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Neuroscience and Biobehavioral Reviews Sep 2016Rodent defense behavior assays have been widely used as preclinical models of anxiety to study possibly therapeutic anxiety-reducing interventions. However, some... (Meta-Analysis)
Meta-Analysis Review
Rodent defense behavior assays have been widely used as preclinical models of anxiety to study possibly therapeutic anxiety-reducing interventions. However, some proposed anxiety-modulating factors - genes, drugs and stressors - have had discordant effects across different studies. To reconcile the effect sizes of purported anxiety factors, we conducted systematic review and meta-analyses of the literature on ten anxiety-linked interventions, as examined in the elevated plus maze, open field and light-dark box assays. Diazepam, 5-HT1A receptor gene knockout and overexpression, SERT gene knockout and overexpression, pain, restraint, social isolation, corticotropin-releasing hormone and Crhr1 were selected for review. Eight interventions had statistically significant effects on rodent anxiety, while Htr1a overexpression and Crh knockout did not. Evidence for publication bias was found in the diazepam, Htt knockout, and social isolation literatures. The Htr1a and Crhr1 results indicate a disconnect between preclinical science and clinical research. Furthermore, the meta-analytic data confirmed that genetic SERT anxiety effects were paradoxical in the context of the clinical use of SERT inhibitors to reduce anxiety.
Topics: Anxiety; Anxiety Disorders; Corticotropin-Releasing Hormone; Humans; Receptors, Corticotropin-Releasing Hormone; Social Isolation
PubMed: 27328783
DOI: 10.1016/j.neubiorev.2016.04.011 -
European Review For Medical and... Jan 2017Thyroid disorders, especially Hashimoto's thyroiditis (HT), are observed significantly more often in patients with polycystic ovary syndrome (PCOS) than in the general... (Review)
Review
OBJECTIVE
Thyroid disorders, especially Hashimoto's thyroiditis (HT), are observed significantly more often in patients with polycystic ovary syndrome (PCOS) than in the general population - approximately 27% and 8%, respectively. This is extremely important in young women, because both disorders are connected with fertility problems. As HT and PCOS occur together, fertility problems may become a serious clinical issue in these patients.
MATERIALS AND METHODS
A systematic literature review in PubMed of PCOS- and HT-related articles in English, published until December 2015 was conducted.
RESULTS
The reasons for joint prevalence still remain unclear. Genetic and autoimmune backgrounds are recognized to be possible common etiological factors. Three genetic polymorphisms have been described to play a role in PCOS as well as in HT. They are polymorphism of the gene for fibrillin 3 (FBN3) regulating the activity of transforming growth factor-b (TGF-b) and regulatory T cell levels, gonadotropin-releasing hormone receptor (GnRHR) polymorphism and CYP1B1 polymorphism standing for estradiol hydroxylation. High estrogen-to-progesterone ratios owing to anovulatory cycles, as well as high estrogen levels during prenatal life, disrupt development of the thymus and its function in maintaining immune tolerance, and are suspected to enhance autoimmune response in PCOS. Vitamin D deficiency could be also involved in the pathogenesis of HT and PCOS.
CONCLUSIONS
The above-mentioned common etiological factors associated with fertility problems in HT and PCOS require further research.
Topics: Cytochrome P-450 CYP1B1; Female; Fibrillins; Hashimoto Disease; Humans; Polycystic Ovary Syndrome; Receptors, LHRH; Transforming Growth Factor beta
PubMed: 28165551
DOI: No ID Found -
Frontiers in Bioscience (Landmark... Jan 2016Treatments for anti-N-methyl-D-aspartate (NMDA) receptor encephalitis include immunotherapy with steroids, intravenous immunoglobulin, plasma exchange, or plasmapheresis... (Review)
Review
Treatments for anti-N-methyl-D-aspartate (NMDA) receptor encephalitis include immunotherapy with steroids, intravenous immunoglobulin, plasma exchange, or plasmapheresis as first-line treatments, immunotherapy with rituximab or cyclophosphamide as second-line treatments, and tumor removal. In this systematic review, we evaluated previous studies and examined the association between certain microRNAs and anti-NMDA receptor encephalitis to investigate the performance of different treatment combinations. The efficacies of different combinations of treatments classified into the following four categories were compared: (I) intravenous immunoglobulin administration, (II) plasmapheresis or plasma exchange, (III) treatment with rituximab or cyclophosphamide and (IV) tumor removal. Statistical analyses showed that treatment combinations including at least two of these categories resulted in higher efficacy rates than treatment with a single form of therapy. These findings suggest that if a patient is not recovering, converting to other therapies is more likely to result in early recovery than continuing on the original therapy.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Child; Child, Preschool; Encephalitis; Female; Humans; Male; Middle Aged; Receptors, N-Methyl-D-Aspartate
PubMed: 26709797
DOI: 10.2741/4412 -
Autoimmunity Reviews Mar 2021Regulatory T cells (Tregs) are a subset of T cells responsible for the regulation of immune responses, thereby maintaining immune homeostasis and providing immune... (Review)
Review
Regulatory T cells (Tregs) are a subset of T cells responsible for the regulation of immune responses, thereby maintaining immune homeostasis and providing immune tolerance to both self and non-self-antigens. An increasing number of studies revealed Treg numbers and functions in a variety of autoimmune diseases. Treg deficiency can cause the development of several autoimmune skin diseases including vitiligo, alopecia areata, pemphigoid and pemphigus, psoriasis, and systemic sclerosis. Many clinical trials have been performed for autoimmune conditions using polyclonal Tregs, but efficiency can be significantly improved using antigen-specific Tregs engineered using T cell receptor (TCR) or chimeric antigen receptor (CAR) constructs. In this review, we systematically reviewed altered frequencies, impaired functions, and phenotypic features of Tregs in autoimmune skin conditions. We also summarized new advances in TCR and CAR based antigen-specific Tregs tested both in animal models and in clinics. The advantages and limitations of each approach were carefully discussed emphasizing possible clinical relevance to patients with autoimmune skin diseases. Moreover, we have reviewed potential approaches for engineering antigen-specific Tregs, and strategies for overcoming possible hurdles in clinical applications. Thereby, antigen-specific Tregs can be infused using autologous adoptive cell transfer to restore Treg numbers and to provide local immune tolerance for autoimmune skin disorders.
Topics: Animals; Autoimmune Diseases; Humans; Immune Tolerance; Receptors, Antigen, T-Cell; Skin Diseases; T-Lymphocytes, Regulatory
PubMed: 33476816
DOI: 10.1016/j.autrev.2021.102761 -
CNS Drugs Nov 2022For decades, treatment of mood disorders, psychoses, anxiety and dementia have been confounded by limited efficacy and high rates of treatment resistance. Preclinical... (Meta-Analysis)
Meta-Analysis
BACKGROUND
For decades, treatment of mood disorders, psychoses, anxiety and dementia have been confounded by limited efficacy and high rates of treatment resistance. Preclinical and clinical evidence have highlighted disruption of cholinergic signalling in several neuropsychiatric conditions and examined intervention strategies including acetylcholinesterase inhibitors and nicotinic receptor-targeted intervention. However, the effectiveness of these approaches is often curtailed by on-target side effects. Post mortem studies implicate muscarinic receptor dysregulation in neuropsychiatric pathophysiology; therefore, we conducted a systematic review and meta-analysis to investigate the therapeutic efficacy and safety of muscarinic receptor-targeted interventions in adults with neuropsychiatric disorders.
METHODS
PubMed, EMBASE, PsycINFO, EBSCO and Web of Science were searched using relevant keywords from database inception to 7 August 2022. Randomised, double-blind, placebo-controlled studies were included if they investigated the effect of muscarinic receptor-targeted intervention in adults with a diagnosis of a neuropsychiatric disorder and were published in English. A narrative synthesis approach was adopted to describe the findings. Wherever three or more studies with a similar intervention were available, effect sizes were calculated, and a meta-analysis was performed. Cochrane risk-of-bias-2 tool was utilised to assess the risk of bias, and sensitivity analyses were performed to identify publication bias. Certainty analysis (high, moderate, low and/or very low) was conducted using GRADE criteria.
RESULTS
Overall, 33 studies met the inclusion criteria and 5 were included in the meta-analysis. Despite a limited pool with several different interventions, we found therapeutic efficacy of xanomeline (M/M agonist) in primary psychotic disorders plus behavioural and psychological symptoms of dementia. Scopolamine showed a significant antidepressant effect in a combined cohort of major depressive and bipolar disorders in the short-term outcome measure, but no effect following cessation of treatment. Results from bias assessments suggest "very low" certainty in the antidepressant effect of scopolamine. Critical limitations of the current literature included low power, high heterogeneity in the patient population and a lack of active comparators.
CONCLUSION
While the results are not definitive, findings on muscarinic receptor-targeted interventions in several mental disorders are promising in terms of efficacy and safety, specifically in treating schizophrenia, mood disorders, and behavioural and psychiatric symptoms of Alzheimer's disease. However, orthosteric muscarinic receptor-targeted interventions are associated with a range of peripheral adverse effects that are thought to be mediated via M/M receptors. The orthosteric binding site of muscarinic acetylcholine receptors is remarkably conserved, posing a challenge for subtype-selective interventions; nonetheless allosteric ligands with biased signalling pathways are now in development. We conclude that adequately powered prospective studies with subtype-selective interventions are required to determine the clinical effectiveness of muscarinic-receptor targeted interventions for the treatment of neuropsychiatric disorders.
Topics: Adult; Humans; Depressive Disorder, Major; Prospective Studies; Acetylcholinesterase; Treatment Outcome; Antidepressive Agents; Receptors, Muscarinic; Scopolamine Derivatives; Dementia; Randomized Controlled Trials as Topic
PubMed: 36269510
DOI: 10.1007/s40263-022-00964-8 -
International Journal of Molecular... Nov 2022Vitamin D, formerly known for its role in calcium-phosphorus homeostasis, was shown to exert a broad influence on immunity and on differentiation and proliferation... (Meta-Analysis)
Meta-Analysis Review
Vitamin D, formerly known for its role in calcium-phosphorus homeostasis, was shown to exert a broad influence on immunity and on differentiation and proliferation processes in the last few years. In the field of endocrinology, there is proof of the potential role of vitamin D and vitamin D-related genes in the pathogenesis of thyroid cancer-the most prevalent endocrine malignancy. Therefore, the study aimed to systematically review the publications on the association between vitamin D-related gene variants (polymorphisms, mutations, etc.) and thyroid cancer. PubMed, EMBASE, Scopus, and Web of Science electronic databases were searched for relevant studies. A total of ten studies were found that met the inclusion criteria. Six vitamin D-related genes were analyzed (-vitamin D receptor, -cytochrome P450 family 2 subfamily R member 1, -cytochrome P450 family 24 subfamily A member 1, -cytochrome P450 family 27 subfamily B member 1, -7-dehydrocholesterol reductase and -cubilin). Moreover, a meta-analysis was conducted to summarize the data from the studies on polymorphisms (rs2228570/I, rs1544410/I, rs7975232/I and rs731236/I). Some associations between thyroid cancer risk (, , ) or the clinical course of the disease () and vitamin D-related gene polymorphisms were described in the literature. However, these results seem inconclusive and need validation. A meta-analysis of the five studies of common polymorphisms did not confirm their association with increased susceptibility to differentiated thyroid cancer. Further efforts are necessary to improve our understanding of thyroid cancer pathogenesis and implement targeted therapies for refractory cases.
Topics: Humans; Genetic Predisposition to Disease; Polymorphism, Single Nucleotide; Vitamin D; Vitamin D3 24-Hydroxylase; Risk Factors; Receptors, Calcitriol; Thyroid Neoplasms; Genotype
PubMed: 36362448
DOI: 10.3390/ijms232113661 -
International Journal of Molecular... Aug 2023Activation of the aryl hydrocarbon receptor (AhR) has been shown to be important in physiological processes other than detoxification, including vascular homeostasis.... (Review)
Review
Activation of the aryl hydrocarbon receptor (AhR) has been shown to be important in physiological processes other than detoxification, including vascular homeostasis. Although AhR is highly expressed in the endothelium, its function has been poorly studied. This systematic review aims to summarise current knowledge on the AhR role in the endothelium and its cardiovascular implications. We focus on endogenous AhR agonists, such as some uremic toxins and other agonists unrelated to environmental pollutants, as well as studies using AhR knockout models. We conclude that AhR activation leads to vascular oxidative stress and endothelial dysfunction and that blocking AhR signalling could provide a new target for the treatment of vascular disorders such as cardiovascular complications in patients with chronic kidney disease or pulmonary arterial hypertension.
Topics: Humans; Receptors, Aryl Hydrocarbon; Vascular Diseases; Environmental Pollutants; Familial Primary Pulmonary Hypertension; Endothelium
PubMed: 37686342
DOI: 10.3390/ijms241713537 -
The 5-HT7 receptor system as a treatment target for mood and anxiety disorders: A systematic review.Journal of Psychopharmacology (Oxford,... Dec 2023Preclinical animal and preliminary human studies indicate that 5-HT7 antagonists have the potential as a new treatment approach for mood and anxiety disorders. In this... (Review)
Review
BACKGROUND
Preclinical animal and preliminary human studies indicate that 5-HT7 antagonists have the potential as a new treatment approach for mood and anxiety disorders. In this systematic review, we aimed to review the relationship between the 5-HT7 receptor system and mood and anxiety disorders, and to explore the pharmacology and therapeutic potential of medications that target the 5-HT7 receptor for their treatment.
METHODS
Medline, Cochrane Library, EMBASE, PsycINFO databases, the National Institute of Health website Clinicaltrials.gov, controlled-trials.com, and relevant grey literature were used to search for original research articles, and reference lists of included articles were then hand searched.
RESULTS
Sixty-four studies were included in the review: 52 animal studies and 12 human studies. Studies used a variety of preclinical paradigms and questionnaires to assess change in mood, and few studies examined sleep or cognition. Forty-four out of 47 (44/47) preclinical 5-HT7 modulation studies identified potential antidepressant effects and 20/23 studies identified potential anxiolytic effects. In clinical studies, 5/7 identified potential antidepressant effects in major depressive disorder, 1/2 identified potential anxiolytic effects in generalized anxiety disorder, and 3/3 identified potential antidepressant effects in bipolar disorders.
CONCLUSION
While there is some evidence that the 5-HT7 receptor system may be a potential target for treating mood and anxiety disorders, many agents included in the review also bind to other receptors. Further research is needed using drugs that bind specifically to 5-HT7 receptors to examine treatment proof of concept further.
Topics: Animals; Humans; Anti-Anxiety Agents; Antidepressive Agents; Anxiety Disorders; Depressive Disorder, Major
PubMed: 37994803
DOI: 10.1177/02698811231211228 -
Molecular Biology Reports Nov 2022Angiotensin-converting enzyme 2 (ACE2) is known as the major viral entry site for SARS-CoV-2. However, viral tissue tropism and high rate of infectivity do not directly... (Review)
Review
BACKGROUND
Angiotensin-converting enzyme 2 (ACE2) is known as the major viral entry site for SARS-CoV-2. However, viral tissue tropism and high rate of infectivity do not directly correspond with the level of ACE2 expression in the organs. It may suggest involvement of other receptors or accessory membrane proteins in SARSCoV-2 cell entry.
METHODS AND RESULTS
A systematic search was carried out in PubMed/Medline, EMBASE, and Cochrane Library for studies reporting SARS-CoV-2 cell entry. We used a group of the MeSH terms including "cell entry", "surface receptor", "ACE2", and "SARS-CoV-2". We reviewed all selected papers published in English up to end of February 2022. We found several receptors or auxiliary membrane proteins (including CD147, NRP-1, CD26, AGTR2, Band3, KREMEN1, ASGR1, ANP, TMEM30A, CLEC4G, and LDLRAD3) along with ACE2 that facilitate virus entry and transmission. Expression of Band3 protein on the surface of erythrocytes and evidence of binding with S protein of SARS-CoV-2 may explain asymptomatic hypoxemia during COVID19 infection. The variants of SARS-CoV-2 including the B.1.1.7 (Alpha), B.1.617.1 (Kappa), B.1.617.2 (Delta), B.1.617.2+ (Delta+), and B.1.1.529 (Omicron) may have different potency to bond with these receptors.
CONCLUSIONS
The high rate of infectivity of SARS-CoV-2 may be due to its ability to enter the host cell through a group of cell surface receptors. These receptors are potential targets to develop novel therapeutic agents for SARS-CoV-2.
Topics: Humans; Angiotensin-Converting Enzyme 2; Asialoglycoprotein Receptor; COVID-19; Protein Binding; Receptors, Virus; SARS-CoV-2; Spike Glycoprotein, Coronavirus
PubMed: 35754059
DOI: 10.1007/s11033-022-07700-x -
Frontiers in Systems Neuroscience 2022Although neural plasticity is now widely studied, there was a time when the idea of adult plasticity was antithetical to the mainstream. The essential stumbling block...
Although neural plasticity is now widely studied, there was a time when the idea of adult plasticity was antithetical to the mainstream. The essential stumbling block arose from the seminal experiments of Hubel and Wiesel who presented convincing evidence that there existed a critical period for plasticity during development after which the brain lost its ability to change in accordance to shifts in sensory input. Despite the zeitgeist that mature brain is relatively immutable to change, there were a number of examples of adult neural plasticity emerging in the scientific literature. Interestingly, some of the earliest of these studies involved visual plasticity in the adult cat. Even earlier, there were reports of what appeared to be functional reorganization in adult rat somatosensory thalamus after dorsal column lesions, a finding that was confirmed and extended with additional experimentation. To demonstrate that these findings reflected more than a response to central injury, and to gain greater control of the extent of the sensory loss, peripheral nerve injuries were used that eliminated ascending sensory information while leaving central pathways intact. Merzenich, Kaas, and colleagues used peripheral nerve transections to reveal unambiguous reorganization in primate somatosensory cortex. Moreover, these same researchers showed that this plasticity proceeded in no less than two stages, one immediate, and one more protracted. These findings were confirmed and extended to more expansive cortical deprivations, and further extended to the thalamus and brainstem. There then began a series of experiments to reveal the physiological, morphological and neurochemical mechanisms that permitted this plasticity. Ultimately, Mowery and colleagues conducted a series of experiments that carefully tracked the levels of expression of several subunits of glutamate (AMPA and NMDA) and GABA (GABAA and GABAB) receptor complexes in primate somatosensory cortex at several time points after peripheral nerve injury. These receptor subunit mapping experiments revealed that membrane expression levels came to reflect those seen in early phases of critical period development. This suggested that under conditions of prolonged sensory deprivation the adult cells were returning to critical period like plastic states, i.e., developmental recapitulation. Here we outline the heuristics that drive this phenomenon.
PubMed: 36762289
DOI: 10.3389/fnsys.2022.1086680