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Cancer Treatment and Research... 2021The significant physical and emotional effects of chemotherapy-induced nausea and vomiting (CINV) are experienced by cancer patients. Severe symptoms decrease the... (Review)
Review
The significant physical and emotional effects of chemotherapy-induced nausea and vomiting (CINV) are experienced by cancer patients. Severe symptoms decrease the patient's quality of life and potentially deters further treatment. The five main forms of CINV (i.e., acute, delayed, anticipatory, breakthrough, and refractory) require different treatment regimens, which often include 5-HT3 receptor antagonists, NK1 receptor antagonists, and corticosteroids. Despite a significant amount of research and development of antiemetic agents, management of CINV remains a great challenge with many needs waiting to be adequately addressed, such as controlling non-acute CINV, developing appropriate CINV treatment protocols for multiple-day chemotherapy patients, and providing options for those prone to CINV despite treatment. Further research is required to optimize CINV management for these patients.
Topics: Antiemetics; Antineoplastic Agents; Glucocorticoids; Humans; Medication Adherence; Nausea; Neoplasms; Neurokinin-1 Receptor Antagonists; Quality of Life; Serotonin 5-HT3 Receptor Antagonists; Vomiting
PubMed: 33360668
DOI: 10.1016/j.ctarc.2020.100278 -
International Journal of Molecular... Jan 2021Serotonin (5-hydroxytryptamine, 5-HT) is a biogenic monoamine produced from the essential amino acid tryptophan. Serotonin's role as a neurotransmitter in the central... (Review)
Review
Serotonin (5-hydroxytryptamine, 5-HT) is a biogenic monoamine produced from the essential amino acid tryptophan. Serotonin's role as a neurotransmitter in the central nervous system and a motility mediator in the gastrointestinal tract has been well defined, and its function in tumorigenesis in various cancers (gliomas, carcinoids, and carcinomas) is being studied. Many studies have shown a potential stimulatory effect of serotonin on cancer cell proliferation, invasion, dissemination, and tumor angiogenesis. Although the underlying mechanism is complex, it is proposed that serotonin levels in the tumor and its interaction with specific receptor subtypes are associated with disease progression. This review article describes serotonin's role in cancer pathogenesis and the utility of the serotonin pathway as a potential therapeutic target in cancer treatment. Octreotide, an inhibitor of serotonin release, is used in well-differentiated neuroendocrine cancers, and the tryptophan hydroxylase (TPH) inhibitor, telotristat, is currently being investigated in clinical trials to treat patients with metastatic neuroendocrine tumors and advanced cholangiocarcinoma. Several in vitro studies have shown the anticancer effect of 5-HT receptor antagonists in various cancers such as prostate cancer, breast cancer, urinary bladder, colorectal cancer, carcinoid, and small-cell lung cancer. More in vivo studies are needed to assess serotonin's role in cancer and its potential use as an anticancer therapeutic target. Serotonin is also being evaluated for its immunoregulatory properties, and studies have shown its potential anti-inflammatory effect. Therefore, it would be of interest to explore the combination of serotonin antagonists with immunotherapy in the future.
Topics: Antineoplastic Agents, Hormonal; Carcinoma, Neuroendocrine; Cell Movement; Cell Proliferation; Cholangiocarcinoma; Gene Expression Regulation, Neoplastic; Humans; Molecular Targeted Therapy; Neovascularization, Pathologic; Octreotide; Phenylalanine; Pyrimidines; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Signal Transduction; Tryptophan Hydroxylase; Tumor Cells, Cultured
PubMed: 33525332
DOI: 10.3390/ijms22031268 -
International Journal of Molecular... Feb 2021In the 21st century and especially during a pandemic, the diagnosis and treatment of depression is an essential part of the daily practice of many family doctors. It... (Review)
Review
In the 21st century and especially during a pandemic, the diagnosis and treatment of depression is an essential part of the daily practice of many family doctors. It mainly affects patients in the age category 15-44 years, regardless of gender. Anxiety disorders are often diagnosed in children and adolescents. Social phobias can account for up to 13% of these diagnoses. Social anxiety manifests itself in fear of negative social assessment and humiliation, which disrupts the quality of social functioning. Treatment of the above-mentioned disorders is based on psychotherapy and pharmacotherapy. Serious side effects or mortality from antidepressant drug overdose are currently rare. Recent studies indicate that paroxetine (ATC code: N06AB), belonging to the selective serotonin reuptake inhibitors, has promising therapeutic effects and is used off-label in children and adolescents. The purpose of this review is to describe the interaction of paroxetine with several molecular targets in various points of view including the basic chemical and pharmaceutical properties. The central point of the review is focused on the pharmacodynamic analysis based on the molecular mechanism of binding paroxetine to various therapeutic targets.
Topics: Animals; Antidepressive Agents, Second-Generation; Depressive Disorder; Humans; Paroxetine; Serotonin Antagonists
PubMed: 33562229
DOI: 10.3390/ijms22041662 -
Gut Jul 2021Irritable bowel syndrome (IBS) remains one of the most common gastrointestinal disorders seen by clinicians in both primary and secondary care. Since publication of the...
Irritable bowel syndrome (IBS) remains one of the most common gastrointestinal disorders seen by clinicians in both primary and secondary care. Since publication of the last British Society of Gastroenterology (BSG) guideline in 2007, substantial advances have been made in understanding its complex pathophysiology, resulting in its re-classification as a disorder of gut-brain interaction, rather than a functional gastrointestinal disorder. Moreover, there has been a considerable amount of new evidence published concerning the diagnosis, investigation and management of IBS. The primary aim of this guideline, commissioned by the BSG, is to review and summarise the current evidence to inform and guide clinical practice, by providing a practical framework for evidence-based management of patients. One of the strengths of this guideline is that the recommendations for treatment are based on evidence derived from a comprehensive search of the medical literature, which was used to inform an update of a series of trial-based and network meta-analyses assessing the efficacy of dietary, pharmacological and psychological therapies in treating IBS. Specific recommendations have been made according to the Grading of Recommendations Assessment, Development and Evaluation system, summarising both the strength of the recommendations and the overall quality of evidence. Finally, this guideline identifies novel treatments that are in development, as well as highlighting areas of unmet need for future research.
Topics: Biomedical Research; Cognitive Behavioral Therapy; Communication; Constipation; Diarrhea; Diet; Drug Development; Humans; Hypnosis; Irritable Bowel Syndrome; Patient Education as Topic; Physician-Patient Relations; Probiotics; Randomized Controlled Trials as Topic; Serotonin Antagonists; United Kingdom
PubMed: 33903147
DOI: 10.1136/gutjnl-2021-324598 -
Neuron Aug 2019The role of serotonin (5-HT) in sleep is controversial: early studies suggested a sleep-promoting role, but eventually the paradigm shifted toward a wake-promoting...
The role of serotonin (5-HT) in sleep is controversial: early studies suggested a sleep-promoting role, but eventually the paradigm shifted toward a wake-promoting function for the serotonergic raphe. Here, we provide evidence from zebrafish and mice that the raphe are critical for the initiation and maintenance of sleep. In zebrafish, genetic ablation of 5-HT production by the raphe reduces sleep, sleep depth, and the homeostatic response to sleep deprivation. Pharmacological inhibition or ablation of the raphe reduces sleep, while optogenetic stimulation increases sleep. Similarly, in mice, ablation of the raphe increases wakefulness and impairs the homeostatic response to sleep deprivation, whereas tonic optogenetic stimulation at a rate similar to baseline activity induces sleep. Interestingly, burst optogenetic stimulation induces wakefulness in accordance with previously described burst activity of the raphe during arousing stimuli. These results indicate that the serotonergic system promotes sleep in both diurnal zebrafish and nocturnal rodents. VIDEO ABSTRACT.
Topics: Animals; Arousal; Buspirone; Circadian Rhythm; Fenclonine; Homeostasis; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Optogenetics; Quipazine; Raphe Nuclei; Serotonergic Neurons; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Sleep; Sleep Deprivation; Tryptophan Hydroxylase; Wakefulness; Zebrafish; Zebrafish Proteins
PubMed: 31248729
DOI: 10.1016/j.neuron.2019.05.038 -
Science (New York, N.Y.) Jun 2024AlphaFold2 (AF2) models have had wide impact but mixed success in retrospective ligand recognition. We prospectively docked large libraries against unrefined AF2 models...
AlphaFold2 (AF2) models have had wide impact but mixed success in retrospective ligand recognition. We prospectively docked large libraries against unrefined AF2 models of the σ and serotonin 2A (5-HT2A) receptors, testing hundreds of new molecules and comparing results with those obtained from docking against the experimental structures. Hit rates were high and similar for the experimental and AF2 structures, as were affinities. Success in docking against the AF2 models was achieved despite differences between orthosteric residue conformations in the AF2 models and the experimental structures. Determination of the cryo-electron microscopy structure for one of the more potent 5-HT2A ligands from the AF2 docking revealed residue accommodations that resembled the AF2 prediction. AF2 models may sample conformations that differ from experimental structures but remain low energy and relevant for ligand discovery, extending the domain of structure-based drug design.
Topics: Humans; Cryoelectron Microscopy; Drug Design; Drug Discovery; Ligands; Molecular Docking Simulation; Protein Conformation; Protein Folding; Receptor, Serotonin, 5-HT2A; Receptors, sigma; Small Molecule Libraries; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Deep Learning
PubMed: 38753765
DOI: 10.1126/science.adn6354 -
International Journal of Molecular... Dec 2021Depression is a multifactorial disorder that affects millions of people worldwide, and none of the currently available therapeutics can completely cure it. Thus, there... (Review)
Review
Depression is a multifactorial disorder that affects millions of people worldwide, and none of the currently available therapeutics can completely cure it. Thus, there is a need for developing novel, potent, and safer agents. Recent medicinal chemistry findings on the structure and function of the serotonin 2A (5-HT) receptor facilitated design and discovery of novel compounds with antidepressant action. Eligible papers highlighting the importance of 5-HT receptors in the pathomechanism of the disorder were identified in the content-screening performed on the popular databases (PubMed, Google Scholar). Articles were critically assessed based on their titles and abstracts. The most accurate papers were chosen to be read and presented in the manuscript. The review summarizes current knowledge on the applicability of 5-HT receptor signaling modulators in the treatment of depression. It provides an insight into the structural and physiological features of this receptor. Moreover, it presents an overview of recently conducted virtual screening campaigns aiming to identify novel, potent 5-HT receptor ligands and additional data on currently synthesized ligands acting through this protein.
Topics: Antidepressive Agents; Depression; Drug Design; Humans; Ligands; Models, Molecular; Protein Conformation; Receptor, Serotonin, 5-HT2A; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Structure-Activity Relationship
PubMed: 35008436
DOI: 10.3390/ijms23010010 -
Parasites & Vectors Jan 2021Serotonin is a phylogenetically ancient molecule that is widely distributed in most metazoans, including flatworms. In addition to its role as a neurotransmitter,...
BACKGROUND
Serotonin is a phylogenetically ancient molecule that is widely distributed in most metazoans, including flatworms. In addition to its role as a neurotransmitter, serotonin acts as a morphogen and regulates developmental processes. Although several studies have focused on the serotonergic nervous system in parasitic flatworms, little is known on the role of serotonin in flatworm development.
METHODS
To study the effects of serotonin on proliferation and development of the cestode Echinococcus multilocularis, we cloned the genes encoding the E. multilocularis serotonin transporter (SERT) and tryptophan hydroxylase (TPH), analyzed gene expression by transcriptome analysis and whole mount in situ hybridization (WMISH) and performed cell culture experiments.
RESULTS
We first characterized orthologues encoding the SERT and TPH, the rate-limiting enzyme in serotonin biosynthesis. WMISH and transcriptomic analyses indicated that the genes for both SERT and TPH are expressed in the parasite nervous system. Long-term treatment of parasite stem cell cultures with serotonin stimulated development towards the parasite metacestode stage. Mature metacestode vesicles treated with serotonin showed increased rates of incorporation of the thymidine analogue 5-ethynyl-2'-deoxyuridine (EdU), indicating stimulated cell proliferation. In contrast, treatment with the selective serotonin reuptake inhibitor paroxetine strongly affected the viability of parasite cells. Paroxetine also caused structural damage in metacestode vesicles, suggesting that serotonin transport is crucial for the integrity of parasite vesicles.
CONCLUSIONS
Our results indicate that serotonin plays an important role in E. multilocularis development and proliferation, providing evidence that the E. multilocularis SERT and TPH are expressed in the nervous system of the protoscolex. Our results further suggest that the E. multilocularis SERT has a secondary role outside the nervous system that is essential for parasite integrity and survival. Since serotonin stimulated E. multilocularis metacestode development and proliferation, serotonin might also contribute to the formation and growth of the parasite in the liver.
Topics: Animals; Cell Proliferation; Echinococcus multilocularis; Gene Expression; Gene Expression Profiling; Helminth Proteins; In Situ Hybridization; Larva; Nervous System; Paroxetine; Serotonin; Serotonin Antagonists; Serotonin Plasma Membrane Transport Proteins; Tryptophan Hydroxylase
PubMed: 33407815
DOI: 10.1186/s13071-020-04533-0 -
International Journal of Molecular... Mar 2022Fine temperature control is essential in homeothermic animals. Both hyper- and hypothermia can have deleterious effects. Multiple, efficient and partly redundant... (Review)
Review
Fine temperature control is essential in homeothermic animals. Both hyper- and hypothermia can have deleterious effects. Multiple, efficient and partly redundant mechanisms of adjusting the body temperature to the value set by the internal thermostat exist. The neural circuitry of temperature control and the neurotransmitters involved are reviewed. The GABAergic inhibitory output from the brain thermostat in the preoptic area POA to subaltern neural circuitry of temperature control (Nucleus Raphe Dorsalis and Nucleus Raphe Pallidus) is a function of the balance between the (opposite) effects mediated by the transient receptor potential receptor TRPM2 and EP3 prostaglandin receptors. Activation of TRPM2-expressing neurons in POA favors hypothermia, while inhibition has the opposite effect. Conversely, EP3 receptors induce elevation in body temperature. Activation of EP3-expressing neurons in POA results in hyperthermia, while inhibition has the opposite effect. Agonists at TRPM2 and/or antagonists at EP3 could be beneficial in hyperthermia control. Activity of the neural circuitry of temperature control is modulated by a variety of 5-HT receptors. Based on the theoretical model presented the "ideal" antidote against serotonin syndrome hyperthermia appears to be an antagonist at the 5-HT receptor subtypes 2, 4 and 6 and an agonist at the receptor subtypes 1, 3 and 7. Very broadly speaking, such a profile translates in a sympatholytic effect. While a compound with such an ideal profile is presently not available, better matches than the conventional antidote cyproheptadine (used off-label in severe serotonin syndrome cases) appear to be possible and need to be identified.
Topics: Animals; Antidotes; Cyproheptadine; Hyperthermia; Hyperthermia, Induced; Hypothermia; Serotonin; Serotonin Syndrome; TRPM Cation Channels
PubMed: 35328784
DOI: 10.3390/ijms23063365 -
Journal of the American Academy of... Sep 2023Antipsychotic-induced hyperprolactinemia is common in children and adolescents, but this quotidian presence in our clinics should neither reassure us nor make us...
Antipsychotic-induced hyperprolactinemia is common in children and adolescents, but this quotidian presence in our clinics should neither reassure us nor make us complacent. The report by Koch and colleagues stands out against the landscape of trials describing the adverse effects of psychotropic medications in youth. It goes beyond the typical examination of adverse effects in most clinical trials. The authors followed children and adolescents aged 4 to 17 years who were dopamine-serotonin receptor antagonist naive (≤1-week exposure) or free, and serially evaluated not only serum prolactin concentrations but medication concentrations and side effects for 12 weeks after participants began aripiprazole, olanzapine, quetiapine, or risperidone. This report provides insights into the temporal course of adverse effects, examines differential tolerability among dopamine-serotonin receptor antagonists, links specific adverse effects-galactorrhea, decreased libido, and erectile dysfunction-with prolactin concentrations in youth, and focuses on the clinical aspects of hyperprolactinemia and related adverse effects in children and adolescents.
Topics: Male; Female; Adolescent; Child; Humans; Antipsychotic Agents; Hyperprolactinemia; Prolactin; Dopamine; Risperidone; Aripiprazole
PubMed: 37172820
DOI: 10.1016/j.jaac.2023.05.003