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Frontiers in Endocrinology 2023Allopregnanolone (Allo) is a neurosteroid with pleiotropic action in the brain that includes neurogenesis, oligogenesis, human and rodent neural stem cell regeneration,...
OBJECTIVE
Allopregnanolone (Allo) is a neurosteroid with pleiotropic action in the brain that includes neurogenesis, oligogenesis, human and rodent neural stem cell regeneration, increased glucose metabolism, mitochondrial respiration and biogenesis, improved cognitive function, and reduction of both inflammation and Alzheimer's disease (AD) pathology. Because the breadth of Allo-induced responses requires activation of multiple systems of biology in the absence of an Allo-specific nuclear receptor, analyses were conducted in both neurons and astrocytes to identify unifying systems and signaling pathways.
METHODS
Mechanisms of Allo action were investigated in embryonic hippocampal neurons and astrocytes cultured in an Aging Model (AM) media. Cellular morphology, mitochondrial function, and transcriptomics were investigated followed by mechanistic pathway analyses.
RESULTS
In hippocampal neurons, Allo significantly increased neurite outgrowth and synaptic protein expression, which were paralleled by upregulated synaptogenesis and long-term potentiation gene expression profiles. Mechanistically, Allo induced Ca/CREB signaling cascades. In parallel, Allo significantly increased maximal mitochondrial respiration, mitochondrial membrane potential, and Complex IV activity while reducing oxidative stress, which required both the GABA and L-type Ca channels. In astrocytes, Allo increased ATP generation, mitochondrial function and dynamics while reducing oxidative stress, inflammasome indicators, and apoptotic signaling. Mechanistically, Allo regulation of astrocytic mitochondrial function required both the GABA and L-type Ca channels. Furthermore, Allo activated NRF1-TFAM signaling and increased the DRP1/OPA1 protein ratio, which led to increased mitochondrial biogenesis and dynamics.
CONCLUSION
Collectively, the cellular, mitochondrial, transcriptional, and pharmacological profiles provide evidence in support of calcium signaling as a unifying mechanism for Allo pleiotropic actions in the brain.
Topics: Humans; Calcium Signaling; Astrocytes; Pregnanolone; Neurons; gamma-Aminobutyric Acid
PubMed: 38189047
DOI: 10.3389/fendo.2023.1286931 -
Frontiers in Nutrition 2023Prediabetes is an intermediate stage in the development of type 2 diabetes mellitus characterized by impaired fasting glucose and/or impaired glucose tolerance.... (Review)
Review
Prediabetes is an intermediate stage in the development of type 2 diabetes mellitus characterized by impaired fasting glucose and/or impaired glucose tolerance. Prediabetes generally has no obvious clinical symptoms, and most patients are found in health examinations or due to other diseases. Reactive hypoglycemia may indicate the possibility of early diabetes. Without effective preventive measures, prediabetes can progress to diabetes leading to serious public health problems. Therefore, early diagnosis and intervention are important. Many animal experiments and clinical trials have proven that natural compounds substantially improve glucose metabolism disorder. The active ingredients are mainly alkaloids, polysaccharides, saponins, terpenoids, flavonoids and polyphenols. Their mechanism of action mainly involves improved insulin sensitivity and insulin resistance, inhibited activity of alpha-glucosidase, antioxidant activity, anti-inflammatory, regulation of gut microbiota and activating of peroxisome proliferator-activated receptor-γ. This paper reviews the mechanisms of action of natural compounds on prediabetes and the status of related research.
PubMed: 38099180
DOI: 10.3389/fnut.2023.1301129 -
PLoS Biology Aug 2023Phosphoinositide-dependent kinase-1 (PDK1) is a master kinase of the protein A, G, and C (AGC) family kinases that play important roles in regulating cancer cell...
Phosphoinositide-dependent kinase-1 (PDK1) is a master kinase of the protein A, G, and C (AGC) family kinases that play important roles in regulating cancer cell proliferation, survival, and metabolism. Besides phosphorylating/activating AKT at the cell membrane in a PI3K-dependent manner, PDK1 also exhibits constitutive activity on many other AGC kinases for tumor-promoting activity. In the latter case, PDK1 protein levels dominate its activity. We previously reported that MAPK4, an atypical MAPK, can PI3K-independently promote AKT activation and tumor growth. Here, using triple-negative breast cancer (TNBC) cell models, we demonstrate that MAPK4 can also enhance PDK1 protein synthesis, thus phosphorylate/activate PDK1 substrates beyond AKT. This new MAPK4-PDK1 axis alone lacks vigorous tumor-promoting activity but cooperates with our previously reported MAPK4-AKT axis to promote tumor growth. Besides enhancing resistance to PI3K blockade, MAPK4 also promotes cancer cell resistance to the more stringent PI3K and PDK1 co-blockade, a recently proposed therapeutic strategy. Currently, there is no MAPK4 inhibitor to treat MAPK4-high cancers. Based on the concerted action of MAPK4-AKT and MAPK4-PDK1 axis in promoting cancer, we predict and confirm that co-targeting AKT and PDK1 effectively represses MAPK4-induced cancer cell growth, suggesting a potential therapeutic strategy to treat MAPK4-high cancers.
Topics: Humans; 3-Phosphoinositide-Dependent Protein Kinases; Mitogen-Activated Protein Kinases; Neoplasms; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction
PubMed: 37531320
DOI: 10.1371/journal.pbio.3002227 -
BioRxiv : the Preprint Server For... Oct 2023Deucravacitinib, 6-(cyclopropanecarbonylamido)-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide, is a highly selective...
Deucravacitinib, 6-(cyclopropanecarbonylamido)-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide, is a highly selective inhibitor of protein tyrosine kinase 2 (TYK2) that targets the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway. The structural basis for its selectivity and allosteric inhibition remains poorly understood. Here, we investigate the inhibition mechanism through analysis of available structures relevant to the STAT pathway, including crystal structures of the truncated TYK2 FERM-SH2 domain bound to the IFNα type I receptor (IFNαR1) and the truncated TYK2 JH2-JH1 domain. Our computational analysis provides a mechanistic hypothesis for the relatively rapid interferon-induced gene expression mediated by TYK2 relative to other cytokines. We find that deucravacitinib inhibits TYK2 kinase in three distinct states: the autoinhibited state and two activated states for autophosphorylation and phosphorylation of downstream protein substrates. Its binding to the TYK2 pseudokinase domain in the autoinhibited state restricts the essential dynamics of the TYK2 kinase domain required for kinase activity. Furthermore, it binds competitively with ATP in the pseudokinase domain, and also directly prevents formation of the active state of TYK2 through steric clashes.
PubMed: 37873392
DOI: 10.1101/2023.10.09.561507 -
Frontiers in Bioscience (Landmark... Dec 2023Nonalcoholic fatty liver disease (NAFLD) is a pathological syndrome characterized by excessive fat deposition in hepatocytes. A sedentary lifestyle is a major risk... (Review)
Review
Nonalcoholic fatty liver disease (NAFLD) is a pathological syndrome characterized by excessive fat deposition in hepatocytes. A sedentary lifestyle is a major risk factor for NAFLD, and regular exercise is considered a cornerstone of NAFLD treatment independent of weight loss. Even low-intensity activity could have beneficial effects on NAFLD. Fibroblast growth factor 21 (FGF21), a cytokine mainly secreted by the liver, improves glucolipid metabolism, reduces inflammation and oxidative stress, increases insulin sensitivity, and acts on multiple organs through autocrine, paracrine, and endocrine actions. Both clinical trials and animal experiments have shown a high correlation between liver fat content and circulating blood FGF21 levels, and abnormal FGF21 signaling appears to be an important mechanism for the development of NAFLD. FGF21 is an exerkine that responds to exercise; therefore, it may be a key target in exercise to improve NAFLD. This review provides an overview of NAFLD and its pathogenesis, and summarizes the effects of exercise intervention on NAFLD, as well as the role of FGF21 in NAFLD. Emphasis is placed on possible mechanisms for improving NAFLD by targeting FGF21 during exercise.
Topics: Animals; Humans; Exercise; Fibroblast Growth Factors; Liver; Non-alcoholic Fatty Liver Disease
PubMed: 38179757
DOI: 10.31083/j.fbl2812351 -
Heliyon Sep 2023Graves' orbitopathy (GO) is an autoimmune disease that involves complex immune systems. The mainstays of clinical management for this disease are surgery, targeted drugs... (Review)
Review
Graves' orbitopathy (GO) is an autoimmune disease that involves complex immune systems. The mainstays of clinical management for this disease are surgery, targeted drugs therapy, and no-targeted drugs drug therapy. targeted drugs can improve therapeutic efficacy and enhance the quality of life for GO patients. However, as a second-line treatment for GO, targeted drugs such as tocilizumab and rituximab have very limited therapeutic effects and may be accompanied by side effects. The introduction of Teprotumumab, which targets IGF-IR, has made significant progress in the clinical management of GO. The pathophysiology of GO still remains uncertain as it involves a variety of immune cells and fibroblast interactions as well as immune responses to relevant disease targets of action. Therfore, learning more about immune response feedback pathways and potential targets of action will assist in the treatment of GO. In this discussion, we explore the pathogenesis of GO and relevant work, and highlight four potential targets for GO: Interleukin-23 receptor (IL-23 R), Leptin receptor (LepR), Orbital fibroblast activating factors, and Plasminogen activator inhibitor-1 (PAI-1). A deeper understanding of the pathogenesis of GO and the role of potential target signaling pathways is crucial for effective treatment of this disease.
PubMed: 37810014
DOI: 10.1016/j.heliyon.2023.e19250 -
PLoS Biology Nov 2023Human cognition and action can be influenced by internal bodily processes such as heartbeats. For instance, somatosensory perception is impaired both during the systolic...
Human cognition and action can be influenced by internal bodily processes such as heartbeats. For instance, somatosensory perception is impaired both during the systolic phase of the cardiac cycle and when heartbeats evoke stronger cortical responses. Here, we test whether these cardiac effects originate from overall changes in cortical excitability. Cortical and corticospinal excitability were assessed using electroencephalographic and electromyographic responses to transcranial magnetic stimulation while concurrently monitoring cardiac activity with electrocardiography. Cortical and corticospinal excitability were found to be highest during systole and following stronger neural responses to heartbeats. Furthermore, in a motor task, hand-muscle activity and the associated desynchronization of sensorimotor oscillations were stronger during systole. These results suggest that systolic cardiac signals have a facilitatory effect on motor excitability-in contrast to sensory attenuation that was previously reported for somatosensory perception. Thus, it is possible that distinct time windows exist across the cardiac cycle, optimizing either perception or action.
Topics: Humans; Motor Cortex; Evoked Potentials, Motor; Hand; Electroencephalography; Transcranial Magnetic Stimulation; Cortical Excitability
PubMed: 38015826
DOI: 10.1371/journal.pbio.3002393 -
JCI Insight Jul 2023Stimulating the Gq-coupled P2Y2 receptor (P2ry2) lowers blood pressure. Global knockout of P2ry2 increases blood pressure. Vascular and renal mechanisms are believed to...
Stimulating the Gq-coupled P2Y2 receptor (P2ry2) lowers blood pressure. Global knockout of P2ry2 increases blood pressure. Vascular and renal mechanisms are believed to participate in P2ry2 effects on blood pressure. To isolate the role of the kidneys in P2ry2 effects on blood pressure and to reveal the molecular and cellular mechanisms of this action, we test here the necessity of the P2ry2 and the sufficiency of Gq-dependent signaling in renal principal cells to the regulation of the epithelial Na+ channel (ENaC), sodium excretion, and blood pressure. Activating P2ry2 in littermate controls but not principal cell-specific P2ry2-knockout mice decreased the activity of ENaC in renal tubules. Moreover, deletion of P2ry2 in principal cells abolished increases in sodium excretion in response to stimulation of P2ry2 and compromised the normal ability to excrete a sodium load. Consequently, principal cell-specific knockout of P2ry2 prevented decreases in blood pressure in response to P2ry2 stimulation in the deoxycorticosterone acetate-salt (DOCA-salt) model of hypertension. In wild-type littermate controls, such stimulation decreased blood pressure in this model of hypertension by promoting a natriuresis. Pharmacogenetic activation of Gq exclusively in principal cells using targeted expression of Gq-designer receptors exclusively activated by designer drugs and clozapine N-oxide decreased the activity of ENaC in renal tubules, promoting a natriuresis that lowered elevated blood pressure in the DOCA-salt model of hypertension. These findings demonstrate that the kidneys play a major role in decreasing blood pressure in response to P2ry2 activation and that inhibition of ENaC activity in response to P2ry2-mediated Gq signaling lowered blood pressure by increasing renal sodium excretion.
Topics: Mice; Animals; Blood Pressure; Receptors, Purinergic P2Y2; Desoxycorticosterone Acetate; Sodium; Hypertension; Mice, Knockout
PubMed: 37279066
DOI: 10.1172/jci.insight.167704 -
Stem Cell Research & Therapy Sep 2023Senescence is a hot topic nowadays, which shows the accumulation of senescent cells and inflammatory factors, leading to the occurrence of various senescence-related... (Review)
Review
Senescence is a hot topic nowadays, which shows the accumulation of senescent cells and inflammatory factors, leading to the occurrence of various senescence-related diseases. Although some methods have been identified to partly delay senescence, such as strengthening exercise, restricting diet, and some drugs, these only slow down the process of senescence and cannot fundamentally delay or even reverse senescence. Stem cell-based therapy is expected to be a potential effective way to alleviate or cure senescence-related disorders in the coming future. Mesenchymal stromal cells (MSCs) are the most widely used cell type in treating various diseases due to their potentials of self-replication and multidirectional differentiation, paracrine action, and immunoregulatory effects. Some biological characteristics of MSCs can be well targeted at the pathological features of aging. Therefore, MSC-based therapy is also a promising strategy to combat senescence-related diseases. Here we review the recent progresses of MSC-based therapies in the research of age-related diseases and the challenges in clinical application, proving further insight and reference for broad application prospects of MSCs in effectively combating senesce in the future.
Topics: Mesenchymal Stem Cells; Cell Differentiation; Exercise; Stem Cell Transplantation
PubMed: 37726805
DOI: 10.1186/s13287-023-03497-z -
Frontiers in Cell and Developmental... 2023The sperm-specific channel CatSper (cation channel of sperm) controls the intracellular Ca concentration ([Ca]) and plays an essential role in sperm function. It is...
The sperm-specific channel CatSper (cation channel of sperm) controls the intracellular Ca concentration ([Ca]) and plays an essential role in sperm function. It is mainly activated by the steroid progesterone (P4) but is also promiscuously activated by a wide range of synthetic and physiological compounds. These compounds include diverse steroids whose action on the channel is so far still controversial. To investigate the effect of these compounds on CatSper and sperm function, we developed a high-throughput screening (HTS) assay to measure changes in [Ca] in human sperm and screened 1,280 approved and off-patent drugs including 90 steroids from the Prestwick chemical library. More than half of the steroids tested (53%) induced an increase in [Ca] and reduced the P4-induced Ca influx in human sperm in a dose-dependent manner. Ten of the most potent steroids (activating and P4-inhibiting) were selected for a detailed analysis of their action on CatSper and their ability to act on sperm acrosome reaction (AR) and penetration in viscous media. We found that these steroids show an inhibitory effect on P4 but not on prostaglandin E1-induced CatSper activation, suggesting that they compete for the same binding site as P4. Pregnenolone, dydrogesterone, epiandrosterone, nandrolone, and dehydroepiandrosterone acetate (DHEA) were found to activate CatSper at physiologically relevant concentrations within the nanomolar range. Like P4, most tested steroids did not significantly affect the AR while stanozolol and estropipate slightly increased sperm penetration into viscous medium. Furthermore, using a hybrid approach integrating pharmacophore analysis and statistical modelling, we were able to screen for steroids that can activate the channel and define the physicochemical and structural properties required for a steroid to exhibit agonist activity against CatSper. Overall, our results indicate that not only physiological but also synthetic steroids can modulate the activity of CatSper with varying potency and if bound to CatSper prior to P4, could impair the timely CatSper activation necessary for proper fertilization to occur.
PubMed: 37547474
DOI: 10.3389/fcell.2023.1221578