Transgelin-2: Biochemical and Clinical Implications in Cancer and Asthma.

Transgelin-2 has been regarded as an actin-binding protein that induces actin gelation and regulates actin cytoskeleton. However, transgelin-2 has recently been shown to relax the myosin cytoskeleton of the airway smooth muscle cells by acting as a receptor for extracellular metallothionein-2. From a clinical perspective, these results support transgelin-2 as a promising therapeutic target for diseases such as cancer and asthma. The inhibition of transgelin-2 prevents actin gelation and thereby cancer cell proliferation, invasion, and metastasis. Conversely, the activation of transgelin-2 with specific agonists relaxes airway smooth muscles and reduces pulmonary resistance in asthma. Here, we review new studies on the biochemical properties of transgelin-2 and discuss their clinical implications for the treatment of immune, oncogenic, and respiratory disorders.

Autonomic Regulation of Inflammation in Conscious Animals.

Bioelectronic medicine is a novel field in modern medicine based on the specific neuronal stimulation to control organ function, cardiovascular, and immune homeostasis. However, most studies addressing neuromodulation of the immune system have been conducted on anesthetized animals, which can affect the nervous system and neuromodulation. Here, we review recent studies involving conscious experimental rodents (rats and mice) to better understand the functional organization of neural control of immune homeostasis. We highlight typical experimental models of cardiovascular regulation, such as electrical activation of the aortic depressor nerve or the carotid sinus nerve, bilateral carotid occlusion, the Bezold-Jarisch reflex, and intravenous administration of the bacterial endotoxin lipopolysaccharide. These models have been used to investigate the relationship between neuromodulation of the cardiovascular and immune systems in conscious rodents (rats and mice). These studies provide critical information about the neuromodulation of the immune system, particularly the role of the autonomic nervous system, i.e., the sympathetic and parasympathetic branches acting both centrally (hypothalamus, nucleus ambiguus, nucleus tractus solitarius, caudal ventrolateral medulla, and rostral ventrolateral medulla), and peripherally (particularly spleen and adrenal medulla). Overall, the studies in conscious experimental models have certainly highlighted to the reader how the methodological approaches used to investigate cardiovascular reflexes in conscious rodents (rats and mice) can also be valuable for investigating the neural mechanisms involved in inflammatory responses. The reviewed studies have clinical implications for future therapeutic approaches of bioelectronic modulation of the nervous system to control organ function and physiological homeostasis in conscious physiology.

Cervical Vagus Nerve Stimulation Improves Neurologic Outcome After Cardiac Arrest in Mice by Attenuating Oxidative Stress and Excessive Autophagy.

BACKGROUND: Cerebral ischemia and reperfusion (I/R) induces oxidative stress and activates autophagy, leading to brain injury and neurologic deficits. Cervical vagus nerve stimulation (VNS) increases cerebral blood flow (CBF). In this study, we investigate the effect of VNS-induced CBF increase on neurologic outcomes after cardiac arrest (CA). MATERIALS AND METHODS: A total of 40 male C57Bl/6 mice were subjected to ten minutes of asphyxia CA and randomized to vagus nerve isolation (VNI) or VNS treatment group. Eight mice received sham surgery and VNI. Immediately after resuscitation, 20 minutes of electrical stimulation (1 mA, 1 ms, and 10 Hz) was started in the VNS group. Electrocardiogram, blood pressure, and CBF were monitored. Neurologic and histologic outcomes were evaluated at 72 hours. Oxidative stress and autophagy were assessed at 3 hours and 24 hours after CA. RESULTS: Baseline characteristics were not different among groups. VNS mice had better behavioral performance (ie, open field, rotarod, and neurologic score) and less neuronal death (p < 0.05, vs VNI) in the hippocampus. CBF was significantly increased in VNS-treated mice at 20 minutes after return of spontaneous circulation (ROSC) (p < 0.05). Furthermore, levels of 8-hydroxy-2'-deoxyguanosine in the blood and autophagy-related proteins (ie, LC-3Ⅱ/Ⅰ, Beclin-1, and p62) in the brain were significantly decreased in VNS mice. Aconitase activity was also reduced, and the p-mTOR/mTOR ratio was increased in VNS mice. CONCLUSIONS: Oxidative stress induced by global brain I/R following CA/ROSC leads to early excessive autophagy and impaired autophagic flux. VNS promoted CBF recovery, ameliorating these changes. Neurologic and histologic outcomes were also improved.

Neuropathies and neurological dysfunction induced by coronaviruses.

During the recent years, viral epidemic due to coronaviruses, such as SARS (Severe Acute Respiratory Syndrome), Middle East Respiratory Coronavirus Syndrome (MERS), and COVID-19 (coronavirus disese-19), has become a global problem. In addition to causing cardiovascular and respiratory lethal dysfunction, these viruses can cause neurodegeneration leading to neurological disorders. Review of the current scientific literature reveals the multiple neuropathies and neuronal dysfunction associated with these viruses. Here, we review the major findings of these studies and discuss the main neurological sequels and outcomes of coronavirus infections with SARS, MERS, and COVID-19. This article analyzes and discusses the main mechanisms of coronavirus-induced neurodegeneration according to the current experimental and clinical studies. Coronaviruses can damage the nerves directly through endovascular dysfunctions thereby affecting nerve structures and synaptic connections. Coronaviruses can also induce neural cell degeneration indirectly via mitochondrial dysfunction inducing oxidative stress, inflammation, and apoptosis. Thus, coronaviruses can cause neurological disorders by inducing neurovascular dysfunction affecting nerve structures and synaptic connections, and by inducing inflammation, oxidative stress, and apoptosis. While some of these mechanisms are similar to other RNA viruses, the neurotoxic mechanisms of COVID-19, MERS, and SARS-CoV viruses are unknown and need detailed clinical and experimental studies.

[Portrayal of cancer prevalence and mortality in Chilean digital media]. / Representación de la incidencia y de la mortalidad por cáncer en los medios de comunicación chilenos.

BACKGROUND: Cancer is the second death cause in Chile. The Chilean National Cancer Act will secure treatment and labor protection for people diagnosed with cancer. AIM: To answer questions regarding the media portrayal of cancer. MATERIAL AND METHODS: Through data-mining and the conduction of content analysis, 2,523 news titles about cancer were analysed. The news titles were obtained from 345 Chilean digital media which published cancer related news on Twitter between January and December 2019. An attempt was made to answer two research questions, namely are cancer incidence and mortality rates portrayed in a corresponding magnitude in the Chilean digital media? and what words are commonly used for this purpose? RESULTS: There is not a coherence between the incidence and mortality of the main cancer types in Chile and the amount of content published in communication media. CONCLUSIONS: Our results are consistent with international studies. We should expect the delivery of complete, timely and effective information about cancer in communication media, aiming to educate the population and reinforce prevention.

Ezrin Orchestrates Signal Transduction in Airway Cells.

Ezrin is a critical structural protein that organizes receptor complexes and orchestrates their signal transduction. In this study, we review the ezrin-meditated regulation of critical receptor complexes, including the epidermal growth factor receptor (EGFR), CD44, vascular cell adhesion molecule (VCAM), and the deleted in colorectal cancer (DCC) receptor. We also analyze the ezrin-meditated regulation of critical pathways associated with asthma, such as the RhoA, Rho-associated protein kinase (ROCK), and protein kinase A (cAMP/PKA) pathways. Mounting evidence suggests that ezrin plays a role in controlling airway cell function and potentially contributes to respiratory diseases. Ezrin can participate in asthma pathogenesis by affecting bronchial epithelium repair, T lymphocyte regulation, and the contraction of the airway smooth muscle cells. These studies provide new insights for the design of novel therapeutic strategies for asthma treatment.

Central angiotensin-(1-7) attenuates systemic inflammation via activation of sympathetic signaling in endotoxemic rats.

Angiotensin-(1-7) [Ang-(1-7)] is an angiotensin-derived neuropeptide with potential anti-hypertensive and anti-inflammatory properties. However, a possible action of Ang-(1-7) in neuroimmune interactions to regulate inflammatory response has not been explored. Thus, the aim of this study was to determine whether the intracerebroventricular (i.c.v.) administration of Ang-(1-7) can modulate systemic inflammation via sympathetic efferent circuits. Wistar male rats received systemic administration of lipopolysaccharide (LPS) (1.5 mg/Kg). Ang-(1-7) (0.3 nmol in 2 µL) promoted the release of splenic norepinephrine and attenuated tumor necrosis factor (TNF) and nitric oxide (NO), but increased interleukin-10 (IL-10), levels in the serum, spleen, and liver in endotoxemic rats. Furthermore, 6-hydroxydopamine-induced chemical sympathectomy (100 mg/Kg, intravenous) or i.c.v. administration of Mas receptor antagonist A779 (3 nmol in 2 µL) abolished the anti-inflammatory effects of central Ang-(1-7) injection. Moreover, this treatment did not alter the plasmatic LPS-induced corticosterone and vasopressin. The administration of Ang-(1-7) reverted the low resistance in response to catecholamines of rings of thoracic aorta isolated from endotoxemic rats, treated or not, with this peptide by a mechanism dependent on the regulation of NO released from perivascular adipose tissue. Together, our results indicate that Ang-(1-7) regulates systemic inflammation and vascular hyporesponsiveness in endotoxemia via activation of a central Mas receptors/sympathetic circuits/norepinephrine axis and provide novel mechanistic insights into the anti-inflammatory Ang-(1-7) properties.

Novel Neuroprotective Potential of Crocin in Neurodegenerative Disorders: An Illustrated Mechanistic Review.

Neurodegenerative disorders are characterized by mitochondrial dysfunction and subsequently oxidative stress, inflammation, and apoptosis that contribute to neuronal cytotoxicity and degeneration. Recent studies reported that crocin, a carotenoid chemical compound common in crocus and gardenia flowers, has protective effects in neurodegenerative disorders due to its anti-oxidative, anti-inflammatory, and anti-apoptotic properties in the nervous system. This article reviews the new experimental, clinical, and pharmacological studies on the neuroprotective properties of crocin and its potential mechanisms to modulate metabolic oxidative stress and inflammation in neurodegenerative disorders.

The role of neutrophils in neuro-immune modulation.

Neutrophils are peripheral immune cells that represent the first recruited innate immune defense against infections and tissue injury. However, these cells can also induce overzealous responses and cause tissue damage. Although the role of neutrophils activating the immune system is well established, only recently their critical implications in neuro-immune interactions are becoming more relevant. Here, we review several aspects of neutrophils in the bidirectional regulation between the nervous and immune systems. First, the role of neutrophils as a diffuse source of acetylcholine and catecholamines is controversial as well as the effects of these neurotransmitters in neutrophil's functions. Second, neutrophils contribute for the activation and sensitization of sensory neurons, and thereby, in events of nociception and pain. In addition, nociceptor activation promotes an axon reflex triggering a local release of neural mediators and provoking neutrophil activation. Third, the recruitment of neutrophils in inflammatory responses in the nervous system suggests these immune cells as innovative targets in the treatment of central infectious, neurological and neurodegenerative disorders. Multidisciplinary studies involving immunologists and neuroscientists are required to define the role of the neurons-neutrophils communication in the pathophysiology of infectious, inflammatory, and neurological disorders.

Stellate Ganglion Blockade: an Intervention for the Management of Ventricular Arrhythmias.

PURPOSE OF REVIEW: To highlight the indications, procedural considerations, and data supporting the use of stellate ganglion blockade (SGB) for management of refractory ventricular arrhythmias. RECENT FINDINGS: In patients with refractory ventricular arrhythmias, unilateral or bilateral SGB can reduce arrhythmia burden and defibrillation events for 24-72 h, allowing time for use of other therapies like catheter ablation, surgical sympathectomy, or heart transplantation. The efficacy of SGB appears to be consistent despite the type (monomorphic vs polymorphic) or etiology (ischemic vs non-ischemic cardiomyopathy) of the ventricular arrhythmia. Ultrasound-guided SGB is safe with low risk for complications, even when performed on anticoagulation. SGB is effective and safe and could be considered for patients with refractory ventricular arrhythmias.

Exercise activates vagal induction of dopamine and attenuates systemic inflammation.

Physical exercise is one of the most important factors improving quality of life, but it is not feasible for patients with morbidity or limited mobility. Most previous studies focused on high-intensity or long-term exercise that causes metabolic stress or physiological adaption, respectively. Here, we studied how moderate-intensity swimming affects systemic inflammation in 6-8 week old C57BL/6J male mice during endotoxemia. One-hour swimming prevented hypokalemia, hypocalcemia, attenuated serum levels of inflammatory cytokines, increased anti-inflammatory cytokines but affected neither IL6 nor glycemia before or after the endotoxic challenge. Exercise attenuated serum TNF levels by inhibiting its production in the spleen through a mechanism mediated by the subdiaphragmatic vagus nerve but independent of the splenic nerve. Exercise increased serum levels of dopamine, and adrenalectomy prevented the potential of exercise to induce dopamine and to attenuate serum TNF levels. Dopaminergic agonist type-1, fenoldopam, inhibited TNF production in splenocytes. Conversely, dopaminergic antagonist type-1, butaclamol, attenuated exercise control of serum TNF levels. These results suggest that vagal induction of dopamine may contribute to the anti-inflammatory potential of physical exercise.

S100A8 protein attenuates airway hyperresponsiveness by suppressing the contraction of airway smooth muscle.

Airway hyperresponsiveness (AHR) is a major clinical problem in allergic asthma mainly caused by the hypercontractility of airway smooth muscles (ASM). S100A8 is an important member of the S100 calcium-binding protein family with a potential to regulate cell contractility. Here, we analyze the potential of S100A8 to regulate allergen-induced AHR and ASM contraction. Treatment with recombinant S100A8 (rS100A8) diminished airway hyperresponsiveness in OVA-sensitized rats. ASM contraction assays showed that rS100A8 reduced hypercontractility in both isolated tracheal rings and primary ASM cells treated by acetylcholine. rS100A8 markedly rescued the phosphorylation level of myosin light chain induced by acetylcholine in ASM cells. These results show that rS100A8 plays a protective role in regulating AHR in asthma by inhibiting ASM contraction. These results support S100A8 as a novel therapeutic target to control ASM contraction in asthma.

Modulation of experimental arthritis by vagal sensory and central brain stimulation.

Articular inflammation is a major clinical burden in multiple inflammatory diseases, especially in rheumatoid arthritis. Biological anti-rheumatic drug therapies are expensive and increase the risk of systemic immunosuppression, infections, and malignancies. Here, we report that vagus nerve stimulation controls arthritic joint inflammation by inducing local regulation of innate immune response. Most of the previous studies of neuromodulation focused on vagal regulation of inflammation via the efferent peripheral pathway toward the viscera. Here, we report that vagal stimulation modulates arthritic joint inflammation through a novel "afferent" pathway mediated by the locus coeruleus (LC) of the central nervous system. Afferent vagal stimulation activates two sympatho-excitatory brain areas: the paraventricular hypothalamic nucleus (PVN) and the LC. The integrity of the LC, but not that of the PVN, is critical for vagal control of arthritic joint inflammation. Afferent vagal stimulation suppresses articular inflammation in the ipsilateral, but not in the contralateral knee to the hemispheric LC lesion. Central stimulation is followed by subsequent activation of joint sympathetic nerve terminals inducing articular norepinephrine release. Selective adrenergic beta-blockers prevent the effects of articular norepinephrine and thereby abrogate vagal control of arthritic joint inflammation. These results reveals a novel neuro-immune brain map with afferent vagal signals controlling side-specific articular inflammation through specific inflammatory-processing brain centers and joint sympathetic innervations.

Therapeutic potential and limitations of cholinergic anti-inflammatory pathway in sepsis.

Sepsis is one of the main causes of mortality in hospitalized patients. Despite the recent technical advances and the development of novel generation of antibiotics, severe sepsis remains a major clinical and scientific challenge in modern medicine. Unsuccessful efforts have been dedicated to the search of therapeutic options to treat the deleterious inflammatory components of sepsis. Recent findings on neuronal networks controlling immunity raised expectations for novel therapeutic strategies to promote the regulation of sterile inflammation, such as autoimmune diseases. Interesting studies have dissected the anatomical constituents of the so-called "cholinergic anti-inflammatory pathway", suggesting that electrical vagus nerve stimulation and pharmacological activation of beta-2 adrenergic and alpha-7 nicotinic receptors could be alternative strategies for improving inflammatory conditions. However, the literature on infectious diseases, such as sepsis, is still controversial and, therefore, the real therapeutic potential of this neuroimmune pathway is not well defined. In this review, we will discuss the beneficial and detrimental effects of neural manipulation in sepsis, which depend on the multiple variables of the immune system and the nature of the infection. These observations suggest future critical studies to validate the clinical implications of vagal parasympathetic signaling in sepsis treatment.

Baroreflex activation in conscious rats modulates the joint inflammatory response via sympathetic function.

The baroreflex is a critical physiological mechanism controlling cardiovascular function by modulating both the sympathetic and parasympathetic activities. Here, we report that electrical activation of the baroreflex attenuates joint inflammation in experimental arthritis induced by the administration of zymosan into the femorotibial cavity. Baroreflex activation combined with lumbar sympathectomy, adrenalectomy, celiac subdiaphragmatic vagotomy or splenectomy dissected the mechanisms involved in the inflammatory modulation, highlighting the role played by sympathetic inhibition in the attenuation of joint inflammation. From the immunological standpoint, baroreflex activation attenuates neutrophil migration and the synovial levels of inflammatory cytokines including TNF, IL-1ß and IL-6, but does not affect the levels of the anti-inflammatory cytokine IL-10. The anti-inflammatory effects of the baroreflex system are not mediated by IL-10, the vagus nerve, adrenal glands or the spleen, but by the inhibition of the sympathetic drive to the knee. These results reveal a novel physiological neuronal network controlling peripheral local inflammation.

Ethical and Legal Debates on Vaccine Infodemics.

Over the course of three and a half years, the global toll of coronavirus disease 2019 (COVID-19) has claimed the lives of millions of individuals. Scientific breakthroughs, exemplified by mRNA vaccines, have emerged as crucial tools in saving numerous lives and fortifying our defenses against future pandemics. However, the battle against the virus has been complicated by the dissemination of misleading political and ethical information, resulting in avoidable fatalities. Recognizing this phenomenon, the term 'infodemics' has been coined to denote the proliferation of false or misleading information that hinders effective social responses. Given the historical prevalence of infodemics surrounding vaccinations, this discussion delves into the ongoing ethical and legal deliberations concerning vaccination mandates, an indispensable health intervention in the face of pandemics. Governments bear the responsibility of safeguarding their citizens, acknowledging the social requirements imposed by the collective well-being. The protection of both citizens and healthcare workers becomes paramount, considering the potential risks of infection and mortality associated with individuals refusing vaccination. Historically, governments have played a pivotal role in eradicating pandemics through the implementation of vaccine mandates. However, the contemporary landscape is marked by the infusion of political and misleading misinformation, presenting new challenges. Governments are now confronted with an ethical duty to ensure that citizens possess the necessary information to make informed decisions and safeguard their well-being. While grappling with the realization that extraordinary circumstances demand extraordinary responses, the lessons from past pandemics underscore the imperative of prioritizing public health, especially in the context of the high numbers of casualties worldwide. This discourse explores the ethical and legal dimensions surrounding vaccine mandates, with particular emphasis on their relevance to healthcare workers.

Complementary and alternative medicine on cognitive defects and neuroinflammation after sepsis.

Sepsis-associated encephalopathy (SAE) is a common manifestation of sepsis, ranging from mild confusion and delirium to severe cognitive impairment and deep coma. SAE is associated with higher mortality and long-term outcomes, particularly substantial declines in cognitive function. The mechanisms of SAE probably include neuroinflammation that is mediated by systemic inflammation and ischemic lesions in the brain, a disrupted blood-brain barrier, oxidative stress, neurotransmitter dysfunction, and severe microglial activation. Increasing evidence suggests that complementary and alternative medicine, especially Traditional Chinese Medicine (TCM), is favorable in alleviating cognitive decline after sepsis. Here, we summarized the studies of traditional herbal remedies, TCM formulas and acupuncture therapy in animal models of neurological dysfunctions after sepsis in recent decades and reviewed their potential mechanisms.

Personal versus therapist perioperative music intervention: a randomized controlled trial.

INTRODUCTION: Music interventions can alleviate patient anxiety and improve post-surgical satisfaction. However, it remains uncertain whether personal music preferences affect efficacy. The authors tested whether personal music intervention with patient-selected songs played ad libitum is more effective than standard therapist-designed treatment with classical music. METHODS: A prospective, parallel-group, single-blinded, randomized controlled trial with 229 participants (aged 18-60 years) previously scheduled for elective surgery. Data analyses followed a modified intention-to-treat principle. The patients were randomized into three groups: Standard care without music (Control), therapist-designed classic music treatment (TT), or personal music intervention with patient-selected songs played ad libitum by the patient (PI). All patients received standard post-anaesthesia care, and music intervention was started upon arrival at the post-anaesthesia care unit. Primary outcomes were anxiety and overall satisfaction at discharge. In contrast, secondary outcomes were systolic blood pressure during music intervention, the sleep quality of the night after surgery, and the occurrence of postoperative nausea and vomiting within the first 24 h after surgery. RESULTS: Compared with therapist-designed music treatment, personal intervention decreased systolic blood pressure (T 0 : 124.3±13.7, 95% CI:121-127.7; T 20min : 117.6±10.4, 95% CI:115-120.1; T 30min : 116.9±10.6, 95% CI:114.3-119.4), prevented postoperative nausea and vomiting (Control: 55.9%, TT: 64.6%, PI: 77.6%), including severe postoperative nausea (VAS score>4; Control: 44.1%; TT: 33.8%; PI: 20.9%) and severe emesis (Frequency≥3, Control: 13.2%; TT: 7.7%; PI: 4.5%). None of the treatments affected sleep quality at night after surgery (Median, Q1-Q3, Control: 3, 1-3; TT: 3, 1-4; PI: 3, 1-3.5). Personal, but not therapist, music intervention significantly prevented anxiety (Control: 36.4±5.9, 95% CI:35.0-37.9; TT: 36.2±7.1, 95% CI: 34.4-37.9; PI: 33.8±5.6, 95% CI: 32.4-35.2) and emesis (Control: 23.9%; TT: 23.4%; PI: 13.2%) and improved patient satisfaction (Median, Q1-Q3, C: 8, 6-8; TT: 8, 7-9; PI: 8, 7-9). CONCLUSIONS: Personal music intervention improved postoperative systolic blood pressure, anxiety, nausea, emesis, and overall satisfaction, but not sleep quality, as compared to therapist-designed classic intervention.

Vagal sensory neuron-derived FGF3 controls insulin secretion.

Vagal nerve stimulation has emerged as a promising modality for treating a wide range of chronic conditions, including metabolic disorders. However, the cellular and molecular pathways driving these clinical benefits remain largely obscure. Here, we demonstrate that fibroblast growth factor 3 (Fgf3) mRNA is upregulated in the mouse vagal ganglia under acute metabolic stress. Systemic and vagal sensory overexpression of Fgf3 enhanced glucose-stimulated insulin secretion (GSIS), improved glucose excursion, and increased energy expenditure and physical activity. Fgf3-elicited insulinotropic and glucose-lowering responses were recapitulated when overexpression of Fgf3 was restricted to the pancreas-projecting vagal sensory neurons. Genetic ablation of Fgf3 in pancreatic vagal afferents exacerbated high-fat diet-induced glucose intolerance and blunted GSIS. Finally, electrostimulation of the vagal afferents enhanced GSIS and glucose clearance independently of efferent outputs. Collectively, we demonstrate a direct role for the vagal afferent signaling in GSIS and identify Fgf3 as a vagal sensory-derived metabolic factor that controls pancreatic ß-cell activity.