Molecular signature of pruriceptive MrgprA3+ neurons

ABSTRACTItch, initiated by the activation of sensory neurons, is frequently associated with dermatological or systemic diseases and significantly affects patient quality of life. MrgprA3+ sensory neurons have been identified as one of the major itch-sensing neuronal populations. Mounting evidence has demonstrated that peripheral pathological conditions induce physiological regulations of sensory neurons, which is critical for the maintenance of chronic itch sensation. However, the underlying molecular mechanisms are not clear. Here we performed RNA sequencing of genetically labeled MrgprA3+ neurons under both naïve and allergic contact dermatitis condition. Our results revealed the unique molecular signature of itch-sensing neurons and the distinct transcriptional profile changes that result in response to dermatitis. We found enrichment of nine Mrgpr family members and two histamine receptors in MrgprA3+ neurons, suggesting that MrgprA3+ neurons are the main, direct neuronal target for histamine and Mrgprs agonists. In addition, Ptpn6 and Pcdh12 were identified as novel and highly selective markers of MrgprA3+ neurons. We also discovered that MrgprA3+ neurons respond to skin dermatitis in a way that is unique from other sensory neurons by regulating a combination of transcriptional factors, ion channels, and key molecules involved in synaptic transmission. These results significantly increase our knowledge of itch transmission and uncover potentially novel targets for combating itch.

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Involvement of sensory neuron-TRPV4 in acute and chronic itch behaviors

10.1101/2021.07.06.451366 ◽

2021 ◽

Author(s):

Quan Fang ◽

Zilong Wang ◽

Abbie Suttle ◽

Yong Chen

Keyword(s):

Sensory Neuron ◽

Sensory Neurons ◽

Well Being ◽

Conditional Knockout ◽

Nonselective Cation Channel ◽

Dry Skin ◽

Skin Cells ◽

Chronic Itch ◽

Allergic Contact

Itch, particularly chronic itch, negatively impacts patients' physical, social, and psychological well-being, leading to deterioration in their quality of life. Limited understanding of itch mechanisms hinders the development of effective antipruritic treatments.TRPV4, a multimodally activated nonselective cation channel, has been detected in sensory neurons of dorsal root and trigeminal ganglion (DRG, TG) and skin cells (e.g. keratinocytes, mast cells, and macrophages). Recent evidence from experimental and clinical relevant studies has implicated that TRPV4 in skin cells plays an important role in both acute and chronic itch. In contrast, little is known whether TRPV4 in sensory neurons directly contributes to scratching behaviors. Here we used sensory neuron-Trpv4 conditional knockout (cKO) mice to address this question. Our results showed that TRPV4 in sensory neurons contributes to scratching behavior evoked by histaminergic (histamine and 48/80) and partial histaminergic (5-HT), but not non-histaminergic (SLIGRL and CQ) pruritogens. Moreover, we observed that TRPV4 in sensory neurons is required for dry skin, but not allergic contact dermatitis, -associated chronic itch. These findings suggest that neuronal-TRPV4 might be specific for some forms of acute and chronic itch.

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Pharmacological Effects and Potential Clinical Usefulness of Polyphenols in Benign Prostatic Hyperplasia

Molecules ◽

10.3390/molecules26020450 ◽

2021 ◽

Vol 26 (2) ◽

pp. 450

Author(s):

Kensuke Mitsunari ◽

Yasuyoshi Miyata ◽

Tomohiro Matsuo ◽

Yuta Mukae ◽

Asato Otsubo ◽

...

Keyword(s):

Benign Prostatic Hyperplasia ◽

Molecular Mechanisms ◽

Prostatic Hyperplasia ◽

Pathological Conditions ◽

Urinary Tract Symptoms ◽

Anti Inflammatory ◽

Lower Urinary

Benign prostatic hyperplasia (BPH) is arguably the most common benign disease among men. This disease is often associated with lower urinary tract symptoms (LUTS) in men and significantly decreases the quality of life. Polyphenol consumption reportedly plays an important role in the prevention of many diseases, including BPH. In recent years, in addition to disease prevention, many studies have reported the efficacy and safety of polyphenol treatment against various pathological conditions in vivo and in vitro. Furthermore, numerous studies have also revealed the molecular mechanisms of the antioxidant and anti-inflammatory effects of polyphenols. We believe that an improved understanding of the detailed pharmacological roles of polyphenol-induced activities at a molecular level is important for the prevention and treatment of BPH. Polyphenols are composed of many members, and their biological roles differ. In this review, we first provide information regarding the pathological roles of oxidative stress and inflammation in BPH. Next, the antioxidant and anti-inflammatory effects of polyphenols, including those of flavonoids and non-flavonoids, are discussed. Finally, we talk about the results and limitations of previous clinical trials that have used polyphenols in BPH, with particular focus on their molecular mechanisms of action.

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Central opioid receptors mediate morphine-induced itch and chronic itch

10.1101/2020.05.31.126805 ◽

2020 ◽

Author(s):

Zilong Wang ◽

Changyu Jiang ◽

Hongyu Yao ◽

Ouyang Chen ◽

Sreya Rahman ◽

...

Keyword(s):

Spinal Cord ◽

Sensory Neurons ◽

Common Side Effect ◽

Cellular Mechanisms ◽

Conditional Deletion ◽

Outward Currents ◽

Clinical Pain ◽

Chronic Itch ◽

Allergic Contact

AbstractOpioids, such as morphine are mainstay treatments for clinical pain conditions. Itch is a common side effect of opioids, particularly as a result of epidural or intrathecal (i.t.) administration. Recent progress has advanced our understanding of itch circuits in the spinal cord. However, the mechanisms underlying opioid-induced itch are not fully understood, although an interaction between µ-opioid receptor (MOR) and gastrin-releasing peptide receptor (GRPR) in spinal GRPR-expressing neurons has been implicated. In this study we investigated the cellular mechanisms of intrathecal (i.t.) opioid-induced itch by conditional deletion of MOR-encoding Oprm1 in distinct populations of interneurons and sensory neurons. We found that i.t. injection of the MOR agonists morphine or DAMGO elicited dose-dependent scratching, but this pruritus was totally abolished in mice with a specific Oprm1 deletion in Vgat+ neurons (Oprm1-Vgat). Loss of MOR in somatostatin+ interneurons and TRPV1+ sensory neurons did not affect morphine-induced itch but impaired morphine-induced antinociception. In situ hybridization revealed Oprm1 expression in 30% of inhibitory and 20% of excitatory interneurons in the spinal dorsal horn. Whole-cell recordings from spinal cord slices showed that DAMGO induced outward currents in 9 out of 19 Vgat+ interneurons examined. Morphine also inhibited action potentials in Vgat+ interneurons and suppressed evoked IPSCs in postsynaptic Vgat- excitatory neurons, suggesting a mechanism of disinhibition by MOR agonists. Notably, morphine-elicited itch was suppressed by i.t. administration of NPY and abolished by spinal ablation of GRPR+ neurons, whereas i.t. GRP-induced itch response remained intact in mice lacking Oprm1-Vgat. Additionally, chronic itch from DNFB-induced allergic contact dermatitis was decreased by Oprm1-Vgat deletion. Finally, naloxone, but not peripherally restricted naloxone methiodide, inhibited chronic itch in the DNFB model and the cutaneous T-cell lymphoma (CTCL) model, indicating a contribution of central MOR signaling to chronic itch. Our findings demonstrate that i.t. morphine elicits itch via acting on MOR on spinal inhibitory interneurons, leading to disinhibition of the spinal itch circuit. Our data also suggest that chronic itch could be effectively treated with CNS-targeted naloxone.

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Itch Signaling in the Nervous System

Physiology ◽

10.1152/physiol.00007.2011 ◽

2011 ◽

Vol 26 (4) ◽

pp. 286-292 ◽

Cited By ~ 50

Author(s):

Joseph Jeffry ◽

Seungil Kim ◽

Zhou-Feng Chen

Keyword(s):

Molecular Mechanisms ◽

Somatosensory System ◽

Mouse Genetics ◽

Molecular Signaling ◽

C Fibers ◽

Chronic Itch ◽

Itch Sensation ◽

Somatic Sensation ◽

Psychophysical Studies ◽

Important Progress

Itch is a major somatic sensation, along with pain, temperature, and touch, detected and relayed by the somatosensory system. Itch can be an acute sensation, associated with mosquito bite, or a chronic condition, like atopic dermatitis ( 29 , 59 ). The origins of the stimulus can be localized in the periphery or systemic, and associated with organ failure or cancer. Itch is also a perception originating in the brain. Itch is broadly characterized as either histamine-dependent (histaminergic) or histamine-independent (nonhistaminergic), both of which are relayed by subsets of C fibers and by the second-order neurons expressing gastrin-releasing peptide receptor (GRPR) and spinothalamic track (STT) neurons in the spinal cord of rodents. Historically, itch research has been primarily limited to clinical and psychophysical studies and to histamine-mediated mechanisms. In contrast, little is known about the signaling mechanisms underlying nonhistaminergic itch, despite the fact that the majority of chronic itch are mediated by nonhistaminergic mechanisms. During the past few years, important progress has been made in understanding the molecular signaling of itch, largely due to the introduction of mouse genetics. In this review, we examine some of the molecular mechanisms underlying itch sensation with an emphasis on recent studies in rodents.

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Sensory Neuron Expressed TRPC3 Mediates Acute and Chronic Itch

10.21203/rs.3.rs-1021582/v1 ◽

2021 ◽

Author(s):

Yan Liu ◽

Yutong Liu ◽

Claire Narang ◽

Nathachit Limjunyawong ◽

Hanna Jamaldeen ◽

...

Keyword(s):

Mrna Expression ◽

Sensory Neurons ◽

Molecular Mechanisms ◽

Immune Cell ◽

Small Diameter ◽

Contact Hypersensitivity ◽

Peripheral Sensitization ◽

Primary Sensory Neurons ◽

Proinflammatory Mediators ◽

Chronic Itch

Abstract Background: Chronic pruritus is a prominent symptom of allergic contact dermatitis (ACD) and represent a huge unmet health problem. However, its underlying cellular and molecular mechanisms remain largely unexplored. TRPC3 is highly expressed in primary sensory neurons and has been implicated in peripheral sensitization induced by proinflammatory mediators. However, the role of TRPC3 in acute and chronic itch is still not well defined. Methods: RNAscope in situ hybridization and immunohistochemical staining were performed on mouse trigeminal ganglion (TG) neurons. Fura-2 calcium imaging was used to characterize the function of TRPC3 in dissociated TG neurons. In native mice, the TRPC3 agonist and pruritogens were subcutaneously injected to the cheek and nape of the neck of mice, respectively. Site directed scratching and/or wiping behaviors were video recorded. Contact hypersensitivity (CHS) model was induced in mouse ears by topical application of SADBE or DNCB. Spontaneous scratching behaviors were recorded by video monitoring. Global and conditional Trpc3 knockout mice were employed to determine the contribution of TRPC3 to acute and chronic itch. The mRNA expression levels of Trpc3 and proinflammatory cytokines were assayed by quantitative real-time PCR. H&E. staining was used for the evaluation of the thickness of mouse ears. Flow cytometry was performed to assess immune cell infiltration in mouse ear tissues. Results: Among mouse TG neurons, RNAscope assay revealed that Trpc3 mRNA was predominantly expressed in nonpeptidergic small diameter neurons. Moreover, Trpc3 mRNA signal was present in the majority of itch sensing neurons. TRPC3 agonism induced TG neuronal activation and acute nonhistaminergic itch- and pain-like behaviors in naïve mice. In addition, genetic deletion of Trpc3 attenuated acute itch evoked by certain common nonhistaminergic pruritogens, including endothelin-1 and SLIGRL-NH2. In a murine model of CHS, Trpc3 mRNA expression level and function were upregulated in the TG following CHS. Pharmacological inhibition and global knockout of Trpc3 significantly alleviated spontaneous scratching behaviors without affecting concurrent cutaneous inflammation in the CHS model. Furthermore, conditional deletion of Trpc3 in primary sensory neurons but not in keratinocytes produced similar antipruritic effects in this model. Conclusions: These findings suggest that TRPC3 expressed in primary sensory neurons may contribute to acute and chronic itch via a histamine independent mechanism and that targeting neuronal TRPC3 might benefit the treatment of chronic itch associated with ACD and other inflammatory skin disorders.

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The visualization and assessment of the anterior surface of the cornea using video keratotopography

The Eye ◽

10.33791/2222-4408-2020-2-36-43 ◽

2020 ◽

Vol 22 (130) ◽

pp. 36-43

Author(s):

Gulnara Andrienko

Keyword(s):

Contact Lenses ◽

Corneal Topography ◽

Topographic Maps ◽

Specific Situation ◽

Main Method ◽

Pathological Conditions ◽

Quality Of Vision ◽

Corneal Shape ◽

Color Map

Corneal topography is the main method for assessing the regularity of the surface of the cornea. Corneal irregularity leads to a deterioration in its refractive properties and a decrease in the quality of vision. Learning the basics of corneal topography will help determine the choice of a color map for a specific situation, as well as understand and analyze the data associated with these maps. This article describes the main types of topographic maps, various patterns of corneal shape in normal and pathological conditions and how to use the data obtained to design and fit contact lenses. Despite the fact that images may vary depending on topographers used, the information presented in this article is universal.

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Molecular mechanisms of Zika virus teratogenesis from animal studies: a systematic review protocol

Systematic Reviews ◽

10.1186/s13643-021-01713-6 ◽

2021 ◽

Vol 10 (1) ◽

Author(s):

Gabriela Elis Wachholz ◽

Julia do Amaral Gomes ◽

Juliano André Boquett ◽

Fernanda Sales Luiz Vianna ◽

Lavínia Schuler-Faccini ◽

...

Keyword(s):

Systematic Review ◽

Animal Models ◽

Zika Virus ◽

Methodological Quality ◽

Molecular Mechanisms ◽

Grey Literature ◽

Standard Form ◽

Teratogenic Effect ◽

Control Group

Abstract Background Due to the diversity of studies in animal models reporting that molecular mechanisms are involved in the teratogenic effect of the Zika virus (ZIKV), the objective of the present study is to evaluate the methodological quality of these studies, as well as to demonstrate which genes and which molecular pathways are affected by ZIKV in different animal models. Methods This search will be performed in four databases: PubMed/MEDLINE, EMBASE, Web of Science, and Scopus, as well as in the grey literature. The studies selection process will be reported through the PRISMA Statement diagram model. All studies describing the molecular mechanisms possibly involved in the development of malformations caused by embryonic/fetal ZIKV exposure in animal models with an appropriate control group and methodology will be included (including, for instance, randomized and non-randomized studies). All animals used as experimental models for ZIKV teratogenesis may be included as long as exposure to the virus occurred during the embryonic/fetal period. From the selected studies, data will be extracted using a previously prepared standard form. Bias risk evaluation will be conducted following the SYRCLE’s Risk of Bias tool. All data obtained will be tabulated and organized by outcomes (morphological and molecular). Discussion With the proposed systematic review, we expect to present results about the methodological quality of the published studies with animal models that investigated the molecular mechanisms involved in the teratogenic effect of ZIKV, as well as to show the studies with greater reliability. Systematic review registration PROSPERO CRD42019157316

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Molecular Mechanisms Associated with ROS-Dependent Angiogenesis in Lower Extremity Artery Disease

Antioxidants ◽

10.3390/antiox10050735 ◽

2021 ◽

Vol 10 (5) ◽

pp. 735

Author(s):

Greg Hutchings ◽

Łukasz Kruszyna ◽

Mariusz J. Nawrocki ◽

Ewa Strauss ◽

Rut Bryl ◽

...

Keyword(s):

Quality Of Life ◽

Blood Vessel ◽

Lower Extremity ◽

Molecular Mechanisms ◽

Lower Extremities ◽

Tissue Response ◽

Peripheral Arteries ◽

Artery Disease ◽

Lower Extremity Artery Disease

Currently, atherosclerosis, which affects the vascular bed of all vital organs and tissues, is considered as a leading cause of death. Most commonly, atherosclerosis involves coronary and peripheral arteries, which results in acute (e.g., myocardial infarction, lower extremities ischemia) or chronic (persistent ischemia leading to severe heart failure) consequences. All of them have a marked unfavorable impact on the quality of life and are associated with increased mortality and morbidity in human populations. Lower extremity artery disease (LEAD, also defined as peripheral artery disease, PAD) refers to atherosclerotic occlusive disease of the lower extremities, where partial or complete obstruction of peripheral arteries is observed. Decreased perfusion can result in ischemic pain, non-healing wounds, and ischemic ulcers, and significantly reduce the quality of life. However, the progressive atherosclerotic changes cause stimulation of tissue response processes, like vessel wall remodeling and neovascularization. These mechanisms of adapting the vascular network to pathological conditions seem to play a key role in reducing the impact of the changes limiting the flow of blood. Neovascularization as a response to ischemia induces sprouting and expansion of the endothelium to repair and grow the vessels of the circulatory system. Neovascularization consists of three different biological processes: vasculogenesis, angiogenesis, and arteriogenesis. Both molecular and environmental factors that may affect the process of development and growth of blood vessels were analyzed. Particular attention was paid to the changes taking place during LEAD. It is important to consider the molecular mechanisms underpinning vessel growth. These mechanisms will also be examined in the context of diseases commonly affecting blood vessel function, or those treatable in part by manipulation of angiogenesis. Furthermore, it may be possible to induce the process of blood vessel development and growth to treat peripheral vascular disease and wound healing. Reactive oxygen species (ROS) play an important role in regulation of essential cellular signaling pathways such as cell differentiation, proliferation, migration and apoptosis. With regard to the repair processes taking place during diseases such as LEAD, prospective therapeutic methods have been described that could significantly improve the treatment of vessel diseases in the future. Summarizing, regenerative medicine holds the potential to transform the therapeutic methods in heart and vessel diseases treatment.

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Comprehensive Analysis of Transcriptome and Metabolome Reveals the Flavonoid Metabolic Pathway Is Associated with Fruit Peel Coloration of Melon

Molecules ◽

10.3390/molecules26092830 ◽

2021 ◽

Vol 26 (9) ◽

pp. 2830

Author(s):

Aiai Zhang ◽

Jing Zheng ◽

Xuemiao Chen ◽

Xueyin Shi ◽

Huaisong Wang ◽

...

Keyword(s):

Molecular Mechanisms ◽

Comprehensive Analysis ◽

Differentially Expressed ◽

Integrated Analysis ◽

Fruit Peel ◽

External Quality ◽

Color Formation ◽

Peel Color ◽

Dark Green

The peel color is an important external quality of melon fruit. To explore the mechanisms of melon peel color formation, we performed an integrated analysis of transcriptome and metabolome with three different fruit peel samples (grey-green ‘W’, dark-green ‘B’, and yellow ‘H’). A total of 40 differentially expressed flavonoids were identified. Integrated transcriptomic and metabolomic analyses revealed that flavonoid biosynthesis was associated with the fruit peel coloration of melon. Twelve differentially expressed genes regulated flavonoids synthesis. Among them, nine (two 4CL, F3H, three F3′H, IFS, FNS, and FLS) up-regulated genes were involved in the accumulation of flavones, flavanones, flavonols, and isoflavones, and three (2 ANS and UFGT) down-regulated genes were involved in the accumulation of anthocyanins. This study laid a foundation to understand the molecular mechanisms of melon peel coloration by exploring valuable genes and metabolites.

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When the Balance Tips: Dysregulation of Mitochondrial Dynamics as a Culprit in Disease

International Journal of Molecular Sciences ◽

10.3390/ijms22094617 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4617

Author(s):

Styliana Kyriakoudi ◽

Anthi Drousiotou ◽

Petros P. Petrou

Keyword(s):

Insulin Resistance ◽

Mitochondrial Function ◽

Human Disease ◽

Molecular Mechanisms ◽

Mitochondrial Dynamics ◽

Mitochondrial Fusion ◽

Mitochondrial Morphology ◽

Disease Development ◽

Pathological Conditions ◽

Wide Range

Mitochondria are dynamic organelles, the morphology of which is tightly linked to their functions. The interplay between the coordinated events of fusion and fission that are collectively described as mitochondrial dynamics regulates mitochondrial morphology and adjusts mitochondrial function. Over the last few years, accruing evidence established a connection between dysregulated mitochondrial dynamics and disease development and progression. Defects in key components of the machinery mediating mitochondrial fusion and fission have been linked to a wide range of pathological conditions, such as insulin resistance and obesity, neurodegenerative diseases and cancer. Here, we provide an update on the molecular mechanisms promoting mitochondrial fusion and fission in mammals and discuss the emerging association of disturbed mitochondrial dynamics with human disease.

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