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Targeting the Cancer-Neuronal Crosstalk in the Pancreatic Cancer Microenvironment.

Pancreatic ductal adenocarcinoma (PDAC) represents one of the most aggressive solid tumors with a dismal prognosis and an increasing incidence. At the time of diagnosis, more than 85% of patients are in an unresectable stage. For these patients, chemotherapy can prolong survival by only a few months. Unfortunately, in recent decades, no groundbreaking therapies have emerged for PDAC, thus raising the question of how to identify novel therapeutic druggable targets to improve prognosis. Recently, the tumor microenvironment and especially its neural component has gained increasing interest in the

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… Accordingly, a higher rate of PDAC was shown in patients who received vagotomy for gastric ulcer disease in the past [ 72 ]. … Furthermore, Renz et al. demonstrated in LSL-Kras+/G12D; Pdx1-Cre (KC) mice that vagotomy accelerated the development of PDAC, whereas treatment with the systemic muscarinic agonist bethanechol restored the normal KC phenotype [ 12 ]. …

Mechanisms of Chemotherapy-Induced Neurotoxicity.

Since the first clinical trials conducted after World War II, chemotherapeutic drugs have been extensively used in the clinic as the main cancer treatment either alone or as an adjuvant therapy before and after surgery. Although the use of chemotherapeutic drugs improved the survival of cancer patients, these drugs are notorious for causing many severe side effects that significantly reduce the efficacy of anti-cancer treatment and patients' quality of life. Many widely used chemotherapy drugs including platinum-based agents, taxanes, vinca alkaloids, proteasome inhibitors, and thalidomide ana

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… Abdominal vagotomies are usually carried out with and without a splanchnic nerve section. … Many of the experiments where vagotomy had been employed were against relatively “high doses” of chemotherapeutic drugs in experiments lasting only a few hours. …

Cancer cachexia--pathophysiology and management.

About half of all cancer patients show a syndrome of cachexia, characterized by anorexia and loss of adipose tissue and skeletal muscle mass. Cachexia can have a profound impact on quality of life, symptom burden, and a patient's sense of dignity. It is a very serious complication, as weight loss during cancer treatment is associated with more chemotherapy-related side effects, fewer completed cycles of chemotherapy, and decreased survival rates. Numerous cytokines have been postulated to play a role in the etiology of cancer cachexia. Cytokines can elicit effects that mimic leptin signaling a

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… Table 2 Nutritional consequences of radical resection of alimentary tract organs Nutritional consequences Tongue or pharynx Need for nutrition by tube (dysphagia) Thoracic oesophagus Gastric stasis (due to vagotomy), malabsorption of fats (due to vagotomy) Stomach Dumping syndrome, anaemia, malabsorption … ), malabsorption of fats (due to vagotomy) Stomach | Dumping syndrome, anaemia, malabsorption of fats, iron, calcium and vitamins Duodenum | Biliary-pancreatic deficiency Jejunum (up to 120 cm) | Reduced absorption of glucose, fats, protein, folic acid, vitamin B12, etc. …

Seizure-Induced Sympathoexcitation Is Caused by Activation of Glutamatergic Receptors in RVLM That Also Causes Proarrhythmogenic Changes Mediated by PACAP and Microglia in Rats.

UNLABELLED: Cardiovascular autonomic dysfunction in seizure is a major cause of sudden unexpected death in epilepsy. The catecholaminergic neurons in the rostral ventrolateral medulla (RVLM) maintain sympathetic vasomotor tone and blood pressure through their direct excitatory projections to the intermediolateral (IML) cell column. Glutamate, the principal excitatory neurotransmitter in brain, is increased in seizures. Pituitary adenylate cyclase activating polypeptide (PACAP) is an excitatory neuropeptide with neuroprotective properties, whereas microglia are key players in inflammatory respo

Cervical spinal erythropoietin induces phrenic motor facilitation via extracellular signal-regulated protein kinase and Akt signaling.

Erythropoietin (EPO) is typically known for its role in erythropoiesis but is also a potent neurotrophic/neuroprotective factor for spinal motor neurons. Another trophic factor regulated by hypoxia-inducible factor-1, vascular endothelial growth factor (VEGF), signals via ERK and Akt activation to elicit long-lasting phrenic motor facilitation (pMF). Because EPO also signals via ERK and Akt activation, we tested the hypothesis that EPO elicits similar pMF. Using retrograde labeling and immunohistochemical techniques, we demonstrate in adult, male, Sprague Dawley rats that EPO and its receptor,

[Perforated duodenal ulcer: benefits and risks of laparoscopic repair].

OBJECTIVE: Laparoscopic perforated duodenal ulcer repair is a minimally invasive technique. Just like any other type of surgery, the laparoscopic approach carries operative risks in itself. The primary goal of this article is to describe the possible risk factors in laparoscopic duodenal ulcer repair. The secondary goal is to clarify benefits of the laparoscopic surgery. MATERIAL AND METHODS: The Medline/Pubmed database was used; 73 articles were analyzed and evaluated. RESULTS: Six retrospective and nine prospective studies are summarized. The retrospective studies' results are as follows:

Evidence for alpha-2 adrenoreceptor modulation of arterial chemoreflexes in the caudal solitary nucleus of the rat.

The caudal region of the nucleus of the solitary tract (cNTS) is the primary central termination site for arterial chemoreceptor afferents originating from the carotid body. The purpose of the present study was to investigate the role of endogenous activation of alpha-2 adrenoreceptors in the cNTS on arterial chemoreflex function. Arterial chemoreflex responses to intravenous injections of potassium cyanide (KCN; 75 microg/kg) were recorded before and following blockade of alpha-2 adrenoreceptors in the cNTS of urethane-anesthetized rats. KCN alone elicited a reflex increase in arterial pressu

Ionotropic glutamate receptors in the external lateral parabrachial nucleus participate in processing cardiac sympathoexcitatory reflexes.

Stimulation of cardiac sympathetic afferents during myocardial ischemia with metabolites such as bradykinin (BK) evokes sympathoexcitatory reflex responses and activates neurons in the external lateral parabrachial nucleus (elPBN). The present study tested the hypothesis that this region in the pons processes sympathoexcitatory cardiac reflexes through an ionotropic glutamate receptor mechanism. The ischemic metabolite BK (0.1-1 μg) was injected into the pericardial space of anesthetized and bilaterally vagotomized or intact cats. Hemodynamic and renal sympathetic nerve activity (RSNA) respons

Cardiovascular responses produced by 5-hydroxytriptamine:a pharmacological update on the receptors/mechanisms involved and therapeutic implications.

The complexity of cardiovascular responses produced by 5-hydroxytryptamine (5-HT, serotonin), including bradycardia or tachycardia, hypotens … (5A/5B) receptor component. Moreover, i.v. 5-HT can increase heart rate in different species (after vagotomy) by a variety of mechanisms/receptors including activation of: (1) myocardial 5-HT(2A) (rat), 5-HT(3) (dog), 5-HT(4) (pig, human), and 5-HT(7) (cat) receptors; (2) adrenomedullary 5-HT(2) (dog) and prejunctional sympatho-excitatory 5-HT(3) (rabbit) …

Role of the parasympathetic nervous system in cardioprotection by remote hindlimb ischaemic preconditioning.

This investigation was designed to determine the participation of the vagus nerve and muscarinic receptors in the remote ischaemic preconditioning (rIPC) mechanism. New Zealand rabbits were anaesthetized, and the femoral artery was dissected. After 30 min of monitoring, the hearts were isolated and subjected to 30 min of global no-flow ischaemia and 180 min of reperfusion (non-rIPC group). The ventricular function was evaluated, considering the left ventricular developed pressure and the left ventricular end-diastolic pressure. In the rIPC group, the rabbits were subjected to three cycles of h

Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve.

There is increasing, but largely indirect, evidence pointing to an effect of commensal gut microbiota on the central nervous system (CNS). However, it is unknown whether lactic acid bacteria such as Lactobacillus rhamnosus could have a direct effect on neurotransmitter receptors in the CNS in normal, healthy animals. GABA is the main CNS inhibitory neurotransmitter and is significantly involved in regulating many physiological and psychological processes. Alterations in central GABA receptor expression are implicated in the pathogenesis of anxiety and depression, which are highly comorbid with

Acute intermittent hypoxia in rat in vivo elicits a robust increase in tonic sympathetic nerve activity that is independent of respiratory drive.

Acute intermittent hypoxia (AIH) elicits long-term increases in respiratory and sympathetic outflow (long-term facilitation, LTF). It is still unclear whether sympathetic LTF is totally dependent on changes in respiration, even though respiratory drive modulates sympathetic nerve activity (SNA). In urethane-anaesthetized, vagotomized mechanically ventilated Sprague-Dawley rats, we investigated the effect of ten 45 s episodes of 10% O2-90% N(2) on splanchnic sympathetic nerve activity (sSNA) and phrenic nerve activity (PNA). We then tested whether or not hypoxic sympathetic chemoreceptor and ba

Evaluation of the guinea pig monophasic action potential (MAP) assay in predicting drug-induced delay of ventricular repolarisation using 12 clinically documented drugs.

INTRODUCTION: While the dog in vivo model is commonly employed in the later phase of discovery for assessing drug-induced QT prolongation, an early screening assay is valuable when selecting compounds for further development and when compound availability usually is low. One such screening assay is the anaesthetised guinea pig monophasic action potential (MAP) model. The aim of the present study was to evaluate the ability of this model to detect proarrhythmic properties by testing a set of reference compounds with known clinical profile. Moreover, these results were compared to data previousl

Neural pathways regulating Brunner's gland secretion in guinea pig duodenum in vitro.

This study examined the neural pathways innervating Brunner's glands using a novel in vitro model of acinar secretion from Brunner's glands in submucosal preparations from the guinea pig duodenum. Neural pathways were activated by focal electrical stimulation and excitatory agonists, and videomicroscopy was used to monitor dilation of acinar lumen. Electrical stimulation of perivascular nerves evoked large dilations that were blocked by TTX (1 microM) or the muscarinic receptor antagonist 4-diphenylacetoxy-N-(2-chloroethyl)-piperidine hydrochloride (1 microM). The nicotinic agonist 1,1-dimethy

Vagal-α7nAChR signaling is required for lung anti-inflammatory responses and arginase 1 expression during an influenza infection.

Vagal circuit-α7 nicotinic acetylcholine receptor (α7nAChR, coded by Chrna7) signaling can modulate lung proinflammatory responses. Arginase 1 (ARG1) plays a crucial role in the resolution of lung inflammation. However, whether vagal-α7nAChR signaling can regulate lung inflammation and ARG1 expression during an influenza infection is elusive. Here, we found that lung and spleen IL-4+ cells and lung ARG1 expression were reduced; however, bronchoalveolar lavage (BAL) protein and leukocytes and lung inflammatory cytokines were increased in PR8 (A/Puerto Rico/8/1934, H1N1)-infected vagotomized mic

Brain acetylcholinesterase activity controls systemic cytokine levels through the cholinergic anti-inflammatory pathway.

The excessive release of cytokines by the immune system contributes importantly to the pathogenesis of inflammatory diseases. Recent advances in understanding the biology of cytokine toxicity led to the discovery of the "cholinergic anti-inflammatory pathway," defined as neural signals transmitted via the vagus nerve that inhibit cytokine release through a mechanism that requires the alpha7 subunit-containing nicotinic acetylcholine receptor (alpha7nAChR). Vagus nerve regulation of peripheral functions is controlled by brain nuclei and neural networks, but despite considerable importance, litt

Induction of immunoreactive prostaglandin H synthases 1 and 2 and fos in response to cerebral hypoperfusion in late-gestation fetal sheep.

OBJECTIVE: The goal of the present study was to localize and quantify immunoreactive prostaglandin H synthase 1 (PGHS-1), PGHS-2, and Fos expression by immunohistochemistry in the fetal brain 30 minutes and 2 hours after the onset of a 10-minute period of cerebral hypoperfusion in barodenervated and chemodenervated fetal sheep. METHODS: Fetal sheep of known gestational age were studied intact or sinoaortic denervated. Fetuses were sacrificed and tissues recovered for immunohistochemistry or real-time polymerase chain reaction measurements of protein and mRNA, respectively. Some fetuses were s