or piperidine ring, thus leading to the introduction of an additional chiral center. By using stereoselective synthesis, we prepared the four respective enantiomeric couples. Notably, only TB62 enantiomer [4-(S), 2-(R)] showed increased selectivity and full agonist activity, highlighting the role of chirality in the interaction with the 5-HT1A receptor.
Preliminary in-vitro studies on mouse spinal cord and hippocampus slices have shown that TB62 activates the 5-HT1A receptors and that its activity is completely antagonized by the 5-HT1A antagonist WAY100635, suggesting a clean profile.
Preliminary in-vivo experiments have shown that TB62 does not impair motor coordination and locomotion, an essential prerequisite for a CNS-acting drug, while it exhibited drug efficacy in a mouse model of persistent pain. In parallel, we assessed the anxiolytic and antidepressant potential of TB62. Indeed, this compound was effective in both elevated plus-maze and forced swimming tests.
In conclusion, the 5-HT1A full agonist, TB62, could represent an effective, non-opioid therapeutic tool for the treatment of chronic pain and its co-morbidities, such as anxiety and depression.
Bibliografia
1. Cohen SP, Vase L, Hooten WM. Chronic pain: an update on burden, best practices, and new advances. Lancet. 2021;397(10289):2082-2097.
2. Kim S, Lee J, Boone D. Protective and Risk Factors at the Intersection of Chronic Pain, Depression, Anxiety, and Somatic Amplification: A Latent Profile Approach. J Pain Res. 2022; 15:1107-1121.
3. Haleem DJ. Targeting Serotonin1A Receptors for Treating Chronic Pain and Depression. Curr Neuropharmacol. 2019;17(12):1098-1108.
4. Prandi A, Franchini S, Manasieva LI, Fossa P, Cichero E, Marucci G, Buccioni M, Cilia A, Pirona L, Brasili L. Synthesis, biological evaluation, and docking studies of tetrahydrofuran- cyclopentanone- and cyclopentanol-based ligands acting at adrenergic α1- and serotonine 5-HT1A receptors. J Med Chem. 2012;55(1):23-36
Benzisothiazolyliminothiazolidin-4-ones with chondroprotective properties: searching for potent and selective inhibitors of MMP-13.
No full textInsulin secretion in patients with gestational diabetes: relationship with pregnancy outcome
No full textThe authors observed that there is wide variability in insulin response to an oral glucose tolerance test in women developing carbohydrate intolerance during pregnancy. This variability ranges from a reduction of pancreatic islet function to a normal or exaggerated secretory pattern of insulin. Moreover the results also suggest that exaggerated insulin secretion and/or high insulin resistance may play a role in the regulation of gestational blood pressure and that a higher glucose/insulin ratio may be positively related to birth weight. Clearly, further studies are needed to investigate the impact of this metabolic situation on the optimization of the clinical control of glucose metabolism and fetal homeostasi
Scouting new sigma receptor ligands: Synthesis, pharmacological evaluation and molecular modeling of 1,3-dioxolane-based structures and derivatives
No full textHerein we report the synthesis and biological activity of new sigma receptor (σR) ligands obtained by combining different substituted five-membered heterocyclic rings with appropriate σR pharmacophoric amines. Radioligand binding assay, performed on guinea pig brain membranes, identified 25b (1-(1,4-dioxaspiro[4.5]decan-2-ylmethyl)-4-benzylpiperazine) as the most interesting compound of the series, displaying high affinity and selectivity for σ1R (pKiσ1 = 9.13; σ1/σ2 = 47). The ability of 25b to modulate the analgesic effect of the κ agonist (-)-U-50,488H and μ agonist morphine was evaluated in vivo by radiant heat tail-flick test. It exhibited anti-opioid effects on both κ and μ receptor-mediated analgesia, suggesting an agonistic behavior at σ1R. Docking studies were performed on the theoretical σ1R homology model. The present work represents a new starting point for the design of more potent and selective σ1R ligands
In vitro effect of antiphospholipid antibody-containing sera on basal and gonadotrophin releasing hormone-dependent human chorionic gonadotrophin release by cultured trophoblast cells
No full textOur objective was to evaluate whether antiphospholipid antibody-containing sera could play a regulatory role in signal transduction induced by gonadotrophin releasing hormone (GnRH) when incubated with normal human trophoblast cells. To test this hypothesis we established an in vitro placental culture system in which GnRH addition in the presence of normal human serum resulted in a significant increase in human chorionic gonadotrophin (hCG) secretion. When GnRH was added to the culture medium with antiphospholipid antibody-containing sera, the hCG increase was inhibited. These results suggest the possibility that antiphospholipid antibody-positive sera can exert their effect on GnRH-induced signal transduction. Further studies are needed to explain their exact site of actio
Molecular Dynamic Simulations to Determine Individualized Therapy: Tetrabenazine for the GNAO1 Encephalopathy E246K Variant
No full textIntroduction: GNAO1 encephalopathy is characterized by severe hypotonia, psychomotor retardation, epilepsy, and movement disorders. Genetic variations in GNAO1 have been linked to neurological symptoms including movement disorders like dystonia. The correlation between the E246K mutation in the Gα subunit and aberrant signal transduction of G proteins has been established but no data are reported regarding the efficacy of medical treatment with tetrabenazine. Methods: Molecular modeling studies were performed to elucidate the molecular mechanisms underlying this mutation. We developed drug efficacy models using molecular dynamic simulations that replicated the behavior of wild-type and mutated proteins in the presence or absence of ligands. Results and discussion: We demonstrated that the absence of the mutation leads to normal signal transduction upon receptor activation by the endogenous ligand, but not in the presence of tetrabenazine. In contrast, the presence of the mutation resulted in abnormal signal transduction in the presence of the endogenous ligand, which was corrected by the drug tetrabenazine. Tetrabenazine was identified as a promising therapeutic option for pediatric patients suffering from encephalopathy due to an E246K mutation in the GNAO1 gene validated through molecular dynamics. This is a potential first example of the use of this technique in a rare neurological pediatric disease
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