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Frontiers in Immunology 2023There are difficulties in creating direct antiviral drugs for all viruses, including new, suddenly arising infections, such as COVID-19. Therefore, pathogenesis-directed...
INTRODUCTION
There are difficulties in creating direct antiviral drugs for all viruses, including new, suddenly arising infections, such as COVID-19. Therefore, pathogenesis-directed therapy is often necessary to treat severe viral infections and comorbidities associated with them. Despite significant differences in the etiopathogenesis of viral diseases, in general, they are associated with significant dysfunction of the immune system. Study of common mechanisms of immune dysfunction caused by different viral infections can help develop novel therapeutic strategies to combat infections and associated comorbidities.
METHODS
To identify common mechanisms of immune functions disruption during infection by nine different viruses (cytomegalovirus, Ebstein-Barr virus, human T-cell leukemia virus type 1, Hepatitis B and C viruses, human immunodeficiency virus, Dengue virus, SARS-CoV, and SARS-CoV-2), we analyzed the corresponding transcription profiles from peripheral blood mononuclear cells (PBMC) using the originally developed pipeline that include transcriptome data collection, processing, normalization, analysis and search for master regulators of several viral infections. The ten datasets containing transcription data from patients infected by nine viruses and healthy people were obtained from Gene Expression Omnibus. The analysis of the data was performed by Genome Enhancer pipeline.
RESULTS
We revealed common pathways, cellular processes, and master regulators for studied viral infections. We found that all nine viral infections cause immune activation, exhaustion, cell proliferation disruption, and increased susceptibility to apoptosis. Using network analysis, we identified PBMC receptors, representing proteins at the top of signaling pathways that may be responsible for the observed transcriptional changes and maintain the current functional state of cells.
DISCUSSION
The identified relationships between some of them and virus-induced alteration of immune functions are new and have not been found earlier, e.g., receptors for autocrine motility factor, insulin, prolactin, angiotensin II, and immunoglobulin epsilon. Modulation of the identified receptors can be investigated as one of therapeutic strategies for the treatment of severe viral infections.
Topics: Humans; Leukocytes, Mononuclear; Transcriptome; Antiviral Agents; COVID-19; Viruses; Immunity
PubMed: 37795081
DOI: 10.3389/fimmu.2023.1199482 -
Journal of Personalized Medicine Feb 2024Sex hormones and migraine are closely interlinked. Women report higher levels of migraine symptoms during periods of sex hormone fluctuation, particularly during... (Review)
Review
Sex hormones and migraine are closely interlinked. Women report higher levels of migraine symptoms during periods of sex hormone fluctuation, particularly during puberty, pregnancy, and perimenopause. Ovarian steroids, such as estrogen and progesterone, exert complex effects on the peripheral and central nervous systems, including pain, a variety of special sensory and autonomic functions, and affective processing. A panel of basic scientists, when challenged to explain what was known about how sex hormones affect the nervous system, focused on two hormones: estrogen and oxytocin. Notably, other hormones, such as progesterone, testosterone, and vasopressin, are less well studied but are also highlighted in this review. When discussing what new therapeutic agent might be an alternative to hormone therapy and menopause replacement therapy for migraine treatment, the panel pointed to oxytocin delivered as a nasal spray. Overall, the conclusion was that progress in the preclinical study of hormones on the nervous system has been challenging and slow, that there remain substantial gaps in our understanding of the complex roles sex hormones play in migraine, and that opportunities remain for improved or novel therapeutic agents. Manipulation of sex hormones, perhaps through biochemical modifications where its positive effects are selected for and side effects are minimized, remains a theoretical goal, one that might have an impact on migraine disease and other symptoms of menopause. This review is a call to action for increased interest and funding for preclinical research on sex hormones, their metabolites, and their receptors. Interdisciplinary research, perhaps facilitated by a collaborative communication network or panel, is a possible strategy to achieve this goal.
PubMed: 38392617
DOI: 10.3390/jpm14020184 -
Reproductive Biology Dec 2023Heme oxygenase 1 (Hmox1), the inducible form of heme degrading enzymes Hmoxs, is important for establishment and maintenance of pregnancy. A growing body of evidence...
Heme oxygenase 1 (Hmox1), the inducible form of heme degrading enzymes Hmoxs, is important for establishment and maintenance of pregnancy. A growing body of evidence suggests an association between Hmox1 and angiogenesis, including placental angiogenesis. In this study, we examined the expression of two angiogenic factors in the placentas of Hmox1 deficient mouse embryos, whose expression was found to be related to that of Hmox1. Relative protein levels and localization of Hmoxs and two angiogenic factors [Vegf and Prolactin along with their receptors, and Cd31/Pecam1] were compared in the placentas of Hmox1 wildtype and knockout mouse embryos using western blotting and immunohistochemistry along with histological analysis. The results revealed tissue disorganisation, reduced area of labyrinth and smaller nuclear size of trophoblast giant cell in the placentas of knockout embryos. The levels of Hmox2, prolactin, and Cd31/Pecam1 were found to be altered in knockout placentas, whereas Vegf and its receptors seem to be unaltered in our samples. Overall, our findings imply that Hmox2 is unlikely to compensate for Hmox1 deficiency in knockout placentas, and altered levels of prolactin and Cd31/Pecam1 hint towards impaired angiogenesis in these placentas. Further investigation would be needed to understand the molecular mechanism of defective angiogenesis in the placentas of Hmox1 knockout mouse embryos.
Topics: Animals; Female; Mice; Pregnancy; Heme Oxygenase-1; Mice, Knockout; Placenta; Prolactin; Vascular Endothelial Growth Factor A
PubMed: 37979494
DOI: 10.1016/j.repbio.2023.100822 -
Cureus May 2024Hyperprolactinemia is an endocrinological disorder that might arise from various physiologic or pathologic conditions, as well as from pharmacologic sources. These...
Hyperprolactinemia is an endocrinological disorder that might arise from various physiologic or pathologic conditions, as well as from pharmacologic sources. These pharmacologic sources include antidepressants, antipsychotics, and dopamine receptor-blocking agents. Amitriptyline is classified as a tricyclic antidepressant. While it is FDA-approved primarily for the treatment of depression, amitriptyline also demonstrates efficacy in managing various other conditions, such as anxiety, post-traumatic stress disorder, insomnia, chronic and neuropathic pain, and migraine prevention. We present a case of a 10-year-old patient with a history of autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and migraine headaches who was incidentally found to have elevated prolactin levels while taking amitriptyline for migraine prophylaxis. While risperidone, an antipsychotic that can be used for ASD management, is commonly known to induce hyperprolactinemia, the association between amitriptyline and elevated prolactin is less frequently described in the literature. This case underscores the necessity for healthcare providers across various specialties to be aware of amitriptyline-induced hyperprolactinemia.
PubMed: 38826982
DOI: 10.7759/cureus.59604 -
Brain : a Journal of Neurology Jun 2024The prevalence of many pain conditions often differs between sexes. In addition to such quantitative distinctions, sexual dimorphism may also be qualitative reflecting...
The prevalence of many pain conditions often differs between sexes. In addition to such quantitative distinctions, sexual dimorphism may also be qualitative reflecting differences in mechanisms that promote pain in men and women. A major factor that influences the likelihood of pain perception is the threshold for activation of nociceptors. Peripheral nociceptor sensitization has been demonstrated to be clinically relevant in many pain conditions. Whether peripheral nociceptor sensitization can occur in a sexually dimorphic fashion, however, has not been extensively studied. To address this fundamental knowledge gap, we used patch clamp electrophysiology to evaluate the excitability of dorsal root ganglion neurones from male or female rodents, non-human primates, and humans following exposure to putative sensitizing agents. Previous studies from our laboratory, and others, have shown that prolactin promotes female-selective pain responses in rodents. Consistent with these observations, dorsal root ganglion neurones from female, but not male, mice were selectively sensitized by exposure to prolactin. The sensitizing action of prolactin was also confirmed in dorsal root ganglion neurones from a female macaque monkey. Critically, neurones recovered from female, but not male, human donors were also selectively sensitized by prolactin. In the course of studies of sleep and pain, we unexpectedly observed that an orexin antagonist could normalize pain responses in male animals. We found that orexin B produced sensitization of male, but not female, mouse, macaque, and human dorsal root ganglion neurones. Consistent with functional responses, increased prolactin receptor and orexin receptor 2 expression was observed in female and male mouse dorsal root ganglia, respectively. Immunohistochemical interrogation of cultured human sensory neurones and whole dorsal root ganglia also suggested increased prolactin receptor expression in females and orexin receptor 2 expression in males. These data reveal a functional double dissociation of nociceptor sensitization by sex, which is conserved across species and is likely directly relevant to human pain conditions. To our knowledge, this is the first demonstration of functional sexual dimorphism in human sensory neurones. Patient sex is currently not a common consideration for the choice of pain therapy. Precision medicine, based on patient sex could improve therapeutic outcomes by selectively targeting mechanisms promoting pain in women or men. Additional implications of these findings are that the design of clinical trials for pain therapies should consider the proportions of male or female patients enrolled. Lastly, re-examination of selected past failed clinical trials with subgroup analysis by sex may be warranted.
PubMed: 38829801
DOI: 10.1093/brain/awae179 -
Heliyon Nov 2023The pathogenesis of hyperplasia of mammary glands (HMG) is a complex process, involving multiple links and systems within the body. Current clinical research indicates... (Review)
Review
BACKGROUND
The pathogenesis of hyperplasia of mammary glands (HMG) is a complex process, involving multiple links and systems within the body. Current clinical research indicates that traditional Chinese medicine (TCM) demonstrates a significant therapeutic effect in treating HMG. Single herbs or herbal pairs (two herbs) are the basic units of preventing and treating HMG. It is of great significance to explore the mechanism of single herbs or herbal pairs in treating HMG for clarifying the mechanism of preventing HMG with TCM.
PURPOSE
This study aimed to review the literature, summarize the known mechanisms of single herbs and herbal pair therapy for treating hyperplasia of mammary glands (HMG), and elucidate the relevant substances involved within and outside the body during these treatments.
STUDY DESIGN
In this study, the action mechanism of single herbs or herbal pairs in treating HMG was selected as the research object. English articles were mainly selected and Chinese articles were supplemented. We conducted a literature search in PubMed, CNKI, WanFang Database, etc,including full-text studies published between January 1992 and December 31, 2022. The primary literature was carefully screened, and the mechanism of action was explored by logical analysis.
METHODS
We conducted a literature review focusing on basic studies that explored the mechanisms underlying the effects of herbal treatments for mammary gland hyperplasia. The literature search was performed in PubMed, CNKI, and WanFang Database, covering full-text articles published from January 1992 to 31 December 2022, using various keywords (e.g., hyperplasia of mammary glands, single herb, herbal pair, effect, mechanism, inclusion criteria). Exclusion criteria were also set. We employed methods such as literature measurement, literature research, and content analysis to logically analyze, induce, and deduce the findings of the collected literature.
RESULTS
This review reveals that several distinct mechanisms contribute to the beneficial effects of single herbs or herbal pairs on the recovery of mammary gland hyperplasia. Regarding hormone levels, Chinese herbs can decrease hormones such as Estradiol(E2) and Prolactin(PRL), increase Progesterone(P) levels, balance the E2/P ratio, reduce the expression of sex hormone receptors, and lessen the self-sensitivity of breast tissue under the influence of E2. Histologically, Chinese herbs can inhibit breast neovascularization and alleviate blood viscosity. At the cellular level, Chinese herbs can modulate the expression of apoptosis genes and proteins, decrease cell proliferation activity, and ultimately inhibit or even reverse breast hyperplasia. From a pharmacological perspective, Chinese herbs exhibit analgesic, anti-inflammatory, antioxidant, and immune-regulating properties.
CONCLUSION
The evidence in this review demonstrates the effectiveness of single herbs or herbal pairs in preventing and treating mammary gland hyperplasia, with precise underlying mechanisms.
PubMed: 37920486
DOI: 10.1016/j.heliyon.2023.e21000 -
Pharmacological Research Dec 2023The burden of metabolic disorders is alarmingly increasing globally. On the other hand, sustainability is the key project of the 21st century. Natural products offer a... (Review)
Review
The burden of metabolic disorders is alarmingly increasing globally. On the other hand, sustainability is the key project of the 21st century. Natural products offer a coherent option for the complementary management of both these challenges. Ficus carica (FC), commonly known as the fig fruit, has an experimentally proven potency for the modulation of cell cycle, immunity, inflammation, metabolism, and oxidative stress. Here, we review the potential of FC-derived products (FCDP) in slowing down the progression of cancers, acute/chronic inflammation-related conditions, infections, metabolic disorders, toxicities, neurological and neuromuscular diseases, gastrointestinal disorders, vascular diseases, and skin-stressing conditions, as well as, in boosting normal healthy functions of the endocrine, immune, metabolic, and nervous systems. It reveals a variety of cellular and molecular targets for FCDP: cytokines (TNF-α, IL-1β, IL-6, IL-10, IL-12, IL-18, IFN-γ), chemokines (CCL2), other inflammatory mediators (CRP, PGE2), immune receptors (TLR-2, TLR-4, FcεRI), oxidative stress-related markers (SOD, GSH, MDA, GPx, catalase, ROS, NO, protein carbonyls), kinases (MAPKs, hexokinase, G6Pase, FBPase, PEPCK, Akt, AMPK, GSK3, CDKs), other enzymes (COX-2, iNOS, MMPs, caspases), growth factors/receptors (VEGF, EGFR), hormones (DHEAS, prolactin, GnRH, FSH, LH, estradiol, DHT, insulin), cell death-related markers (Bcl-2, Bax, Bak, FasL, gasdermins, cytochrome C), glucose transporter protein (Glut4), and transcription factors (NF-κB, HNF-4α, Foxo, PGC-1α, PPAR-γ, C/EBP-α, CREB, NFATC1, STAT3). FCDP cause both activation and inhibition of AMPK, MAPK, and NF-κB signaling to confer condition-specific advantages. Such a broad-range activity might be attributed to different mechanisms of action of FCDP in modulating functions within the classical immunometabolic system, but also beyond.
Topics: Humans; NF-kappa B; Ficus; AMP-Activated Protein Kinases; Glycogen Synthase Kinase 3; Inflammation; Metabolic Diseases
PubMed: 37995897
DOI: 10.1016/j.phrs.2023.107010 -
The Journal of Biological Chemistry Aug 2023Human growth hormone (hGH) is a pituitary-derived endocrine protein that regulates several critical postnatal physiologic processes including growth, organ development,...
Human growth hormone (hGH) is a pituitary-derived endocrine protein that regulates several critical postnatal physiologic processes including growth, organ development, and metabolism. Following adulthood, GH is also a regulator of multiple pathologies like fibrosis, cancer, and diabetes. Therefore, there is a significant pharmaceutical interest in developing antagonists of hGH action. Currently, there is a single FDA-approved antagonist of the hGH receptor (hGHR) prescribed for treating patients with acromegaly and discovered in our laboratory almost 3 decades ago. Here, we present the first data on the structure and function of a new set of protein antagonists with the full range of hGH actions-dual antagonists of hGH binding to the GHR as well as that of hGH binding to the prolactin receptor. We describe the site-specific PEG conjugation, purification, and subsequent characterization using MALDI-TOF, size-exclusion chromatography, thermostability, and biochemical activity in terms of ELISA-based binding affinities with GHR and prolactin receptor. Moreover, these novel hGHR antagonists display distinct antagonism of GH-induced GHR intracellular signaling in vitro and marked reduction in hepatic insulin-like growth factor 1 output in vivo. Lastly, we observed potent anticancer biological efficacies of these novel hGHR antagonists against human cancer cell lines. In conclusion, we propose that these new GHR antagonists have potential for development towards multiple clinical applications related to GH-associated pathologies.
Topics: Humans; Carrier Proteins; Cell Line; Human Growth Hormone; Prolactin; Receptors, Prolactin; Receptors, Somatotropin; Polyethylene Glycols
PubMed: 37442239
DOI: 10.1016/j.jbc.2023.105030 -
Journal of Neuroendocrinology Dec 2023Offspring development relies on numerous physiological changes that occur in a mother's body, with hormones driving many of these adaptations. Amongst these, the... (Review)
Review
Offspring development relies on numerous physiological changes that occur in a mother's body, with hormones driving many of these adaptations. Amongst these, the physiological functions controlled by the autonomic nervous system are required for the mother to survive and are adjusted to meet the demands of the growing foetus and to ensure a successful birth. The hormones oestrogen, progesterone, and lactogenic hormones rise significantly during pregnancy, suggesting they may also play a role in regulating the maternal adaptations linked to autonomic nervous system functions, including respiratory, cardiovascular, and thermoregulatory functions. Indeed, expression of pregnancy hormone receptors spans multiple brain regions known to regulate these physiological functions. This review examines how respiratory, cardiovascular, and thermoregulatory functions are controlled by these pregnancy hormones by focusing on their action on central nervous system circuits. Inadequate adaptations in these systems during pregnancy can give rise to several pregnancy complications, highlighting the importance in understanding the mechanistic underpinnings of these changes and potentially identifying ways to treat pregnancy-associated afflictions using hormones.
Topics: Pregnancy; Female; Humans; Progesterone; Estrogens; Prolactin; Cardiovascular System; Pregnancy Complications
PubMed: 37936545
DOI: 10.1111/jne.13348 -
Molecular Nutrition & Food Research Jun 2024Organisms maintain their cellular homeostatic balance by interacting with their environment through the use of their cell surface receptors. Membrane based receptors... (Review)
Review
Organisms maintain their cellular homeostatic balance by interacting with their environment through the use of their cell surface receptors. Membrane based receptors such as the transforming growth factor β receptor (TGFR), the prolactin receptor (PRLR), and hepatocyte growth factor receptor (HGFR), along with their associated signaling cascade, play significant roles in retaining cellular homeostasis. While these receptors and related signaling pathways are essential for health of cell and organism, their dysregulation can lead to imbalance in cell function with severe pathological conditions such as cell death or cancer. Ochratoxin A (OTA) can disrupt cellular homeostasis by altering expression levels of these receptors and/or receptor-associated intracellular downstream signaling modulators and/or pattern and levels of their phosphorylation/dephosphorylation. Recent studies have shown that the activity of the TGFR, the PRLR, and HGFR and their associated signaling cascades change upon OTA exposure. A critical evaluation of these findings suggests that while increased activity of the HGFR and TGFR signaling pathways leads to an increase in cell survival and fibrosis, decreased activity of the PRLR signaling pathway leads to tissue damage. This review explores the roles of these receptors in OTA-related pathologies and effects on cellular homeostasis.
PubMed: 38880772
DOI: 10.1002/mnfr.202300777