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International Journal of Molecular... Aug 2023Glucagon exerts effects on the mammalian heart. These effects include alterations in the force of contraction, beating rate, and changes in the cardiac conduction system... (Review)
Review
Glucagon exerts effects on the mammalian heart. These effects include alterations in the force of contraction, beating rate, and changes in the cardiac conduction system axis. The cardiac effects of glucagon vary according to species, region, age, and concomitant disease. Depending on the species and region studied, the contractile effects of glucagon can be robust, modest, or even absent. Glucagon is detected in the mammalian heart and might act with an autocrine or paracrine effect on the cardiac glucagon receptors. The glucagon levels in the blood and glucagon receptor levels in the heart can change with disease or simultaneous drug application. Glucagon might signal via the glucagon receptors but, albeit less potently, glucagon might also signal via glucagon-like-peptide-1-receptors (GLP1-receptors). Glucagon receptors signal in a species- and region-dependent fashion. Small molecules or antibodies act as antagonists to glucagon receptors, which may become an additional treatment option for diabetes mellitus. Hence, a novel review of the role of glucagon and the glucagon receptors in the mammalian heart, with an eye on the mouse and human heart, appears relevant. Mouse hearts are addressed here because they can be easily genetically modified to generate mice that may serve as models for better studying the human glucagon receptor.
Topics: Humans; Animals; Mice; Glucagon; Receptors, Glucagon; Heart; Heart Conduction System; Antibodies; Glucagon-Like Peptide-1 Receptor; Mammals
PubMed: 37629010
DOI: 10.3390/ijms241612829 -
Experimental and Molecular Pathology Aug 2023In recent years, the physiological and molecular functions of vitamin D (Vit-D) have been deeply investigated. At first, Vit-D was considered a regulator of mineral and... (Review)
Review
In recent years, the physiological and molecular functions of vitamin D (Vit-D) have been deeply investigated. At first, Vit-D was considered a regulator of mineral and skeletal homeostasis. However, due to the extensive-expression pattern of Vit-D receptor (VDR) in almost every non-skeletal cell, Vit-D is considered mainly a multifunctional agent with broad effects on various tissues, notably the immune system. The expression of VDR in immune cells such as dendritic cells, monocyte/macrophage, neutrophils, B cells and T cells has been well demonstrated. Besides, such immune cells are capable of metabolizing the active form of Vit-D which means that it can module the immune system in both paracrine and autocrine manners. Vit-D binding protein (DBP), that regulates the levels and homeostasis of Vit-D, is another key molecule capable of modulating the immune system. Recent studies indicate that dysregulation of Vit-D axis, variations in the DBP and VDR genes, and Vit-D levels might be risk factors for the development of autoimmune disease. Here, the current evidence regarding the role of Vit-D axis on the immune system, as well as its role in the development of autoimmune disease will be clarified. Further insight will be given to those studies that investigated the association between single nucleotide polymorphisms of DBP and VDR genes with autoimmune disease susceptibility.
Topics: Humans; Vitamin D; Receptors, Calcitriol; Immune System; Autoimmune Diseases
PubMed: 37572961
DOI: 10.1016/j.yexmp.2023.104866 -
BioRxiv : the Preprint Server For... Jul 2023In solid tissues homeostasis and regeneration after injury involve a complex interplay between many different cell types. The mammalian liver harbors numerous epithelial...
In solid tissues homeostasis and regeneration after injury involve a complex interplay between many different cell types. The mammalian liver harbors numerous epithelial and non-epithelial cells and little is known about the global signaling networks that govern their interactions. To better understand the hepatic cell network, we isolated and purified 10 different cell populations from normal and regenerative mouse livers. Their transcriptomes were analyzed by bulk RNA-seq and a computational platform was used to analyze the cell-cell and ligand-receptor interactions among the 10 populations. Over 50,000 potential cell-cell interactions were found in both the ground state and after partial hepatectomy. Importantly, about half of these differed between the two states, indicating massive changes in the cell network during regeneration. Our study provides the first comprehensive database of potential cell-cell interactions in mammalian liver cell homeostasis and regeneration. With the help of this prediction model, we identified and validated two previously unknown signaling interactions involved in accelerating and delaying liver regeneration. Overall, we provide a novel platform for investigating autocrine/paracrine pathways in tissue regeneration, which can be adapted to other complex multicellular systems.
PubMed: 37503083
DOI: 10.1101/2023.07.16.549116 -
Clinical and Translational Medicine Jul 2023Skeletal muscle-secreted myokines widely participate in lipids metabolism through autocrine, paracrine and endocrine actions. The myokines represented by FGF21 and...
BACKGROUND
Skeletal muscle-secreted myokines widely participate in lipids metabolism through autocrine, paracrine and endocrine actions. The myokines represented by FGF21 and Irisin can promote the browning of adipocytes and serve as promising targets for treating obesity. Although recombinant myokines replacement therapy and AAV (adeno-associated virus)-based myokines overexpression have shown a definite effect in ameliorating obesity, novel myokine activation strategies with higher efficacy and safety are still in pressing need. This study aimed to evaluate the therapeutic potential of a novel CRISPR-based myokines activation strategy in obesity treatments.
METHODS
In this study, we used lentivirus and a single AAV vector containing dCas9-VP64 with a single-guide RNA to selectively activate Fgf21 and Fndc5 expression in skeletal muscles both in vitro and in vivo. The activation efficacy of the CRISPRa system was determined by qRT-PCR, Western blotting and ELISA. The treatment effect of CRISPR-based myokines activation was tested in 3T3-L1-derived adipocytes and diet-induced obese (DIO) mice (male C57BL/6 mice, induced at 6-week-old for 10 weeks).
RESULTS
The virus upregulates myokines expression in both mRNA and protein levels of muscle cells in vitro and in vivo. Myokines secreted by muscle cells promoted browning of 3T3-L1-derived adipocytes. In vivo activation of myokines by AAVs can reduce body weight and fat mass, increase the adipocytes browning and improve glucose tolerance and insulin sensitivity in DIO mice.
CONCLUSIONS
Our study provides a novel CRISPR-based myokines activation strategy that can ameliorate obesity by promoting adipocytes browning.
Topics: Mice; Animals; Male; Fibronectins; Adipose Tissue, Brown; Mice, Inbred C57BL; Adipocytes; Transcription Factors; Obesity
PubMed: 37462619
DOI: 10.1002/ctm2.1326 -
Cancers Jun 2023VIP (vasoactive intestinal peptide) is a 28-amino acid peptide hormone expressed by cancer and the healthy nervous system, digestive tract, cardiovascular, and immune...
VIP (vasoactive intestinal peptide) is a 28-amino acid peptide hormone expressed by cancer and the healthy nervous system, digestive tract, cardiovascular, and immune cell tissues. Many cancers express VIP and its surface receptors VPAC1 and VPAC2, but the role of autocrine VIP signaling in cancer as a targetable prognostic and predictive biomarker remains poorly understood. Therefore, we conducted an in silico gene expression analysis to study the mechanisms of autocrine VIP signaling in cancer. VIP expression from TCGA PANCAN tissue samples was analyzed against the expression levels of 760 cancer-associated genes. Of the 760 genes, 10 (MAPK3, ZEB1, TEK, NOS2, PTCH1 EIF4G1, GMPS, CDK2, RUVBL1, and TIMELESS) showed statistically meaningful associations with the VIP (Pearson's -coefficient > |0.3|; < 0.05) across all cancer histologies. The strongest association with the VIP was for the epithelial-mesenchymal transition regulator ZEB1 in gastrointestinal malignancies. Similar positive correlations between the VIP and ZEB1 expression were also observed in healthy gastrointestinal tissues. Gene set analysis indicates the VIP is involved in the EMT and cell cycle pathways, and a high VIP and ZEB1 expression is associated with higher median estimate and stromal scores These findings uncover novel mechanisms for VIP- signaling in cancer and specifically suggest a role for VIP as a biomarker of ZEB1-mediated EMT. Further studies are warranted to characterize the specific mechanism of this interaction.
PubMed: 37444395
DOI: 10.3390/cancers15133284 -
Cells Jul 2023In multiple sclerosis (MS), glial cells astrocytes interact with the autoreactive immune cells that attack the central nervous system (CNS), which causes and sustains...
In multiple sclerosis (MS), glial cells astrocytes interact with the autoreactive immune cells that attack the central nervous system (CNS), which causes and sustains neuroinflammation. However, little is known about the direct interaction between these cells when they are in close proximity in the inflamed CNS. By using an experimental autoimmune encephalomyelitis (EAE) model of MS, we previously found that in the proximity of autoreactive CNS-infiltrated immune cells (CNS-IICs), astrocytes respond with a rapid calcium increase that is mediated by the autocrine P2X7 receptor (P2X7R) activation. We now reveal that the mechanisms regulating this direct interaction of astrocytes and CNS-IICs involve the coupling between P2X7R, connexin-43, and β-integrin. We found that P2X7R and astroglial connexin-43 interact and concentrate in the immediate proximity of the CNS-IICs in EAE. P2X7R also interacts with β-integrin, and the block of astroglial αβ-integrin reduces the P2X7R-dependent calcium response of astrocytes upon encountering CNS-IICs. This interaction was dependent on astroglial mitochondrial activity, which regulated the ATP-driven P2X7R activation and facilitated the termination of the astrocytic calcium response evoked by CNS-IICs. By further defining the interactions between the CNS and the immune system, our findings provide a novel perspective toward expanding integrin-targeting therapeutic approaches for MS treatment by controlling the cell-cell interactions between astrocytes and CNS-IICs.
Topics: Animals; Encephalomyelitis, Autoimmune, Experimental; Astrocytes; Receptors, Purinergic P2X7; Integrin beta3; Calcium; Multiple Sclerosis; Cell Communication
PubMed: 37443820
DOI: 10.3390/cells12131786 -
Cells Jun 2023Ever since its presence was reported in the brain, the nature and role of hydrogen sulfide (HS) in the Central Nervous System (CNS) have changed. Consequently, HS has... (Review)
Review
Ever since its presence was reported in the brain, the nature and role of hydrogen sulfide (HS) in the Central Nervous System (CNS) have changed. Consequently, HS has been elected as the third gas transmitter, along with carbon monoxide and nitric oxide, and a number of studies have focused on its neuromodulatory and protectant functions in physiological conditions. The research on HS has highlighted its many facets in the periphery and in the CNS, and its role as a double-faced compound, switching from protective to toxic depending on its concentration. In this review, we will focus on the bell-shaped nature of HS as an angiogenic factor and as a molecule released by glial cells (mainly astrocytes) and non-neuronal cells acting on the surrounding environment (paracrine) or on the releasing cells themselves (autocrine). Finally, we will discuss its role in Amyotrophic Lateral Sclerosis, a paradigm of a neurodegenerative disease.
Topics: Humans; Hydrogen Sulfide; Neurodegenerative Diseases; Amyotrophic Lateral Sclerosis; Central Nervous System; Nitric Oxide
PubMed: 37443723
DOI: 10.3390/cells12131691 -
Journal of Experimental & Clinical... Jul 2023After diagnosis, glioblastoma (GBM) patients undertake tremendous psychological problems such as anxiety and depression, which may contribute to GBM progression....
BACKGROUND
After diagnosis, glioblastoma (GBM) patients undertake tremendous psychological problems such as anxiety and depression, which may contribute to GBM progression. However, systematic study about the relationship between depression and GBM progression is still lacking.
METHODS
Chronic unpredictable mild stress and chronic restrain stress were used to mimic human depression in mice. Human GBM cells and intracranial GBM model were used to assess the effects of chronic stress on GBM growth. Targeted neurotransmitter sequencing, RNA-seq, immunoblotting and immunohistochemistry were used to detect the related molecular mechanism.
RESULTS
Chronic stress promoted GBM progression and up-regulated the level of dopamine (DA) and its receptor type 2 (DRD2) in tumor tissues. Down-regulation or inhibition of DRD2 abolished the promoting effect of chronic stress on GBM progression. Mechanistically, the elevated DA and DRD2 activated ERK1/2 and consequently inhibited GSK3β activity, leading to β-catenin activation. Meanwhile, the activated ERK1/2 up-regulated tyrosine hydroxylase (TH) level in GBM cells and then promoted DA secretion, forming an autocrine positive feedback loop. Remarkably, patients with high-depression exhibited high DRD2 and β-catenin levels, which showed poor prognosis. Additionally, DRD2 specific inhibitor pimozide combined with temozolomide synergistically inhibited GBM growth.
CONCLUSIONS
Our study revealed that chronic stress accelerates GBM progression via DRD2/ERK/β-catenin axis and Dopamine/ERK/TH positive feedback loop. DRD2 together with β-catenin may serve as a potential predictive biomarker for worse prognosis as well as therapeutic target of GBM patients with depression.
Topics: Humans; Animals; Mice; Glioblastoma; Dopamine; Tyrosine 3-Monooxygenase; beta Catenin; Feedback; Cell Line, Tumor; Brain Neoplasms; Cell Proliferation; Receptors, Dopamine D2
PubMed: 37415171
DOI: 10.1186/s13046-023-02728-8 -
Cells May 2023Osteoarthritis (OA) is the most common cause of disability worldwide among the elderly. Alarmingly, the incidence of OA in individuals less than 40 years of age is... (Review)
Review
Therapeutic Perspectives for Inflammation and Senescence in Osteoarthritis Using Mesenchymal Stem Cells, Mesenchymal Stem Cell-Derived Extracellular Vesicles and Senolytic Agents.
Osteoarthritis (OA) is the most common cause of disability worldwide among the elderly. Alarmingly, the incidence of OA in individuals less than 40 years of age is rising, likely due to the increase in obesity and post-traumatic osteoarthritis (PTOA). In recent years, due to a better understanding of the underlying pathophysiology of OA, several potential therapeutic approaches targeting specific molecular pathways have been identified. In particular, the role of inflammation and the immune system has been increasingly recognized as important in a variety of musculoskeletal diseases, including OA. Similarly, higher levels of host cellular senescence, characterized by cessation of cell division and the secretion of a senescence-associated secretory phenotype (SASP) within the local tissue microenvironments, have also been linked to OA and its progression. New advances in the field, including stem cell therapies and senolytics, are emerging with the goal of slowing disease progression. Mesenchymal stem/stromal cells (MSCs) are a subset of multipotent adult stem cells that have demonstrated the potential to modulate unchecked inflammation, reverse fibrosis, attenuate pain, and potentially treat patients with OA. Numerous studies have demonstrated the potential of MSC extracellular vesicles (EVs) as cell-free treatments that comply with FDA regulations. EVs, including exosomes and microvesicles, are released by numerous cell types and are increasingly recognized as playing a critical role in cell-cell communication in age-related diseases, including OA. Treatment strategies for OA are being developed that target senescent cells and the paracrine and autocrine secretions of SASP. This article highlights the encouraging potential for MSC or MSC-derived products alone or in combination with senolytics to control patient symptoms and potentially mitigate the progression of OA. We will also explore the application of genomic principles to the study of OA and the potential for the discovery of OA phenotypes that can motivate more precise patient-driven treatments.
Topics: Humans; Senotherapeutics; Extracellular Vesicles; Osteoarthritis; Inflammation; Mesenchymal Stem Cells
PubMed: 37408255
DOI: 10.3390/cells12101421 -
Frontiers in Neuroscience 2023Circadian desynchronizations are associated with psychiatric disorders as well as with higher suicidal risk. Brown adipose tissue (BAT) is important in the regulation of...
Circadian desynchronizations are associated with psychiatric disorders as well as with higher suicidal risk. Brown adipose tissue (BAT) is important in the regulation of body temperature and contributes to the homeostasis of the metabolic, cardiovascular, skeletal muscle or central nervous system. BAT is under neuronal, hormonal and immune control and secrets batokines: i.e., autocrine, paracrine and endocrine active substances. Moreover, BAT is involved in circadian system. Light, ambient temperature as well as exogen substances interact with BAT. Thus, a dysregulation of BAT can indirectly worsen psychiatric conditions and the risk of suicide, as one of previously suggested explanations for the seasonality of suicide rate. Furthermore, overactivation of BAT is associated with lower body weight and lower level of blood lipids. Reduced body mass index (BMI) or decrease in BMI respectively, as well as lower triglyceride concentrations were found to correlate with higher risk of suicide, however the findings are inconclusive. Hyperactivation or dysregulation of BAT in relation to the circadian system as a possible common factor is discussed. Interestingly, substances with proven efficacy in reducing suicidal risk, like clozapine or lithium, interact with BAT. The effects of clozapine on fat tissue are stronger and might differ qualitatively from other antipsychotics; however, the significance remains unclear. We suggest that BAT is involved in the brain/environment homeostasis and deserves attention from a psychiatric point of view. Better understanding of circadian disruptions and its mechanisms can contribute to personalized diagnostic and therapy as well as better assessment of suicide risk.
PubMed: 37360180
DOI: 10.3389/fnins.2023.1196029