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Medicina (Kaunas, Lithuania) Jun 2024Hyperprolactinemia, as a potential side-effect of some antipsychotic medications, is associated with decreased bone density and an increased risk of fractures. This...
Hyperprolactinemia, as a potential side-effect of some antipsychotic medications, is associated with decreased bone density and an increased risk of fractures. This study investigates whether calcium and vitamin D supplementation affects prolactin receptor ( gene expression in the duodenum, vertebrae, and kidneys of female rats with sulpiride-induced hyperprolactinemia. Twenty-one-week-old female Wistar rats were assigned to three groups: Group S consisted of ten rats who received sulpiride injections (10 mg/kg) twice daily for 6 weeks; Group D (10 rats) received daily supplementation of 50 mg calcium and 500 IU vitamin D along with sulpiride for the last 3 weeks; and Group C consisting of seven age-matched nulliparous rats serving as a control group. Real-time PCR was used to assess gene expression in the duodenum, vertebrae, and kidneys. In Group S, Prlr gene expression was notably decreased in the duodenum ( < 0.01) but elevated in the vertebrae and kidneys compared to Group C. Conversely, Group D exhibited significantly increased Prlr expression in the duodenum ( < 0.01) alongside elevated expression in the vertebrae and kidneys. In sulpiride-induced hyperprolactinemia, decreased Prlr gene expression in the duodenum may lead to reduced intestinal calcium absorption. Consequently, prolactin may draw calcium from the skeletal system to maintain calcium balance, facilitated by increased Prlr gene expression in the vertebrae. However, vitamin D supplementation in sulpiride-induced hyperprolactinemia notably enhances Prlr gene expression in the duodenum, potentially ameliorating intestinal calcium absorption and mitigating adverse effects on bone health.
Topics: Animals; Hyperprolactinemia; Sulpiride; Rats, Wistar; Female; Vitamin D; Rats; Calcium; Duodenum; Receptors, Prolactin; Gene Expression
PubMed: 38929559
DOI: 10.3390/medicina60060942 -
International Journal of Molecular... Jun 2024Understanding the transport mechanism is crucial for developing inhibitors that block allergen absorption and transport and prevent allergic reactions. However, the...
Understanding the transport mechanism is crucial for developing inhibitors that block allergen absorption and transport and prevent allergic reactions. However, the process of how beta-conglycinin, the primary allergen in soybeans, crosses the intestinal mucosal barrier remains unclear. The present study indicated that the transport of beta-conglycinin hydrolysates by IPEC-J2 monolayers occurred in a time- and quantity-dependent manner. The beta-conglycinin hydrolysates were absorbed into the cytoplasm of IPEC-J2 monolayers, while none were detected in the intercellular spaces. Furthermore, inhibitors such as methyl-beta-cyclodextrin (MβCD) and chlorpromazine (CPZ) significantly suppressed the absorption and transport of beta-conglycinin hydrolysates. Of particular interest, sodium cromoglycate (SCG) exhibited a quantity-dependent nonlinear suppression model on the absorption and transport of beta-conglycinin hydrolysates. In conclusion, beta-conglycinin crossed the IPEC-J2 monolayers through a transcellular pathway, involving both clathrin-mediated and caveolae-dependent endocytosis mechanisms. SCG suppressed the absorption and transport of beta-conglycinin hydrolysates by the IPEC-J2 monolayers by a quantity-dependent nonlinear model via clathrin-mediated and caveolae-dependent endocytosis. These findings provide promising targets for both the prevention and treatment of soybean allergies.
Topics: Globulins; Seed Storage Proteins; Antigens, Plant; Soybean Proteins; Animals; Cromolyn Sodium; Chlorpromazine; Endocytosis; beta-Cyclodextrins; Cell Line; Biological Transport; Glycine max; Intestinal Mucosa; Swine
PubMed: 38928351
DOI: 10.3390/ijms25126636 -
International Journal of Molecular... Jun 2024Schizophrenia spectrum disorders (SSD) are a group of diseases characterized by one or more abnormal features in perception, thought processing and behavior. Patients...
Schizophrenia spectrum disorders (SSD) are a group of diseases characterized by one or more abnormal features in perception, thought processing and behavior. Patients suffering from SSD are at risk of developing life-threatening complications. Pharmacogenetic studies have shown promising results on personalized treatment of psychosis. In the current study, 103 patients diagnosed with SSD treated with risperidone as antipsychotic monotherapy were enrolled. Socio-demographics and clinical data were recorded, and laboratory tests and genotyping standard procedure for cytochrome P450 (CYP) 2D6*4 were performed. Patients were evaluated by the Positive and Negative Syndrome Scale (PANSS) on admission and at discharge. Based on the reduction in the PANSS total score, subjects were divided into non-responders, partial responders and full responders. Only 11 subjects had a full response to risperidone (10.67%), 53 subjects (51.45%) had a partial response, and 39 participants (37.86%) were non-responders. Patients at first episode psychosis showed significantly higher levels of blood glucose and prolactin levels, while chronic patients showed significantly higher LDL levels. Adverse drug reactions (ADR) such as tremor and stiffness significantly correlated with genetic phenotypes ( = 0.0145). While CYP2D6 showed no impact on treatment response, ADR were significantly more frequent among poor and intermediate metabolizers.
Topics: Humans; Cytochrome P-450 CYP2D6; Risperidone; Male; Female; Schizophrenia; Adult; Antipsychotic Agents; Middle Aged; Genotype; Young Adult
PubMed: 38928058
DOI: 10.3390/ijms25126350 -
Biomolecules Jun 2024Modafinil analogs with either a sulfoxide or sulfide moiety have improved binding affinities at the human dopamine transporter (hDAT) compared to modafinil, with lead...
Modafinil analogs with either a sulfoxide or sulfide moiety have improved binding affinities at the human dopamine transporter (hDAT) compared to modafinil, with lead sulfoxide-substituted analogs showing characteristics of atypical inhibition (e.g., JJC8-091). Interestingly, the only distinction between sulfoxide and sulfide substitution is the presence of one additional oxygen atom. To elucidate why such a subtle difference in ligand structure can result in different typical or atypical profiles, we investigated two pairs of analogs. Our quantum mechanical calculations revealed a more negatively charged distribution of the electrostatic potential surface of the sulfoxide substitution. Using molecular dynamics simulations, we demonstrated that sulfoxide-substituted modafinil analogs have a propensity to attract more water into the binding pocket. They also exhibited a tendency to dissociate from Asp79 and form a new interaction with Asp421, consequently promoting an inward-facing conformation of hDAT. In contrast, sulfide-substituted analogs did not display these effects. These findings elucidate the structural basis of the activity cliff observed with modafinil analogs and also enhance our understanding of the functionally relevant conformational spectrum of hDAT.
Topics: Modafinil; Dopamine Plasma Membrane Transport Proteins; Humans; Molecular Dynamics Simulation; Binding Sites; Dopamine Uptake Inhibitors; Structure-Activity Relationship; Protein Binding
PubMed: 38927116
DOI: 10.3390/biom14060713 -
Biomolecules Jun 2024Induced pluripotent stem cell (iPSC) based neuronal differentiation is valuable for studying neuropsychiatric disorders and pharmacological mechanisms at the cellular...
BACKGROUND
Induced pluripotent stem cell (iPSC) based neuronal differentiation is valuable for studying neuropsychiatric disorders and pharmacological mechanisms at the cellular level. We aimed to examine the effects of typical and atypical antipsychotics on human iPSC-derived neural progenitor cells (NPCs).
METHODS
Proliferation and neurite outgrowth were measured by live cell imaging, and gene expression levels related to neuronal identity were analyzed by RT-QPCR and immunocytochemistry during differentiation into hippocampal dentate gyrus granule cells following treatment of low- and high-dose antipsychotics (haloperidol, olanzapine, and risperidone).
RESULTS
Antipsychotics did not modify the growth properties of NPCs after 3 days of treatment. However, the characteristics of neurite outgrowth changed significantly in response to haloperidol and olanzapine. After three weeks of differentiation, mRNA expression levels of the selected neuronal markers increased (except for MAP2), while antipsychotics caused only subtle changes. Additionally, we found no changes in MAP2 or GFAP protein expression levels as a result of antipsychotic treatment.
CONCLUSIONS
Altogether, antipsychotic medications promoted neurogenesis in vitro by influencing neurite outgrowth rather than changing cell survival or gene expression. This study provides insights into the effects of antipsychotics on neuronal differentiation and highlights the importance of considering neurite outgrowth as a potential target of action.
Topics: Humans; Olanzapine; Risperidone; Neurogenesis; Hippocampus; Haloperidol; Antipsychotic Agents; Induced Pluripotent Stem Cells; Neural Stem Cells; Cell Differentiation; Cell Proliferation; Cells, Cultured; Neuronal Outgrowth
PubMed: 38927091
DOI: 10.3390/biom14060688 -
Frontiers in Psychiatry 2024Abuse or misuse of tobacco, e-cigarettes, or antidepressants may have serious clinical consequences during adolescence, a sensitive period during brain development when...
INTRODUCTION
Abuse or misuse of tobacco, e-cigarettes, or antidepressants may have serious clinical consequences during adolescence, a sensitive period during brain development when the distinct neurobiology of adolescent serotonin (5-HT) and dopamine (DA) systems create unique behavioral vulnerabilities to drugs of abuse.
METHODS
Using a pharmacological approach, we modeled the behavioral and neurochemical effects of subchronic (4-day) nicotine (60µg/kg, i.v.) or fluoxetine (1mg/kg, i.v.) exposure in adolescent and adult male rats.
RESULTS
Nicotine and fluoxetine significantly enhance quinpirole-induced locomotor activity and initial cocaine self-administration in adolescents, but not adults. These effects were blocked by serotonin 5-HT receptor antagonists, WAY-100,635 (100 µg/kg, i.v.) or S-15535 (300 µg/kg, i.v.). Neurochemical and anatomical autoradiographic analysis of 8-OH-DPAT-stimulated [S]GTPγS reveal that prior exposure to nicotine and fluoxetine results in both overlapping and distinct effects on regional 5-HT1A receptor activity. Both fluoxetine and nicotine enhance adolescent 5-HT1A receptor activity in the primary motor cortex (M1), whereas fluoxetine alone targets prefrontal cortical neurocircuitry and nicotine alone targets the amygdala.
DISCUSSION
Given their different pharmacological profiles, comparison between WAY-100,635 and S-15535 indicates that postsynaptic 5-HT receptors mediate the behavioral effects of prior nicotine and fluoxetine exposure. In addition, within the adolescent M1, maladaptive changes in 5-HT signaling and 5-HT activity after nicotine or fluoxetine exposure may potentiate hyper-responsiveness to dopaminergic drugs and prime adolescent vulnerability for future substance abuse.
PubMed: 38919632
DOI: 10.3389/fpsyt.2024.1380123 -
Biomolecules & Therapeutics Jun 2024Colorectal cancer (CRC) continues to demonstrate high incidence and mortality rates, emphasizing that implementing strategic measures for prevention and treatment is...
Colorectal cancer (CRC) continues to demonstrate high incidence and mortality rates, emphasizing that implementing strategic measures for prevention and treatment is crucial. Recently, the dopamine receptor D2 (DRD2), a G protein-coupled receptor, has been reported to play multiple roles in growth of tumor cells. This study investigated the anticancer potential of domperidone, a dopamine receptor D2 antagonist, in HCT116 human CRC cells. Domperidone demonstrated concentration- and time-dependent reductions in cell viability, thereby inducing apoptosis. The molecular mechanism revealed that domperidone modulated the mitochondrial pathway, decreasing mitochondrial Bcl-2 levels, elevating cytosolic cytochrome C expression, and triggering caspase- 3, -7, and -9 cleavage. Domperidone decreased in formation of β-arrestin2/MEK complex, which contributing to inhibition of ERK activation. Additionally, treatment with domperidone diminished JAK2 and STAT3 activation. Treatment of U0126, the MEK inhibitor, resulted in reduced phosphorylation of MEK, ERK, and STAT3 without alteration of JAK2 activation, indicating that domperidone targeted both MEK-ERK-STAT3 and JAK2-STAT3 signaling pathways, respectively. Immunoblot analysis revealed that domperidone also downregulated DRD2 expression. Domperidone-induced reactive oxygen species (ROS) generation and -acetylcysteine treatment mitigated ROS levels and restored cell viability. An xenograft study verified the significant antitumor effects of domperidone. These results emphasize the multifaceted anticancer effects of domperidone, highlighting its potential as a promising therapeutic agent for human CRC.
PubMed: 38914471
DOI: 10.4062/biomolther.2024.048 -
PloS One 2024Antibiotic resistance genes (ARGs) transfer rapidly among bacterial species all over the world contributing to the aggravation of antibiotic resistance crisis....
BACKGROUND
Antibiotic resistance genes (ARGs) transfer rapidly among bacterial species all over the world contributing to the aggravation of antibiotic resistance crisis. Antibiotics at sub-inhibitory concentration induce horizontal gene transfer (HRT) between bacteria, especially through conjugation. The role of common non-antibiotic pharmaceuticals in the market in disseminating antibiotic resistance is not well studied.
OBJECTIVES
In this work, we indicated the effect of some commonly used non-antibiotic pharmaceuticals including antiemetic (metoclopramide HCl) and antispasmodics (hyoscine butyl bromide and tiemonium methyl sulfate) on the plasmid-mediated conjugal transfer of antibiotic resistance genes between pathogenic E. coli in the gastric intestinal tract (GIT).
METHODS
Broth microdilution assay was used to test the antibacterial activity of the tested non-antibiotic pharmaceuticals. A conjugation mating system was applied in presence of the studied non-antibiotic pharmaceuticals to test their effect on conjugal transfer frequency. Plasmid extraction and PCR were performed to confirm the conjugation process. Transmission electron microscopy (TEM) was used for imaging the effect of non-antibiotic pharmaceuticals on bacterial cells.
RESULTS
No antibacterial activity was reported for the used non-antibiotic pharmaceuticals. Plasmid-mediated conjugal transfer between isolates was induced by metoclopramide HCl but suppressed by hyoscine butyl bromide. Tiemonium methylsulfate slightly promoted conjugal transfer. Aggregation between cells and periplasmic bridges was clear in the case of metoclopramide HCl while in presence of hyoscine butyl bromide little affinity was observed.
CONCLUSION
This study indicates the contribution of non-antibiotic pharmaceuticals to the dissemination and evolution of antibiotic resistance at the community level. Metoclopramide HCl showed an important role in the spread of antibiotic resistance.
Topics: Escherichia coli; Gene Transfer, Horizontal; Plasmids; Metoclopramide; Microbial Sensitivity Tests; Anti-Bacterial Agents; Drug Resistance, Bacterial; Conjugation, Genetic; Drug Resistance, Microbial
PubMed: 38905247
DOI: 10.1371/journal.pone.0304980 -
Psychiatry Research Jun 2024The risk of fatal choking for people with schizophrenia and associations with antipsychotic medication are largely unknown. Therefore, we calculated the choking-related...
The risk of fatal choking for people with schizophrenia and associations with antipsychotic medication are largely unknown. Therefore, we calculated the choking-related standardized mortality ratio for schizophrenia relative to the general population (SMR). We also computed adjusted hazard ratios (aHR) of choking-related mortality for antipsychotics in a nationwide cohort of patients with schizophrenia (N = 59,916). SMR was 20.5 (95 % confidence interval (CI)=17.1-23.9). The aHR was 1.74 (95 %CI=1.19-2.55) for strong dopamine 2-antagonists. For other antipsychotics, CIs included 1. Importantly, aHRs were particularly high for high dose categories of strong dopamine D2 receptor (D2R) antagonists. In conclusion, a schizophrenia diagnosis is associated with a 20-fold risk of death due to choking. This risk is elevated during use of strong D2R antagonist antipsychotics, particularly when prescribed in high dosages.
PubMed: 38901365
DOI: 10.1016/j.psychres.2024.116012 -
Molecules (Basel, Switzerland) Jun 2024Sigma receptors (SRs), including SR1 and SR2 subtypes, have attracted increasing interest in recent years due to their involvement in a wide range of activities,...
Sigma receptors (SRs), including SR1 and SR2 subtypes, have attracted increasing interest in recent years due to their involvement in a wide range of activities, including the modulation of opioid analgesia, neuroprotection, and potential anticancer activity. In this context, haloperidol (HAL), a commonly used antipsychotic drug, also possesses SR activity and cytotoxic effects. Herein, we describe the identification of novel SR ligands, obtained by a chemical hybridization approach. There wereendowed with pan-affinity for both SR subtypes and evaluated their potential anticancer activity against SH-SY5Y and HUH-7 cancer cell lines. Through a chemical hybridization approach, we identified novel compounds (, , , and ) with dual affinity for SR1 and SR2 receptors. These compounds were subjected to cytotoxicity testing using a resazurin assay. The results revealed potent cytotoxic effects against both cancer cell lines, with IC values comparable to HAL. Interestingly, the cytotoxic potency of the novel compounds resembled that of the SR1 antagonist HAL rather than the SR2 agonist siramesine (SRM), indicating the potential role of SR1 antagonism in their mechanism of action. The further exploration of their structure-activity relationships and their evaluation in additional cancer cell lines will elucidate their therapeutic potential and may pave the way for the development of novel anticancer agents that target SRs.
Topics: Receptors, sigma; Haloperidol; Humans; Antineoplastic Agents; Cell Line, Tumor; Drug Design; Structure-Activity Relationship; Molecular Structure; Cell Survival; Ligands; Cell Proliferation; Drug Screening Assays, Antitumor
PubMed: 38893570
DOI: 10.3390/molecules29112697