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International Journal of Molecular... Jun 2020Somatostatin is a peptide hormone, which most commonly is produced by endocrine cells and the central nervous system. In mammals, somatostatin originates from... (Review)
Review
Somatostatin is a peptide hormone, which most commonly is produced by endocrine cells and the central nervous system. In mammals, somatostatin originates from pre-prosomatostatin and is processed to a shorter form, i.e., somatostatin-14, and a longer form, i.e., somatostatin-28. The two peptides repress growth hormone secretion and are involved in the regulation of glucagon and insulin synthesis in the pancreas. In recent years, the processing and secretion of somatostatin have been studied intensively. However, little attention has been paid to the regulatory mechanisms that control its expression. This review provides an up-to-date overview of these mechanisms. In particular, it focuses on the role of enhancers and silencers within the promoter region as well as on the binding of modulatory transcription factors to these elements. Moreover, it addresses extracellular factors, which trigger key signaling pathways, leading to an enhanced somatostatin expression in health and disease.
Topics: Animals; Autocrine Communication; Enhancer Elements, Genetic; Feedback, Physiological; Gene Expression Regulation; Humans; Promoter Regions, Genetic; Somatostatin; Transcription Factors
PubMed: 32545257
DOI: 10.3390/ijms21114170 -
Journal of Molecular Biology Mar 2022An effective innate antiviral response is critical for the mitigation of severe disease and host survival following infection. In vivo, the innate antiviral response is... (Review)
Review
An effective innate antiviral response is critical for the mitigation of severe disease and host survival following infection. In vivo, the innate antiviral response is triggered by cells that detect the invading pathogen and then communicate through autocrine and paracrine signaling to stimulate the expression of genes that inhibit viral replication, curtail cell proliferation, or modulate the immune response. In other words, the innate antiviral response is complex and dynamic. Notably, in the laboratory, culturing viruses and assaying viral life cycles frequently utilizes cells that are derived from tissues other than those that support viral replication during natural infection, while the study of viral pathogenesis often employs animal models. In recapitulating the human antiviral response, it is important to consider that variation in the expression and function of innate immune sensors and antiviral effectors exists across species, cell types, and cell differentiation states, as well as when cells are placed in different contexts. Thus, to gain novel insight into the dynamics of the host response and how specific sensors and effectors impact infection kinetics by a particular virus, the model system must be selected carefully. In this review, we briefly introduce key signaling pathways involved in the innate antiviral response and highlight how these differ between systems. We then review the application of tissue-engineered or 3D models for studying the antiviral response, and suggest how these in vitro culture systems could be further utilized to assay physiologically-relevant host responses and reveal novel insight into virus-host interactions.
Topics: Animals; Host-Pathogen Interactions; Immunity, Innate; Signal Transduction; Virus Replication; Viruses
PubMed: 34863779
DOI: 10.1016/j.jmb.2021.167374 -
Frontiers in Neural Circuits 2021Here, we present and discuss the characteristics and properties of neurotransmitter segregation, a subtype of neurotransmitter cotransmission. We review early evidence... (Review)
Review
Here, we present and discuss the characteristics and properties of neurotransmitter segregation, a subtype of neurotransmitter cotransmission. We review early evidence of segregation and discuss its properties, such as plasticity, while placing special emphasis on its probable functional implications, either in the central nervous system (CNS) or the autonomic nervous system. Neurotransmitter segregation is a process by which neurons separately route transmitters to independent and distant or to neighboring neuronal processes; it is a plastic phenomenon that changes according to synaptic transmission requirements and is regulated by target-derived signals. Distant neurotransmitter segregation in the CNS has been shown to be related to an autocrine/paracrine function of some neurotransmitters. In retinal amacrine cells, segregation of acetylcholine (ACh) and GABA, and glycine and glutamate to neighboring terminals has been related to the regulation of the firing rate of direction-selective ganglion cells. In the rat superior cervical ganglion, segregation of ACh and GABA to neighboring varicosities shows a heterogeneous regional distribution, which is correlated to a similar regional distribution in transmission strength. We propose that greater segregation of ACh and GABA produces less GABAergic inhibition, strengthening ganglionic transmission. Segregation of ACh and GABA varies in different physiopathological conditions; specifically, segregation increases in acute sympathetic hyperactivity that occurs in cold stress, does not vary in chronic hyperactivity that occurs in hypertension, and rises in early ages of normotensive and hypertensive rats. Given this, we propose that variations in the extent of transmitter segregation may contribute to the alteration of neural activity that occurs in some physiopathological conditions and with age.
Topics: Acetylcholine; Amacrine Cells; Animals; Glutamic Acid; Neurotransmitter Agents; Rats; Synaptic Transmission
PubMed: 34720888
DOI: 10.3389/fncir.2021.738516 -
International Journal of Molecular... Aug 2019Atrial natriuretic peptide (ANP) is a cardiac hormone belonging to the family of natriuretic peptides (NPs). ANP exerts diuretic, natriuretic, and vasodilatory effects... (Review)
Review
Atrial natriuretic peptide (ANP) is a cardiac hormone belonging to the family of natriuretic peptides (NPs). ANP exerts diuretic, natriuretic, and vasodilatory effects that contribute to maintain water-salt balance and regulate blood pressure. Besides these systemic properties, ANP displays important pleiotropic effects in the heart and in the vascular system that are independent of blood pressure regulation. These functions occur through autocrine and paracrine mechanisms. Previous works examining the cardiac phenotype of loss-of-function mouse models of ANP signaling showed that both mice with gene deletion of ANP or its receptor natriuretic peptide receptor A (NPR-A) developed cardiac hypertrophy and dysfunction in response to pressure overload and chronic ischemic remodeling. Conversely, ANP administration has been shown to improve cardiac function in response to remodeling and reduces ischemia-reperfusion (I/R) injury. ANP also acts as a pro-angiogenetic, anti-inflammatory, and anti-atherosclerotic factor in the vascular system. Pleiotropic effects regarding brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) were also reported. In this review, we discuss the current evidence underlying the pleiotropic effects of NPs, underlying their importance in cardiovascular homeostasis.
Topics: Animals; Cardiovascular System; Humans; Myocytes, Cardiac; Natriuretic Peptide, Brain; Natriuretic Peptides; Reperfusion Injury; Vascular Remodeling; Ventricular Remodeling
PubMed: 31398927
DOI: 10.3390/ijms20163874 -
Experimental Neurology Sep 2022Neural stem cell (NSC) based therapies are at the forefront of regenerative medicine strategies to combat illness and injury of the central nervous system (CNS). In... (Review)
Review
Neural stem cell (NSC) based therapies are at the forefront of regenerative medicine strategies to combat illness and injury of the central nervous system (CNS). In addition to their ability to produce new cells, NSCs secrete a variety of products, known collectively as the NSC secretome, that have been shown to ameliorate CNS disease pathology and promote recovery. As pre-clinical and clinical research to harness the NSC secretome for therapeutic purposes advances, a more thorough understanding of the endogenous NSC secretome can provide useful insight into the functional capabilities of NSCs. In this review, we focus on research investigating the autocrine and paracrine functions of the endogenous NSC secretome across life. Throughout development and adulthood, we find evidence that the NSC secretome is a critical component of how endogenous NSCs regulate themselves and their niche. We also find gaps in current literature, most notably in the clinically-relevant domain of endogenous NSC paracrine function in the injured CNS. Future investigations to further define the endogenous NSC secretome and its role in CNS tissue regulation are necessary to bolster our understanding of NSC-niche interactions and to aid in the generation of safe and effective NSC-based therapies.
Topics: Central Nervous System; Neural Stem Cells; Secretome; Stem Cell Niche
PubMed: 35709983
DOI: 10.1016/j.expneurol.2022.114142 -
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 -
Biomolecules Sep 2023Endometriosis (EMs) is a common disease among women whose pathogenesis is still unclear, although there are various hypotheses. Recent studies have considered... (Review)
Review
Endometriosis (EMs) is a common disease among women whose pathogenesis is still unclear, although there are various hypotheses. Recent studies have considered macrophages the key part of the immune system in developing EMs, inducing inflammation, the growth and invasion of the ectopic endometrium, and angiogenesis. Extracellular vesicles (EVs) as novel intercellular vesicle traffic, can be secreted by many kinds of cells, including macrophages. By carrying long non-coding RNA (lncRNA), microRNA (miRNA), or other molecules, EVs can regulate the biological functions of macrophages in an autocrine and paracrine manner, including ectopic lesion growth, immune dysfunction, angiogenesis, and can further accelerate the progression of EMs. In this review, the interactions between macrophages and EVs for the pathogenesis of EMs are summarized. Notably, the regulatory pathways and molecular mechanisms of EVs secreted by macrophages during EMs are reviewed.
PubMed: 37759776
DOI: 10.3390/biom13091376 -
Frontiers in Endocrinology 2022Purinergic receptors are ubiquitously expressed throughout the body and they participate in the autocrine and paracrine regulation of cell function during normal... (Review)
Review
Purinergic receptors are ubiquitously expressed throughout the body and they participate in the autocrine and paracrine regulation of cell function during normal physiological and pathophysiological conditions. Extracellular nucleotides activate several types of plasma membrane purinergic receptors that form three distinct families: P1 receptors are activated by adenosine, P2X receptors are activated by ATP, and P2Y receptors are activated by nucleotides including ATP, ADP, UTP, UDP, and UDP-glucose. These specific pharmacological fingerprints and the distinct intracellular signaling pathways they trigger govern a large variety of cellular responses in an organ-specific manner. As such, purinergic signaling regulates several physiological cell functions, including cell proliferation, differentiation and death, smooth muscle contraction, vasodilatation, and transepithelial transport of water, solute, and protons, as well as pathological pathways such as inflammation. While purinergic signaling was first discovered more than 90 years ago, we are just starting to understand how deleterious signals mediated through purinergic receptors may be involved in male infertility. A large fraction of male infertility remains unexplained illustrating our poor understanding of male reproductive health. Purinergic signaling plays a variety of physiological and pathophysiological roles in the male reproductive system, but our knowledge in this context remains limited. This review focuses on the distribution of purinergic receptors in the testis, epididymis, and vas deferens, and their role in the establishment and maintenance of male fertility.
Topics: Humans; Male; Testis; Infertility, Male; Nucleotides; Adenosine Triphosphate; Uridine Diphosphate
PubMed: 36419764
DOI: 10.3389/fendo.2022.1049511 -
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 -
Metabolites Apr 2022Early research has suggested a rather straightforward relation between phosphate exposure, increased serum FGF23 (Fibroblast Growth Factor 23) concentrations and... (Review)
Review
Early research has suggested a rather straightforward relation between phosphate exposure, increased serum FGF23 (Fibroblast Growth Factor 23) concentrations and clinical endpoints. Unsurprisingly, however, subsequent studies have revealed a much more complex interplay between autocrine and paracrine factors locally in bone like PHEX and DMP1, concentrations of minerals in particular calcium and phosphate, calciprotein particles, and endocrine systems like parathyroid hormone PTH and the vitamin D system. In addition to these physiological regulators, an expanding list of disease states are shown to influence FGF23 levels, usually increasing it, and as such increase the burden of disease. While some of these physiological or pathological factors, like inflammatory cytokines, may partially confound the association of FGF23 and clinical endpoints, others are in the same causal path, are targetable and hence hold the promise of future treatment options to alleviate FGF23-driven toxicity, for instance in chronic kidney disease, the FGF23-associated disease with the highest prevalence by far. These factors will be reviewed here and their relative importance described, thereby possibly opening potential means for future therapeutic strategies.
PubMed: 35629904
DOI: 10.3390/metabo12050401