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Pharmacological Reviews Sep 2023The two -arrestins, -arrestin-1 and -2 (systematic names: arrestin-2 and -3, respectively), are multifunctional intracellular proteins that regulate the activity of a... (Review)
Review
The two -arrestins, -arrestin-1 and -2 (systematic names: arrestin-2 and -3, respectively), are multifunctional intracellular proteins that regulate the activity of a very large number of cellular signaling pathways and physiologic functions. The two proteins were discovered for their ability to disrupt signaling via G protein-coupled receptors (GPCRs) via binding to the activated receptors. However, it is now well recognized that both -arrestins can also act as direct modulators of numerous cellular processes via either GPCR-dependent or -independent mechanisms. Recent structural, biophysical, and biochemical studies have provided novel insights into how -arrestins bind to activated GPCRs and downstream effector proteins. Studies with -arrestin mutant mice have identified numerous physiologic and pathophysiological processes regulated by -arrestin-1 and/or -2. Following a short summary of recent structural studies, this review primarily focuses on -arrestin-regulated physiologic functions, with particular focus on the central nervous system and the roles of -arrestins in carcinogenesis and key metabolic processes including the maintenance of glucose and energy homeostasis. This review also highlights potential therapeutic implications of these studies and discusses strategies that could prove useful for targeting specific -arrestin-regulated signaling pathways for therapeutic purposes. SIGNIFICANCE STATEMENT: The two β-arrestins, structurally closely related intracellular proteins that are evolutionarily highly conserved, have emerged as multifunctional proteins able to regulate a vast array of cellular and physiological functions. The outcome of studies with β-arrestin mutant mice and cultured cells, complemented by novel insights into β-arrestin structure and function, should pave the way for the development of novel classes of therapeutically useful drugs capable of regulating specific β-arrestin functions.
Topics: Mice; Animals; beta-Arrestins; Arrestins; Signal Transduction; Receptors, G-Protein-Coupled; beta-Arrestin 1
PubMed: 37028945
DOI: 10.1124/pharmrev.121.000302 -
PeerJ 2023Safe and effective local anesthesia is a prerequisite for emergency oral surgeries and most dental treatments. Pregnancy is characterized by complex physiological... (Review)
Review
BACKGROUND
Safe and effective local anesthesia is a prerequisite for emergency oral surgeries and most dental treatments. Pregnancy is characterized by complex physiological changes, and increased sensitivity to pain. Pregnant women are particularly vulnerable to oral diseases, such as caries, gingivitis, pyogenic granuloma and third molar pericoronitis. Maternally administered drugs can affect the fetus through the placenta. Therefore, many physicians and patients are reluctant to provide or accept necessary local anesthesia, which leads to delays in the condition and adverse consequences. This review is intended to comprehensively discuss the instructions for local anesthesia in the oral treatment of pregnant patients.
METHODOLOGY
An in-depth search on Medline, Embase, and the Cochrane Library was performed to review articles concerned with maternal and fetal physiology, local anesthetic pharmacology, and their applications for oral treatment.
RESULTS
Standard oral local anesthesia is safe throughout the pregnancy. At present, 2% lidocaine with 1:200,000 epinephrine is considered to be the anesthetic agent that best balances safety and efficacy for pregnant women. Maternal and fetal considerations must be taken into account to accommodate the physiological and pharmacological changes in the gestation period. Semi-supine position, blood pressure monitoring, and reassurance are suggested for high-risk mothers to reduce the risk of transient changes in blood pressure, hypoxemia, and hypoglycemia. For patients with underlying diseases, such as eclampsia, hypertension, hypotension, and gestational diabetes, the physicians should use epinephrine cautiously and control the dose of anesthetic. New local anesthesia formulations and equipment, which contribute to minimizing injection pain and relieving the anxiety, have and are being developed but remain understudied.
CONCLUSIONS
Understanding the physiological and pharmacological changes during pregnancy is essential to ensure the safety and efficiency of local anesthesia. Optimal outcomes for the mother and fetus hinge on a robust understanding of the physiologic alterations and the appropriate selection of anesthetic drugs and approaches.
Topics: Humans; Female; Pregnancy; Anesthesia, Local; Anesthetics, Local; Lidocaine; Epinephrine; Pain
PubMed: 37404472
DOI: 10.7717/peerj.15585 -
Cell Aug 2023The properties of dorsal root ganglia (DRG) neurons that innervate the distal colon are poorly defined, hindering our understanding of their roles in normal physiology...
The properties of dorsal root ganglia (DRG) neurons that innervate the distal colon are poorly defined, hindering our understanding of their roles in normal physiology and gastrointestinal (GI) disease. Here, we report genetically defined subsets of colon-innervating DRG neurons with diverse morphologic and physiologic properties. Four colon-innervating DRG neuron populations are mechanosensitive and exhibit distinct force thresholds to colon distension. The highest threshold population, selectively labeled using Bmpr1b genetic tools, is necessary and sufficient for behavioral responses to high colon distension, which is partly mediated by the mechanosensory ion channel Piezo2. This Aδ-HTMR population mediates behavioral over-reactivity to colon distension caused by inflammation in a model of inflammatory bowel disease. Thus, like cutaneous DRG mechanoreceptor populations, colon-innervating mechanoreceptors exhibit distinct anatomical and physiological properties and tile force threshold space, and genetically defined colon-innervating HTMRs mediate pathophysiological responses to colon distension, revealing a target population for therapeutic intervention.
Topics: Ganglia, Spinal; Mechanoreceptors; Colon; Neurons; Skin
PubMed: 37541195
DOI: 10.1016/j.cell.2023.07.007 -
Cell Mar 2024Dorsal root ganglia (DRG) somatosensory neurons detect mechanical, thermal, and chemical stimuli acting on the body. Achieving a holistic view of how different DRG...
Dorsal root ganglia (DRG) somatosensory neurons detect mechanical, thermal, and chemical stimuli acting on the body. Achieving a holistic view of how different DRG neuron subtypes relay neural signals from the periphery to the CNS has been challenging with existing tools. Here, we develop and curate a mouse genetic toolkit that allows for interrogating the properties and functions of distinct cutaneous targeting DRG neuron subtypes. These tools have enabled a broad morphological analysis, which revealed distinct cutaneous axon arborization areas and branching patterns of the transcriptionally distinct DRG neuron subtypes. Moreover, in vivo physiological analysis revealed that each subtype has a distinct threshold and range of responses to mechanical and/or thermal stimuli. These findings support a model in which morphologically and physiologically distinct cutaneous DRG sensory neuron subtypes tile mechanical and thermal stimulus space to collectively encode a wide range of natural stimuli.
Topics: Animals; Mice; Ganglia, Spinal; Sensory Receptor Cells; Single-Cell Gene Expression Analysis; Skin
PubMed: 38442711
DOI: 10.1016/j.cell.2024.02.006 -
International Journal of Molecular... Jul 2023Discovered almost 40 years ago, the potent vasoconstrictor peptide endothelin-1 (ET-1) has a wide range of roles both physiologically and pathologically. In recent... (Review)
Review
Discovered almost 40 years ago, the potent vasoconstrictor peptide endothelin-1 (ET-1) has a wide range of roles both physiologically and pathologically. In recent years, there has been a focus on the contribution of ET-1 to disease. This has led to the development of various ET receptor antagonists, some of which are approved for the treatment of pulmonary arterial hypertension, while clinical trials for other diseases have been numerous yet, for the most part, unsuccessful. However, given the vast physiological impact of ET-1, it is both surprising and disappointing that therapeutics targeting the ET-1 pathway remain limited. Strategies aimed at the pathways influencing the synthesis and release of ET-1 could provide new therapeutic avenues, yet research using cultured cells in vitro has had little follow up in intact ex vivo and in vivo preparations. This article summarises what is currently known about the synthesis, storage and release of ET-1 as well as the role of ET-1 in several diseases including cardiovascular diseases, COVID-19 and chronic pain. Unravelling the ET-1 pathway and identifying therapeutic targets has the potential to treat many diseases whether through disease prevention, slowing disease progression or reversing pathology.
Topics: Humans; Cardiovascular Diseases; COVID-19; Endothelin-1; Endothelins; Chronic Pain
PubMed: 37511055
DOI: 10.3390/ijms241411295 -
European Respiratory Review : An... Jun 2023There is a well-recognised importance for personalising mechanical ventilation settings to protect the lungs and the diaphragm for each individual patient. Measurement... (Review)
Review
There is a well-recognised importance for personalising mechanical ventilation settings to protect the lungs and the diaphragm for each individual patient. Measurement of oesophageal pressure ( ) as an estimate of pleural pressure allows assessment of partitioned respiratory mechanics and quantification of lung stress, which helps our understanding of the patient's respiratory physiology and could guide individualisation of ventilator settings. Oesophageal manometry also allows breathing effort quantification, which could contribute to improving settings during assisted ventilation and mechanical ventilation weaning. In parallel with technological improvements, monitoring is now available for daily clinical practice. This review provides a fundamental understanding of the relevant physiological concepts that can be assessed using measurements, both during spontaneous breathing and mechanical ventilation. We also present a practical approach for implementing oesophageal manometry at the bedside. While more clinical data are awaited to confirm the benefits of -guided mechanical ventilation and to determine optimal targets under different conditions, we discuss potential practical approaches, including positive end-expiratory pressure setting in controlled ventilation and assessment of inspiratory effort during assisted modes.
Topics: Humans; Respiration, Artificial; Lung; Respiratory Mechanics; Ventilators, Mechanical; Monitoring, Physiologic
PubMed: 37197768
DOI: 10.1183/16000617.0186-2022