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17 pages, 792 KiB

Open AccessArticle

Alternative Splicing of Neuropeptide Prohormone and Receptor Genes Associated with Pain Sensitivity Was Detected with Zero-Inflated Models

by Bruce R. Southey and Sandra L. Rodriguez-Zas

Biomedicines 2022, 10(4), 877; https://doi.org/10.3390/biomedicines10040877 - 10 Apr 2022

Cited by 6 | Viewed by 1878

Abstract

Migraine is often accompanied by exacerbated sensitivity to stimuli and pain associated with alternative splicing of genes in signaling pathways. Complementary analyses of alternative splicing of neuropeptide prohormone and receptor genes involved in cell–cell communication in the trigeminal ganglia and nucleus accumbens regions [...] Read more.

Migraine is often accompanied by exacerbated sensitivity to stimuli and pain associated with alternative splicing of genes in signaling pathways. Complementary analyses of alternative splicing of neuropeptide prohormone and receptor genes involved in cell–cell communication in the trigeminal ganglia and nucleus accumbens regions of mice presenting nitroglycerin-elicited hypersensitivity and control mice were conducted. De novo sequence assembly detected 540 isoforms from 168 neuropeptide prohormone and receptor genes. A zero-inflated negative binomial model that accommodates for potential excess of zero isoform counts enabled the detection of 27, 202, and 12 differentially expressed isoforms associated with hypersensitivity, regions, and the interaction between hypersensitivity and regions, respectively. Skipped exons and alternative 3′ splice sites were the most frequent splicing events detected in the genes studied. Significant differential splicing associated with hypersensitivity was identified in CALCA and VGF neuropeptide prohormone genes and ADCYAP1R1, CRHR2, and IGF1R neuropeptide receptor genes. The prevalent region effect on differential isoform levels (202 isoforms) and alternative splicing (82 events) were consistent with the distinct splicing known to differentiate central nervous structures. Our findings highlight the changes in alternative splicing in neuropeptide prohormone and receptor genes associated with hypersensitivity to pain and the necessity to target isoform profiles for enhanced understanding and treatment of associated disorders such as migraine. Full article

(This article belongs to the Special Issue Neuropeptides in Biomedicines)

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10 pages, 2138 KiB

Open AccessCommunication

Immunohistochemical Analysis of Neurotransmitters in Neurosecretory Protein GL-Producing Neurons of the Mouse Hypothalamus

by Mana Naito, Eiko Iwakoshi-Ukena, Shogo Moriwaki, Yuki Narimatsu, Masaki Kato, Megumi Furumitsu, Yuta Miyamoto, Shigeyuki Esumi and Kazuyoshi Ukena

Biomedicines 2022, 10(2), 454; https://doi.org/10.3390/biomedicines10020454 - 15 Feb 2022

Cited by 2 | Viewed by 2826

Abstract

We recently discovered a novel neuropeptide of 80 amino acid residues: neurosecretory protein GL (NPGL), in the hypothalamus of birds and rodents. NPGL is localized in the lateral posterior part of the arcuate nucleus (ArcLP), and it enhances feeding behavior and fat accumulation [...] Read more.

We recently discovered a novel neuropeptide of 80 amino acid residues: neurosecretory protein GL (NPGL), in the hypothalamus of birds and rodents. NPGL is localized in the lateral posterior part of the arcuate nucleus (ArcLP), and it enhances feeding behavior and fat accumulation in mice. Various neurotransmitters, such as catecholamine, glutamate, and γ-aminobutyric acid (GABA), produced in the hypothalamus are also involved in energy metabolism. The colocalization of neurotransmitters and NPGL in neurons of the ArcLP leads to the elucidation of the regulatory mechanism of NPGL neurons. In this study, we performed double immunofluorescence staining to elucidate the relationship between NPGL and neurotransmitters in mice. The present study revealed that NPGL neurons did not co-express tyrosine hydroxylase as a marker of catecholaminergic neurons and vesicular glutamate transporter-2 as a marker of glutamatergic neurons. In contrast, NPGL neurons co-produced glutamate decarboxylase 67, a marker for GABAergic neurons. In addition, approximately 50% of NPGL neurons were identical to GABAergic neurons. These results suggest that some functions of NPGL neurons may be related to those of GABA. This study provides insights into the neural network of NPGL neurons that regulate energy homeostasis, including feeding behavior and fat accumulation. Full article

(This article belongs to the Special Issue Neuropeptides in Biomedicines)

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13 pages, 4252 KiB

Open AccessArticle

Asymmetric Interaction of Neuropeptidase Activities between Cortico-Limbic Structures, Plasma and Cardiovascular Function after Unilateral Dopamine Depletions of the Nigrostriatal System

by Inmaculada Banegas, Isabel Prieto, Ana Belén Segarra, Francisco Vives, Magdalena Martínez-Cañamero, Raquel Durán, Juan de Dios Luna, Marc de Gasparo, Germán Domínguez-Vías and Manuel Ramírez-Sánchez

Biomedicines 2022, 10(2), 326; https://doi.org/10.3390/biomedicines10020326 - 29 Jan 2022

Cited by 1 | Viewed by 2050

Abstract

In emotional processing, dopamine (DA) plays an essential role, and its deterioration involves important consequences. Under physiological conditions, dopamine exhibits brain asymmetry and coexists with various neuropeptides that can coordinate the processing of brain functions. Brain asymmetry can extend into a broader concept [...] Read more.

In emotional processing, dopamine (DA) plays an essential role, and its deterioration involves important consequences. Under physiological conditions, dopamine exhibits brain asymmetry and coexists with various neuropeptides that can coordinate the processing of brain functions. Brain asymmetry can extend into a broader concept of asymmetric neurovisceral integration, including behavior. The study of the activity of neuropeptide regulatory enzymes (neuropeptidases, NPs) is illustrative. We have observed that the left and right brain areas interact intra- and inter-hemispherically, as well as with peripheral tissues or with physiological parameters such as blood pressure or with behaviors such as turning preference. To obtain data that reflect this integrative behavior, we simultaneously analyzed the impact of left or right brain DA depletion on the activity of various NPs in corticolimbic regions of the left and right hemispheres, such as the medial prefrontal cortex, amygdala and hippocampus, as well as on the plasma activity of the same aminopeptidase activities (APs) and on systolic blood pressure (SBP). Intra- and inter-hemispheric interactions as well as the interactions of NPs from the left or right hemispheres were analyzed with the same plasma APs and the SBP obtained from sham and from left or right lesioned rats. The results demonstrate a complex profile depending on the hemisphere considered. They definitively confirm an asymmetric neurovisceral integration and reveal a higher level of inter-hemispheric corticolimbic interactions including with SBP after left dopamine depletion. Full article

(This article belongs to the Special Issue Neuropeptides in Biomedicines)

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10 pages, 2019 KiB

Open AccessArticle

Serpinin in the Skin

by Cristina Fraquelli, Jasmine Hauzinger, Christian Humpel, Maria Nolano, Vincenzo Provitera, Vinay Kumar Sharma, Peng Loh, Zenon Pidsudko, Georgios Blatsios and Josef Troger

Biomedicines 2022, 10(1), 183; https://doi.org/10.3390/biomedicines10010183 - 16 Jan 2022

Viewed by 1929

Abstract

The serpinins are relatively novel peptides generated by proteolytic processing of chromogranin A and they are comprised of free serpinin, serpinin-RRG and pGlu-serpinin. In this study, the presence and source of these peptides were studied in the skin. By Western blot analysis, a [...] Read more.

The serpinins are relatively novel peptides generated by proteolytic processing of chromogranin A and they are comprised of free serpinin, serpinin-RRG and pGlu-serpinin. In this study, the presence and source of these peptides were studied in the skin. By Western blot analysis, a 40 kDa and a 50 kDa protein containing the sequence of serpinin were detected in the trigeminal ganglion and dorsal root ganglia in rats but none in the skin. RP-HPLC followed by EIA revealed that the three serpinins are present in similar, moderate amounts in rat dorsal root ganglia, whereas in the rat skin, free serpinin represents the predominant molecular form. There were abundant serpinin-positive cells in rat dorsal root ganglia and colocalization with substance P was evident. However, much more widespread distribution of the serpinins was found in dorsal root ganglia when compared with substance P. In the skin, serpinin immunoreactivity was found in sensory nerves and showed colocalization with substance P; as well, some was present in autonomic nerves. Thus, although not exclusively, there is evidence that serpinin is a constituent of the sensory innervation of the skin. The serpinins are biologically highly active and might therefore be of functional significance in the skin. Full article

(This article belongs to the Special Issue Neuropeptides in Biomedicines)

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19 pages, 7516 KiB

Open AccessArticle

The Organization of Somatostatin-Immunoreactive Cells in the Visual Cortex of the Gerbil

by Kyung-Min Kwon, Myung-Jun Lee, Han-Saem Chung, Jae-Hong Pak and Chang-Jin Jeon

Biomedicines 2022, 10(1), 92; https://doi.org/10.3390/biomedicines10010092 - 01 Jan 2022

Cited by 2 | Viewed by 2211

Abstract

Somatostatin (SST) is widely expressed in the brain and plays various, vital roles involved in neuromodulation. The purpose of this study is to characterize the organization of SST neurons in the Mongolian gerbil visual cortex (VC) using immunocytochemistry, quantitative analysis, and confocal microscopy. [...] Read more.

Somatostatin (SST) is widely expressed in the brain and plays various, vital roles involved in neuromodulation. The purpose of this study is to characterize the organization of SST neurons in the Mongolian gerbil visual cortex (VC) using immunocytochemistry, quantitative analysis, and confocal microscopy. As a diurnal animal, the Mongolian gerbil provides us with a different perspective to other commonly used nocturnal rodent models. In this study, SST neurons were located in all layers of the VC except in layer I; they were most common in layer V. Most SST neurons were multipolar round/oval or stellate cells. No pyramidal neurons were found. Moreover, 2-color immunofluorescence revealed that only 33.50%, 24.05%, 16.73%, 0%, and 64.57% of SST neurons contained gamma-aminobutyric acid, calbindin-D28K, calretinin, parvalbumin, and calcium/calmodulin-dependent protein kinase II, respectively. In contrast, neuropeptide Y and nitric oxide synthase were abundantly expressed, with 80.07% and 75.41% in SST neurons, respectively. Our immunocytochemical analyses of SST with D₁ and D₂ dopamine receptors and choline acetyltransferase, α₇ and β₂ nicotinic acetylcholine receptors suggest that dopaminergic and cholinergic fibers contact some SST neurons. The results showed some distinguishable features of SST neurons and provided some insight into their afferent circuitry in the gerbil VC. These findings may support future studies investigating the role of SST neurons in visual processing. Full article

(This article belongs to the Special Issue Neuropeptides in Biomedicines)

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13 pages, 29838 KiB

Open AccessArticle

Decode the Stable Cell Communications Based on Neuropeptide-Receptors Network in 36746 Tumor Cells

by Yining Liu and Min Zhao

Biomedicines 2022, 10(1), 14; https://doi.org/10.3390/biomedicines10010014 - 22 Dec 2021

Cited by 2 | Viewed by 2202

Abstract

Background: As chemical signals of hormones, neuropeptides are essential to regulate cell growth by interacting with their receptors to achieve cell communications in cancer tissues. Previously, neuropeptide transcriptome analysis was limited to tissue-based bulk expression levels. The molecular mechanisms of neuropeptides and their [...] Read more.

Background: As chemical signals of hormones, neuropeptides are essential to regulate cell growth by interacting with their receptors to achieve cell communications in cancer tissues. Previously, neuropeptide transcriptome analysis was limited to tissue-based bulk expression levels. The molecular mechanisms of neuropeptides and their receptors at the single-cell level remain unclear. We conducted a systematic single-cell transcriptome data integration analysis to clarify the similarities and variations of neuropeptide-mediated cell communication between various malignancies. Methods: Based on the single-cell expression information in 72 cancer datasets across 24 cancer types, we characterized actively expressed neuropeptides and receptors as having log values of the quantitative transcripts per million ≥ 1. Then, we created the putative cell-to-cell communication network for each dataset by using the known interaction of those actively expressed neuropeptides and receptors. To focus on the stable cell communication events, we identified neuropeptide and downstream receptors whose interactions were detected in more than half of all conceivable cell-cell interactions (square of the total cell population) in a dataset. Results: Focusing on those actively expressed neuropeptides and receptors, we built over 76 million cell-to-cell communications across 70 cancer datasets. Then the stable cell communication analyses were applied to each dataset, and about 14 million stable cell-to-cell communications could be detected based on 16 neuropeptides and 23 receptors. Further functional analysis indicates these 39 genes could regulate blood pressure and are significantly associated with patients’ survival among over ten thousand The Cancer Genome Atlas (TCGA)pan-cancer samples. By zooming in lung cancer-specific clinical features, we discovered the 39 genes appeared to be enriched in the patients with smoking. In skin cancer, they may differ in the patients with the distinct histological subtype and molecular drivers. Conclusions: At the single-cell level, stable cell communications across cancer types demonstrated some common and distinct neuropeptide-receptor patterns, which could be helpful in determining the status of neuropeptide-based cell communication and developing a peptide-based therapy strategy. Full article

(This article belongs to the Special Issue Neuropeptides in Biomedicines)

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11 pages, 1377 KiB

Open AccessArticle

Functional Characterization of Spinocerebellar Ataxia Associated Dynorphin A Mutant Peptides

by Andreas Lieb, Germana Thaler, Barbara Fogli, Olga Trovato, Mitja Amon Posch, Teresa Kaserer and Luca Zangrandi

Biomedicines 2021, 9(12), 1882; https://doi.org/10.3390/biomedicines9121882 - 11 Dec 2021

Cited by 6 | Viewed by 2634

Abstract

Mutations in the prodynorphin gene (PDYN) are associated with the development of spinocerebellar ataxia type 23 (SCA23). Pathogenic missense mutations are localized predominantly in the PDYN region coding for the dynorphin A (DynA) neuropeptide and lead to persistently elevated mutant peptide [...] Read more.

Mutations in the prodynorphin gene (PDYN) are associated with the development of spinocerebellar ataxia type 23 (SCA23). Pathogenic missense mutations are localized predominantly in the PDYN region coding for the dynorphin A (DynA) neuropeptide and lead to persistently elevated mutant peptide levels with neurotoxic properties. The main DynA target in the central nervous system is the kappa opioid receptor (KOR), a member of the G-protein coupled receptor family, which can elicit signaling cascades mediated by G-protein dissociation as well as β-arrestin recruitment. To date, a thorough analysis of the functional profile for the pathogenic SCA23 DynA mutants at KOR is still missing. To elucidate the role of DynA mutants, we used a combination of assays to investigate the differential activation of G-protein subunits and β-arrestin. In addition, we applied molecular modelling techniques to provide a rationale for the underlying mechanism. Our results demonstrate that DynA mutations, associated with a severe ataxic phenotype, decrease potency of KOR activation, both for G-protein dissociation as well as β-arrestin recruitment. Molecular modelling suggests that this loss of function is due to disruption of critical interactions between DynA and the receptor. In conclusion, this study advances our understanding of KOR signal transduction upon DynA wild type or mutant peptide binding. Full article

(This article belongs to the Special Issue Neuropeptides in Biomedicines)

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16 pages, 4232 KiB

Open AccessArticle

The Neuropeptide VIP Limits Human Osteoclastogenesis: Clinical Associations with Bone Metabolism Markers in Patients with Early Arthritis

by David Castro-Vazquez, Amalia Lamana, Paula Arribas-Castaño, Irene Gutiérrez-Cañas, Raúl Villanueva-Romero, Selene Pérez-García, Carmen Martínez, Yasmina Juarranz, Sara Fernández de Córdoba, Isidoro González-Álvaro, Rosa P. Gomariz and Mar Carrión

Biomedicines 2021, 9(12), 1880; https://doi.org/10.3390/biomedicines9121880 - 10 Dec 2021

Cited by 3 | Viewed by 2250

Abstract

We aimed to evaluate the direct action of VIP on crucial molecules involved in human osteoclast differentiation and function. We also investigated the relationship between VIP serum levels and bone remodeling mediators in early arthritis patients. The expression of VIP receptors and osteoclast [...] Read more.

We aimed to evaluate the direct action of VIP on crucial molecules involved in human osteoclast differentiation and function. We also investigated the relationship between VIP serum levels and bone remodeling mediators in early arthritis patients. The expression of VIP receptors and osteoclast gene markers in monocytes and in vitro differentiated osteoclasts was studied by real-time PCR. NFATc1 activity was measured using a TransAM^® kit. Osteoclastogenesis was confirmed by quantification of tartrate-resistant acid phosphatase positive multinucleated cells. OsteoAssay^® Surface Multiple Well Plate was used to evaluate bone-resorbing activity. The ring-shaped actin cytoskeleton and the VPAC1 and VPAC2 expression were analyzed by immunofluorescence. We described the presence of VIP receptors in monocytes and mature osteoclasts. Osteoclasts that formed in the presence of VIP showed a decreased expression of osteoclast differentiation gene markers and proteolytic enzymes involved in bone resorption. VIP reduced the resorption activity and decreased both β3 integrin expression and actin ring formation. Elevated serum VIP levels in early arthritis patients were associated with lower BMD loss and higher serum OPG concentration. These results demonstrate that VIP exerts an anti-osteoclastogenic action impairing both differentiation and resorption activity mainly through the negative regulation of NFATc1, evidencing its bone-protective effects in humans. Full article

(This article belongs to the Special Issue Neuropeptides in Biomedicines)

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16 pages, 4867 KiB

Open AccessArticle

Neuromodulation Induced by Sitagliptin: A New Strategy for Treating Diabetic Retinopathy

by Hugo Ramos, Patricia Bogdanov, David Sabater, Jordi Huerta, Marta Valeri, Cristina Hernández and Rafael Simó

Biomedicines 2021, 9(12), 1772; https://doi.org/10.3390/biomedicines9121772 - 26 Nov 2021

Cited by 6 | Viewed by 2159

Abstract

Diabetic retinopathy (DR) involves progressive neurovascular degeneration of the retina. Reduction in synaptic protein expression has been observed in retinas from several diabetic animal models and human retinas. We previously reported that the topical administration (eye drops) of sitagliptin, a dipeptidyl peptidase-4 (DPP-4) [...] Read more.

Diabetic retinopathy (DR) involves progressive neurovascular degeneration of the retina. Reduction in synaptic protein expression has been observed in retinas from several diabetic animal models and human retinas. We previously reported that the topical administration (eye drops) of sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, prevented retinal neurodegeneration induced by diabetes in db/db mice. The aim of the present study is to examine whether the modulation of presynaptic proteins is a mechanism involved in the neuroprotective effect of sitagliptin. For this purpose, 12 db/db mice, aged 12 weeks, received a topical administration of sitagliptin (5 μL; concentration: 10 mg/mL) twice per day for 2 weeks, while other 12 db/db mice were treated with vehicle (5 μL). Twelve non-diabetic mice (db/+) were used as a control group. Protein levels were assessed by western blot and immunohistochemistry (IHC), and mRNA levels were evaluated by reverse transcription polymerase chain reaction (RT-PCR). Our results revealed a downregulation (protein and mRNA levels) of several presynaptic proteins such as synapsin I (Syn1), synaptophysin (Syp), synaptotagmin (Syt1), syntaxin 1A (Stx1a), vesicle-associated membrane protein 2 (Vamp2), and synaptosomal-associated protein of 25 kDa (Snap25) in diabetic mice treated with vehicle in comparison with non-diabetic mice. These proteins are involved in vesicle biogenesis, mobilization and docking, membrane fusion and recycling, and synaptic neurotransmission. Sitagliptin was able to significantly prevent the downregulation of all these proteins. We conclude that sitagliptin exerts beneficial effects in the retinas of db/db mice by preventing the downregulation of crucial presynaptic proteins. These neuroprotective effects open a new avenue for treating DR as well other retinal diseases in which neurodegeneration/synaptic abnormalities play a relevant role. Full article

(This article belongs to the Special Issue Neuropeptides in Biomedicines)

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12 pages, 2380 KiB

Open AccessArticle

The Role of Neuropeptide Y in Adipocyte-Macrophage Crosstalk during High Fat Diet-Induced Adipose Inflammation and Liver Steatosis

by Seongjoon Park, Toshimitsu Komatsu, Hiroko Hayashi, Ryoichi Mori and Isao Shimokawa

Biomedicines 2021, 9(11), 1739; https://doi.org/10.3390/biomedicines9111739 - 22 Nov 2021

Cited by 7 | Viewed by 2089

Abstract

Obesity is associated with an increased risk of non-alcoholic fatty liver disease (NAFLD), which is initiated by adipocyte-macrophage crosstalk. Among the possible molecules regulating this crosstalk, we focused on neuropeptide Y (NPY), which is known to be involved in hypothalamic appetite and adipose [...] Read more.

Obesity is associated with an increased risk of non-alcoholic fatty liver disease (NAFLD), which is initiated by adipocyte-macrophage crosstalk. Among the possible molecules regulating this crosstalk, we focused on neuropeptide Y (NPY), which is known to be involved in hypothalamic appetite and adipose tissue inflammation and metabolism. In this study, the NPY^−/− mice showed a marked decrease in body weight and adiposity, and lower free fatty acid and adipose inflammation without food intake alteration during a high fat diet (HFD). Moreover, NPY deficiency increased the thermogenic genes expression in brown adipose tissue. Notably, NPY-mRNA expression was upregulated in macrophages from the HFD mice compared to that from the mice on a standard diet. The NPY-mRNA expression also positively correlated with the liver mass/body weight ratio. NPY deletion alleviated HFD-induced adipose inflammation and liver steatosis. Hence, our findings point toward a novel intracellular mechanism of NPY in the regulation of adipocyte-macrophage crosstalk and highlight NPY antagonism as a promising target for therapeutic approaches against obesity and NAFLD. Full article

(This article belongs to the Special Issue Neuropeptides in Biomedicines)

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14 pages, 32935 KiB

Open AccessArticle

Salusin-β in Intermediate Dorsal Motor Nucleus of the Vagus Regulates Sympathetic-Parasympathetic Balance and Blood Pressure

by Lu-Lu Wu, Jin-Hua Bo, Fen Zheng, Feng Zhang, Qi Chen, Yue-Hua Li, Yu-Ming Kang and Guo-Qing Zhu

Biomedicines 2021, 9(9), 1118; https://doi.org/10.3390/biomedicines9091118 - 31 Aug 2021

Cited by 6 | Viewed by 2240

Abstract

The dorsal motor nucleus of the vagus (DMV) is known to control vagal activity. It is unknown whether the DMV regulates sympathetic activity and whether salusin-β in the DMV contributes to autonomic nervous activity. We investigated the roles of salusin-β in DMV in [...] Read more.

The dorsal motor nucleus of the vagus (DMV) is known to control vagal activity. It is unknown whether the DMV regulates sympathetic activity and whether salusin-β in the DMV contributes to autonomic nervous activity. We investigated the roles of salusin-β in DMV in regulating sympathetic-parasympathetic balance and its underline mechanisms. Microinjections were carried out in the DMV and hypothalamic paraventricular nucleus (PVN) in male adult anesthetized rats. Renal sympathetic nerve activity (RSNA), blood pressure and heart rate were recorded. Immunohistochemistry for salusin-β and reactive oxidative species (ROS) production in the DMV were examined. Salusin-β was expressed in the intermediate DMV (iDMV). Salusin-β in the iDMV not only inhibited RSNA but also enhanced vagal activity and thereby reduced blood pressure and heart rate. The roles of salusin-β in causing vagal activation were mediated by NAD(P)H oxidase-dependent superoxide anion production in the iDMV. The roles of salusin-β in inhibiting RSNA were mediated by not only the NAD(P)H oxidase-originated superoxide anion production in the iDMV but also the γ-aminobutyric acid (GABA)_A receptor activation in PVN. Moreover, endogenous salusin-β and ROS production in the iDMV play a tonic role in inhibiting RSNA. These results indicate that salusin-β in the iDMV inhibits sympathetic activity and enhances vagal activity, and thereby reduces blood pressure and heart rate, which are mediated by NAD(P)H oxidase-dependent ROS production in the iDMV. Moreover, GABA_A receptor in the PVN mediates the effect of salusin-β on sympathetic inhibition. Endogenous salusin-β and ROS production in the iDMV play a tonic role in inhibiting sympathetic activity. Full article

(This article belongs to the Special Issue Neuropeptides in Biomedicines)

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Review

Jump to: Research

53 pages, 5758 KiB

Open AccessReview

Immunomodulatory Role of Neuropeptides in the Cornea

by Sudan Puri, Brendan M. Kenyon and Pedram Hamrah

Biomedicines 2022, 10(8), 1985; https://doi.org/10.3390/biomedicines10081985 - 16 Aug 2022

Cited by 14 | Viewed by 4284

Abstract

The transparency of the cornea along with its dense sensory innervation and resident leukocyte populations make it an ideal tissue to study interactions between the nervous and immune systems. The cornea is the most densely innervated tissue of the body and possesses both [...] Read more.

The transparency of the cornea along with its dense sensory innervation and resident leukocyte populations make it an ideal tissue to study interactions between the nervous and immune systems. The cornea is the most densely innervated tissue of the body and possesses both immune and vascular privilege, in part due to its unique repertoire of resident immune cells. Corneal nerves produce various neuropeptides that have a wide range of functions on immune cells. As research in this area expands, further insights are made into the role of neuropeptides and their immunomodulatory functions in the healthy and diseased cornea. Much remains to be known regarding the details of neuropeptide signaling and how it contributes to pathophysiology, which is likely due to complex interactions among neuropeptides, receptor isoform-specific signaling events, and the inflammatory microenvironment in disease. However, progress in this area has led to an increase in studies that have begun modulating neuropeptide activity for the treatment of corneal diseases with promising results, necessitating the need for a comprehensive review of the literature. This review focuses on the role of neuropeptides in maintaining the homeostasis of the ocular surface, alterations in disease settings, and the possible therapeutic potential of targeting these systems. Full article

(This article belongs to the Special Issue Neuropeptides in Biomedicines)

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21 pages, 3100 KiB

Open AccessReview

Signal Transduction by VIP and PACAP Receptors

by Ingrid Langer, Jérôme Jeandriens, Alain Couvineau, Swapnil Sanmukh and Dorota Latek

Biomedicines 2022, 10(2), 406; https://doi.org/10.3390/biomedicines10020406 - 09 Feb 2022

Cited by 24 | Viewed by 3685

Abstract

Homeostasis of the human immune system is regulated by many cellular components, including two neuropeptides, VIP and PACAP, primary stimuli for three class B G protein-coupled receptors, VPAC1, VPAC2, and PAC1. Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) regulate intestinal [...] Read more.

Homeostasis of the human immune system is regulated by many cellular components, including two neuropeptides, VIP and PACAP, primary stimuli for three class B G protein-coupled receptors, VPAC1, VPAC2, and PAC1. Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) regulate intestinal motility and secretion and influence the functioning of the endocrine and immune systems. Inhibition of VIP and PACAP receptors is an emerging concept for new pharmacotherapies for chronic inflammation and cancer, while activation of their receptors provides neuroprotection. A small number of known active compounds for these receptors still impose limitations on their use in therapeutics. Recent cryo-EM structures of VPAC1 and PAC1 receptors in their agonist-bound active state have provided insights regarding their mechanism of activation. Here, we describe major molecular switches of VPAC1, VPAC2, and PAC1 that may act as triggers for receptor activation and compare them with similar non-covalent interactions changing upon activation that were observed for other GPCRs. Interhelical interactions in VIP and PACAP receptors that are important for agonist binding and/or activation provide a molecular basis for the design of novel selective drugs demonstrating anti-inflammatory, anti-cancer, and neuroprotective effects. The impact of genetic variants of VIP, PACAP, and their receptors on signalling mediated by endogenous agonists is also described. This sequence diversity resulting from gene splicing has a significant impact on agonist selectivity and potency as well as on the signalling properties of VIP and PACAP receptors. Full article

(This article belongs to the Special Issue Neuropeptides in Biomedicines)

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27 pages, 1029 KiB

Open AccessReview

Potentials of Neuropeptides as Therapeutic Agents for Neurological Diseases

by Xin Yi Yeo, Grace Cunliffe, Roger C. Ho, Su Seong Lee and Sangyong Jung

Biomedicines 2022, 10(2), 343; https://doi.org/10.3390/biomedicines10020343 - 01 Feb 2022

Cited by 14 | Viewed by 3367

Abstract

Despite recent leaps in modern medicine, progress in the treatment of neurological diseases remains slow. The near impermeable blood-brain barrier (BBB) that prevents the entry of therapeutics into the brain, and the complexity of neurological processes, limits the specificity of potential therapeutics. Moreover, [...] Read more.

Despite recent leaps in modern medicine, progress in the treatment of neurological diseases remains slow. The near impermeable blood-brain barrier (BBB) that prevents the entry of therapeutics into the brain, and the complexity of neurological processes, limits the specificity of potential therapeutics. Moreover, a lack of etiological understanding and the irreversible nature of neurological conditions have resulted in low tolerability and high failure rates towards existing small molecule-based treatments. Neuropeptides, which are small proteinaceous molecules produced by the body, either in the nervous system or the peripheral organs, modulate neurological function. Although peptide-based therapeutics originated from the treatment of metabolic diseases in the 1920s, the adoption and development of peptide drugs for neurological conditions are relatively recent. In this review, we examine the natural roles of neuropeptides in the modulation of neurological function and the development of neurological disorders. Furthermore, we highlight the potential of these proteinaceous molecules in filling gaps in current therapeutics. Full article

(This article belongs to the Special Issue Neuropeptides in Biomedicines)

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10 pages, 292 KiB

Open AccessReview

The Local Neuropeptide System of Keratinocytes

by Nicola Cirillo

Biomedicines 2021, 9(12), 1854; https://doi.org/10.3390/biomedicines9121854 - 07 Dec 2021

Cited by 9 | Viewed by 2259

Abstract

Neuropeptides have been known for over 50 years as chemical signals in the brain. However, it is now well established that the synthesis of this class of peptides is not restricted to neurons. For example, human skin not only expresses several functional receptors [...] Read more.

Neuropeptides have been known for over 50 years as chemical signals in the brain. However, it is now well established that the synthesis of this class of peptides is not restricted to neurons. For example, human skin not only expresses several functional receptors for neuropeptides but, also, can serve as a local source of neuroactive molecules such as corticotropin-releasing hormone, melanocortins, and β-endorphin. In contrast, an equivalent of the hypothalamic-pituitary axis in the oral mucosa has not been well characterized to date. In view of the differences in the morphology and function of oral mucosal and skin cells, in this review I surveyed the existing evidence for a local synthesis of hypothalamic-pituitary, opiate, neurohypophyseal, and neuroendocrine neuropeptides in both epidermal and oral keratinocytes. Full article

(This article belongs to the Special Issue Neuropeptides in Biomedicines)

15 pages, 1627 KiB

Open AccessReview

Somatostatin and Somatostatin Receptors: From Signaling to Clinical Applications in Neuroendocrine Neoplasms

by Maria Isabel del Olmo-Garcia, Stefan Prado-Wohlwend, Alexia Andres, Jose M. Soriano, Pilar Bello and Juan Francisco Merino-Torres

Biomedicines 2021, 9(12), 1810; https://doi.org/10.3390/biomedicines9121810 - 01 Dec 2021

Cited by 7 | Viewed by 2398

Abstract

Neuroendocrine neoplasms (NENs) are heterogeneous neoplasms which arise from neuroendocrine cells that are distributed widely throughout the body. Although heterogenous, many of them share their ability to overexpress somatostatin receptors (SSTR) on their cell surface. Due to this, SSTR and somatostatin have been [...] Read more.

Neuroendocrine neoplasms (NENs) are heterogeneous neoplasms which arise from neuroendocrine cells that are distributed widely throughout the body. Although heterogenous, many of them share their ability to overexpress somatostatin receptors (SSTR) on their cell surface. Due to this, SSTR and somatostatin have been a large subject of interest in the discovery of potential biomarkers and treatment options for the disease. The aim of this review is to describe the molecular characteristics of somatostatin and somatostatin receptors and its application in diagnosis and therapy on patients with NENs as well as the use in the near future of somatostatin antagonists. Full article

(This article belongs to the Special Issue Neuropeptides in Biomedicines)

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Somatostatin and Its Receptor System in Colorectal Cancer

by Aldona Kasprzak

Biomedicines 2021, 9(11), 1743; https://doi.org/10.3390/biomedicines9111743 - 22 Nov 2021

Cited by 6 | Viewed by 2711

Abstract

Somatostatin (SST)/somatotropin release-inhibiting factor (SRIF) is a well-known neuropeptide, widely distributed in the central and peripheral nervous systems, that regulates the endocrine system and affects neurotransmission via interaction with five SST receptors (SST1-5). In the gastrointestinal tract, the main SST-producing cells include intestinal [...] Read more.

Somatostatin (SST)/somatotropin release-inhibiting factor (SRIF) is a well-known neuropeptide, widely distributed in the central and peripheral nervous systems, that regulates the endocrine system and affects neurotransmission via interaction with five SST receptors (SST1-5). In the gastrointestinal tract, the main SST-producing cells include intestinal enteroendocrine cells (EECs) restricted to the mucosa, and neurons of the submucosal and myenteric plexuses. The action of the SRIF system is based on the inhibition of endocrine and exocrine secretion, as well as the proliferative responses of target cells. The SST1–5 share common signaling pathways, and are not only widely expressed on normal tissues, but also frequently overexpressed by several tumors, particularly neuroendocrine neoplasms (NENs). Furthermore, the SRIF system represents the only peptide/G protein-coupled receptor (GPCR) system with multiple approved clinical applications for the diagnosis and treatment of several NENs. The role of the SRIF system in the histogenesis of colorectal cancer (CRC) subtypes (e.g., adenocarcinoma and signet ring-cell carcinoma), as well as diagnosis and prognosis of mixed adenoneuroendocrine carcinoma (MANEC) and pure adenocarcinoma, is poorly understood. Moreover, the impact of the SRIF system signaling on CRC cell proliferation and its potential role in the progression of this cancer remains unknown. Therefore, this review summarizes the recent collective knowledge and understanding of the clinical significance of the SRIF system signaling in CRC, aiming to evaluate the potential role of its components in CRC histogenesis, diagnosis, and potential therapy. Full article

(This article belongs to the Special Issue Neuropeptides in Biomedicines)

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12 pages, 416 KiB

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Neuropeptides Involved in Facial Nerve Regeneration

by Inhyeok Kim, Yonjae Kim, Daewoong Kang, Junyang Jung, Sungsoo Kim, Hwasung Rim, Sanghoon Kim and Seung-Geun Yeo

Biomedicines 2021, 9(11), 1575; https://doi.org/10.3390/biomedicines9111575 - 29 Oct 2021

Cited by 3 | Viewed by 1768

Abstract

Neuropeptides and neurotransmitters act as intermediaries to transmit impulses from one neuron to another via a synapse. These neuropeptides are also related to nerve degeneration and regeneration during nerve damage. Although there are various neuropeptides, three are associated with neural regeneration in facial [...] Read more.

Neuropeptides and neurotransmitters act as intermediaries to transmit impulses from one neuron to another via a synapse. These neuropeptides are also related to nerve degeneration and regeneration during nerve damage. Although there are various neuropeptides, three are associated with neural regeneration in facial nerve damage: calcitonin gene-related peptide (CGRP), galanin, and pituitary adenylyl cyclase-activating peptide (PACAP). Alpha CGRP in facial motoneurons is a signaling factor involved in neuroglial and neuromuscular interactions during regeneration. Thus, it may be a marker for facial nerve regeneration. Galanin is a marker of injured axons rather than nerve regeneration. PACAP has various effects on nerve regeneration by regulating the surrounding cells and providing neurotrophic factors. Thus, it may also be used as a marker for facial nerve regeneration. However, the precise roles of these substances in nerve generation are not yet fully understood. Animal studies have demonstrated that they may act as neuromodulators to promote neurotrophic factors involved in nerve regeneration as they appear early, before changes in the injured cells and their environment. Therefore, they may be markers of nerve regeneration. Full article

(This article belongs to the Special Issue Neuropeptides in Biomedicines)

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