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Cell Reports Feb 2021Extensive hierarchical yet highly reciprocal interactions among cortical areas are fundamental for information processing. However, connectivity rules governing the...
Extensive hierarchical yet highly reciprocal interactions among cortical areas are fundamental for information processing. However, connectivity rules governing the specificity of such corticocortical connections, and top-down feedback projections in particular, are poorly understood. We analyze synaptic strength from functionally relevant brain areas to diverse neuronal types in the primary somatosensory cortex (S1). Long-range projections from different areas preferentially engage specific sets of GABAergic neurons in S1. Projections from other somatosensory cortices strongly recruit parvalbumin (PV)-positive GABAergic neurons and lead to PV neuron-mediated feedforward inhibition of pyramidal neurons in S1. In contrast, inputs from whisker-related primary motor cortex are biased to vasoactive intestinal peptide (VIP)-positive GABAergic neurons and potentially result in VIP neuron-mediated disinhibition. Regardless of the input areas, somatostatin-positive neurons receive relatively weak long-range inputs. Computational analyses suggest that a characteristic combination of synaptic inputs to different GABAergic IN types in S1 represents a specific long-range input area.
Topics: Animals; Female; GABAergic Neurons; Interneurons; Male; Mice, Transgenic; Neural Inhibition; Neural Pathways; Neuroanatomical Tract-Tracing Techniques; Parvalbumins; Pyramidal Cells; Somatosensory Cortex; Synaptic Transmission; Vasoactive Intestinal Peptide; Vibrissae; gamma-Aminobutyric Acid
PubMed: 33626343
DOI: 10.1016/j.celrep.2021.108774 -
Nature Communications Oct 2022A paucity of effector T cells within tumors renders pancreatic ductal adenocarcinoma (PDAC) resistant to immune checkpoint therapies. While several under-development...
A paucity of effector T cells within tumors renders pancreatic ductal adenocarcinoma (PDAC) resistant to immune checkpoint therapies. While several under-development approaches target immune-suppressive cells in the tumor microenvironment, there is less focus on improving T cell function. Here we show that inhibiting vasoactive intestinal peptide receptor (VIP-R) signaling enhances anti-tumor immunity in murine PDAC models. In silico data mining and immunohistochemistry analysis of primary tumors indicate overexpression of the neuropeptide vasoactive intestinal peptide (VIP) in human PDAC tumors. Elevated VIP levels are also present in PDAC patient plasma and supernatants of cultured PDAC cells. Furthermore, T cells up-regulate VIP receptors after activation, identifying the VIP signaling pathway as a potential target to enhance T cell function. In mouse PDAC models, VIP-R antagonist peptides synergize with anti-PD-1 antibody treatment in improving T cell recruitment into the tumors, activation of tumor-antigen-specific T cells, and inhibition of T cell exhaustion. In contrast to the limited single-agent activity of anti-PD1 antibodies or VIP-R antagonist peptides, combining both therapies eliminate tumors in up to 40% of animals. Furthermore, tumor-free mice resist tumor re-challenge, indicating anti-cancer immunological memory generation. VIP-R signaling thus represents a tumor-protective immune-modulatory pathway that is targetable in PDAC.
Topics: Humans; Mice; Animals; Vasoactive Intestinal Peptide; Carcinoma, Pancreatic Ductal; Pancreatic Neoplasms; Receptors, Vasoactive Intestinal Peptide; Signal Transduction; Tumor Microenvironment
PubMed: 36302761
DOI: 10.1038/s41467-022-34242-4 -
Frontiers in Endocrinology 2022Owing to the increasing prevalence of type 2 diabetes, the development of novel hypoglycemic drugs has become a research hotspot, with the ultimate goal of developing... (Review)
Review
Owing to the increasing prevalence of type 2 diabetes, the development of novel hypoglycemic drugs has become a research hotspot, with the ultimate goal of developing therapeutic drugs that stimulate glucose-induced insulin secretion without inducing hypoglycemia. Vasoactive intestinal peptide (VIP), a 28-amino-acid peptide, can stimulate glucose-dependent insulin secretion, particularly by binding to VPAC2 receptors. VIP also promotes islet β-cell proliferation through the forkhead box M1 pathway, but the specific molecular mechanism remains to be studied. The clinical application of VIP is limited because of its short half-life and wide distribution in the human body. Based on the binding properties of VIP and VPAC2 receptors, VPAC2-selective agonists have been developed to serve as novel hypoglycemic drugs. This review summarizes the physiological significance of VIP in glucose homeostasis and the potential therapeutic value of VPAC2-selective agonists in type 2 diabetes.
Topics: Diabetes Mellitus, Type 2; Glucose; Humans; Hypoglycemic Agents; Insulin Secretion; Receptors, Vasoactive Intestinal Peptide, Type II; Vasoactive Intestinal Peptide
PubMed: 36204104
DOI: 10.3389/fendo.2022.984198 -
International Urology and Nephrology Dec 2019Hyperlipidemia and oxidative stress are indispensable features of chronic kidney disease (CKD) that favor the development of atherogenic plaques and cardiovascular... (Review)
Review
Hyperlipidemia and oxidative stress are indispensable features of chronic kidney disease (CKD) that favor the development of atherogenic plaques and cardiovascular disease (CVD). A number of vasoactive mediators including proprotein convertase subtilisin-kexin type 9 (PCSK9), endothelin-1, nitric oxide, and angiotensin II have fundamental roles in the pathophysiology of atherosclerotic events; moreover, their levels are affected by dyslipidemia and oxidative stress due to renal dysfunction. Therefore, therapeutic measures aimed at correcting dyslipidemia and alleviating oxidative stress could potentially protect against CVD in CKD patients. In this review, we discuss the relation between dyslipidemia, oxidative stress, and vasoactive mediators as well as the available treatment options against these disturbances in CKD patients.
Topics: Angiotensin II; Dyslipidemias; Endothelin-1; Humans; Nitric Oxide; Oxidative Stress; Proprotein Convertase 9; Renal Insufficiency, Chronic
PubMed: 31641998
DOI: 10.1007/s11255-019-02319-7 -
Placenta Apr 2022In pregnancy, placental circulation occurs through two independent circulation systems: foetoplacental and uterine (spiral artery)-placental lake. Crosstalk between the... (Review)
Review
In pregnancy, placental circulation occurs through two independent circulation systems: foetoplacental and uterine (spiral artery)-placental lake. Crosstalk between the foetal peptide hormones, angiotensin II (A-II) and vasopressin (AVP), and their degrading placental aminopeptidases (APs), aminopeptidase A for A-II and placental leucine aminopeptidase for both AVP and oxytocin, primarily regulate placental circulation. On the other hand, placental circulation represents an arteriovenous shunt. In normal pregnancy, the blood pressure decreases, despite increased cardiac output and plasma volume, probably due to the arteriovenous shunt in the growing placenta. Actually, the foetal vasoactive hormones in the foetoplacental circulation are much higher than those in the maternal circulation throughout pregnancy. In normal pregnancy, AP activity derived from the placenta in maternal blood increases with gestation and placental growth. Foetal hypoxia increases the secretion of foetal both AVP and A-II. Although there is an increase in both AP activities in the maternal blood in normal pregnancy, their activities increase more than those in normal pregnancy during mild preeclampsia. However, both AP activities decline significantly compared than those in severe preeclampsia. This suggests that AP prevents leakage of increased foetal vasoactive hormones into the maternal blood in mild preeclampsia, and its protective role breaks down in severe preeclampsia, leading to a massive leak of the hormones into maternal circulation and consequent marked contraction of both the maternal vessels and the uterus. Consequently, AP activity in both placenta and maternal blood acts as the foeto-maternal barrier for foetal vasoactive hormones and thus contributes to the onset of preeclampsia.
Topics: Cystinyl Aminopeptidase; Female; Hormones; Humans; Peptide Hormones; Placenta; Placental Circulation; Pre-Eclampsia; Pregnancy
PubMed: 35255376
DOI: 10.1016/j.placenta.2022.02.016 -
Pediatric Critical Care Medicine : a... Aug 2022To compare the prevalence of adverse events related to vasoactive drug infusions administered via a peripheral venous catheter versus a central venous or intraosseous... (Observational Study)
Observational Study
OBJECTIVES
To compare the prevalence of adverse events related to vasoactive drug infusions administered via a peripheral venous catheter versus a central venous or intraosseous catheter.
DESIGN
Retrospective observational study.
SETTING
A pediatric critical care transport team, and the PICUs and regional hospitals within the North Thames and East Anglia regions of the United Kingdom.
PATIENTS
Children (up to 18 yr old) transported by the Children's Acute Transport Service receiving an infusion of a vasoactive drug (epinephrine, dobutamine, dopamine, norepinephrine, and vasopressin).
INTERVENTIONS
None.
MEASUREMENTS AND MAIN RESULTS
The medical records of all children transported between April 2017 and May 2020 receiving a vasoactive drug infusion were reviewed and cross-referenced with the service critical incident database. The outcome measure was anatomic catheter-related adverse events (including extravasation) reported during transport or in the first 24 hours on the PICU. During the study period, the service undertook 3,836 transports. Vasoactive drugs were administered during 558 patient transports (14.5%). During 198 of 558 transports (35.5%), vasoactive drugs were administered via a peripheral venous catheter, with seven of 198 (3.5%) adverse events. One extravasation event resulted in tissue necrosis. The median time to injury after the infusion was commenced was 60 minutes (interquartile range, 30-60 min). During 360 of 558 transports (64.5%), vasoactive infusions were administered by central venous or intraosseous catheter, with nine of 360 (2.5%) adverse events.
CONCLUSIONS
During pediatric critical care transport, we did not find a difference in prevalence of adverse events following the administration of vasoactive drugs via peripheral venous catheters or via central venous and intraosseous catheters.
Topics: Child; Critical Care; Dobutamine; Dopamine; Epinephrine; Humans; Norepinephrine; Retrospective Studies
PubMed: 35481954
DOI: 10.1097/PCC.0000000000002972 -
Current Medicinal Chemistry 2021Parkinson's disease is one of the most common neurodegenerative disorders and although its aetiology is not yet fully understood, neuroinflammation has been identified...
BACKGROUND
Parkinson's disease is one of the most common neurodegenerative disorders and although its aetiology is not yet fully understood, neuroinflammation has been identified as a key factor in the progression of the disease. Vasoactive intestinal peptide and pituitary adenylate-cyclase activating polypeptide are two neuropeptides that exhibit anti-inflammatory and neuroprotective properties, modulating the production of cytokines and chemokines and the behaviour of immune cells. However, the role of chemokines and cytokines modulated by the endogenous receptors of the peptides varies according to the stage of the disease.
METHODS
We present an overview of the relationship between some cytokines and chemokines with vasoactive intestinal peptide, pituitary adenylate cyclase activating polypeptide and their endogenous receptors in the context of Parkinson's disease neuroinflammation and oxidative stress, as well as the modulation of microglial cells by the peptides in this context.
RESULTS
The two peptides exhibit neuroprotective and anti-inflammatory properties in models of Parkinson's disease, as they ameliorate cognitive functions, decrease the level of neuroinflammation and promote dopaminergic neuronal survival. The peptides have been tested in a variety of in vivo and in vitro models of Parkinson's disease, demonstrating the potential for therapeutic application.
CONCLUSION
More studies are needed to establish the clinical use of vasoactive intestinal peptide and pituitary adenylate cyclase activating polypeptide as safe candidates for treating Parkinson's disease, as the use of the peptides in different stages of the disease could produce different results concerning effectiveness.
Topics: Humans; Parkinson Disease; Pituitary Adenylate Cyclase-Activating Polypeptide; RNA, Messenger; Receptors, Vasoactive Intestinal Polypeptide, Type I; Vasoactive Intestinal Peptide
PubMed: 32196442
DOI: 10.2174/0929867327666200320162436 -
Endocrine, Metabolic & Immune Disorders... 2020Rheumatoid arthritis (RA) is an autoimmune inflammatory disease comparing the inflammation of synovium. Macrophage-like synoviocytes and fibroblast-like synoviocytes... (Review)
Review
Rheumatoid arthritis (RA) is an autoimmune inflammatory disease comparing the inflammation of synovium. Macrophage-like synoviocytes and fibroblast-like synoviocytes (synoviocytes) are crucial ingredients of synovium. Therein, a lot of research has focused on synoviocytes. Researches demonstrated that TLR1, TLR2, TLR3, TLR4, TLR5, TLR6 TLR7 and TLR9 are expressed in synoviocyte. Additionally, the expression of TLR2, TLR3, TLR4 and TLR5 is increased in RA synoviocyte. In this paper, we review the exact role of TLR2, TLR3, TLR4 and TLR5 participate in regulating the production of inflammatory factors in RA synoviocyte. Furthermore, we discuss the role of vasoactive intestinal peptide (VIP), MicroRNA, Monome of Chinese herb and other cells (Monocyte and T cell) influence the function of synoviocyte by regulating TLRs. The activation of toll-like receptors (TLRs) in synoviocyte leads to the aggravation of arthritis, comparing with angiogenesis and bone destruction. Above all, TLRs are promising targets for managing RA.
Topics: Animals; Antirheumatic Agents; Arthritis, Rheumatoid; Humans; MicroRNAs; RANK Ligand; Synovial Membrane; Synoviocytes; T-Lymphocytes; Toll-Like Receptors; Vasoactive Intestinal Peptide
PubMed: 32338225
DOI: 10.2174/1871530320666200427115225 -
Brain Research Bulletin Oct 2022Vasoactive intestinal peptide (VIP), a neuromodulator present in the hypothalamus, plays an important role in the regulation of food intake. Paraventricular nucleus of...
Vasoactive intestinal peptide (VIP), a neuromodulator present in the hypothalamus, plays an important role in the regulation of food intake. Paraventricular nucleus of the hypothalamus (PVN) is involved in ingestive responses and regulates the nitric oxide (NO) pathway. The main objectives of this study were to investigate metabolic changes established after different doses and times of VIP microinjection on the PVN, and the effect of VIP microinjection on the PVN on food intake and the role of NO in this control. In anesthetized rats, increased blood plasma glucose and insulin levels were observed following the doses of 40 and 80 ng/g of body weight. At the dose of 40 ng/g, VIP promoted hyperglycemia and hyperinsulinemia 5, 10, and 30 min after microinjection, and increased free fatty acids and total lipids plasma levels after 5 min, and triglycerides after 10 min. In awake animals, once again, VIP administration increased plasmatic levels of glucose, free fatty acids, corticosterone, and insulin 10 min after the microinjection. Moreover, VIP promoted hypophagia in the morning and night periods, and L-arginine (L-Arg) and monosodium glutamate (MSG) or a combination of both attenuated VIP-induced reduction on food intake. In addition, nitrate concentration in the PVN was decreased after VIP microinjection. Our data show that the PVN participates in the anorexigenic and metabolic effects of VIP, and that VIP-induced hypophagia is likely mediated by reduction of NO.
Topics: Animals; Arginine; Blood Glucose; Corticosterone; Fatty Acids, Nonesterified; Insulins; Neurotransmitter Agents; Nitrates; Nitric Oxide; Paraventricular Hypothalamic Nucleus; Rats; Sodium Glutamate; Triglycerides; Vasoactive Intestinal Peptide
PubMed: 36029978
DOI: 10.1016/j.brainresbull.2022.08.021 -
Journal of Biological Rhythms Apr 2024It has been 50 years since the suprachiasmatic nucleus (SCN) was first identified as the central circadian clock and 25 years since the last overview of developments... (Review)
Review
It has been 50 years since the suprachiasmatic nucleus (SCN) was first identified as the central circadian clock and 25 years since the last overview of developments in the field was published in the . Here, we explore new mechanisms and concepts that have emerged in the subsequent 25 years. Since 1997, methodological developments, such as luminescent and fluorescent reporter techniques, have revealed intricate relationships between cellular and network-level mechanisms. In particular, specific neuropeptides such as arginine vasopressin, vasoactive intestinal peptide, and gastrin-releasing peptide have been identified as key players in the synchronization of cellular circadian rhythms within the SCN. The discovery of multiple oscillators governing behavioral and physiological rhythms has significantly advanced our understanding of the circadian clock. The interaction between neurons and glial cells has been found to play a crucial role in regulating these circadian rhythms within the SCN. Furthermore, the properties of the SCN network vary across ontogenetic stages. The application of cell type-specific genetic manipulations has revealed components of the functional input-output system of the SCN and their correlation with physiological functions. This review concludes with the high-risk effort of identifying open questions and challenges that lie ahead.
Topics: Circadian Rhythm; Neuropeptides; Suprachiasmatic Nucleus; Vasoactive Intestinal Peptide; Gastrin-Releasing Peptide
PubMed: 38366616
DOI: 10.1177/07487304231225706