-
Frontiers in Cellular Neuroscience 2024Acetylcholine (ACh) is a prevalent neurotransmitter throughout the nervous system. In the brain, ACh is widely regarded as a potent neuromodulator. In neurons, ACh... (Review)
Review
Acetylcholine (ACh) is a prevalent neurotransmitter throughout the nervous system. In the brain, ACh is widely regarded as a potent neuromodulator. In neurons, ACh signals are conferred through a variety of receptors that influence a broad range of neurophysiological phenomena such as transmitter release or membrane excitability. In sensory circuitry, ACh modifies neural responses to stimuli and coordinates the activity of neurons across multiple levels of processing. These factors enable individual neurons or entire circuits to rapidly adapt to the dynamics of complex sensory stimuli, underscoring an essential role for ACh in sensory processing. In the auditory system, histological evidence shows that acetylcholine receptors (AChRs) are expressed at virtually every level of the ascending auditory pathway. Despite its apparent ubiquity in auditory circuitry, investigation of the roles of this cholinergic network has been mainly focused on the inner ear or forebrain structures, while less attention has been directed at regions between the cochlear nuclei and midbrain. In this review, we highlight what is known about cholinergic function throughout the auditory system from the ear to the cortex, but with a particular emphasis on brainstem and midbrain auditory centers. We will focus on receptor expression, mechanisms of modulation, and the functional implications of ACh for sound processing, with the broad goal of providing an overview of a newly emerging view of impactful cholinergic modulation throughout the auditory pathway.
PubMed: 38962512
DOI: 10.3389/fncel.2024.1414484 -
Journal of Inflammation (London,... Jul 2024Pollution harms the health of people with asthma. The effect of the anti-inflammatory cholinergic pathway in chronic allergic inflammation associated to pollution is...
INTRODUCTION
Pollution harms the health of people with asthma. The effect of the anti-inflammatory cholinergic pathway in chronic allergic inflammation associated to pollution is poorly understood.
METHODS
One hundred eight animals were divided into 18 groups (6 animals). Groups included: wild type mice (WT), genetically modified with reduced VAChT (VAChTKD), and those sensitized with ovalbumin (VAChTKDA), exposed to metal powder due to iron pelletizing in mining company (Local1) or 3.21 miles away from a mining company (Local2) in their locations for 2 weeks during summer and winter seasons. It was analyzed for hyperresponsivity, inflammation, remodeling, oxidative stress responses and the cholinergic system.
RESULTS
During summer, animals without changes in the cholinergic system revealed that Local1 exposure increased the hyperresponsiveness (%Rrs, %Raw), and inflammation (IL-17) relative to vivarium animals, while animals exposed to Local2 also exhibited elevated IL-17. During winter, animals without changes in the cholinergic system revealed that Local2 exposure increased the hyperresponsiveness (%Rrs) relative to vivarium animals. Comparing the exposure local of these animals during summer, animals exposed to Local1 showed elevated %Rrs, Raw, and IL-5 compared to Local 2, while in winter, Local2 exposure led to more IL-17 than Local1. Animals with VAChT attenuation displayed increased %Rrs, NFkappaB, IL-5, and IL-13 but reduced alpha-7 compared to animals without changes in the cholinergic system WT. Animals with VAChT attenuation and asthma showed increased the hyperresponsiveness, all inflammatory markers, remodeling and oxidative stress compared to animals without chronic lung inflammation. Exposure to Local1 exacerbated the hyperresponsiveness, oxidative stressand inflammation in animals with VAChT attenuation associated asthma, while Local2 exposure led to increased inflammation, remodeling and oxidative stress.
CONCLUSIONS
Reduced cholinergic signaling amplifies lung inflammation in a model of chronic allergic lung inflammation. Furthermore, when associated with pollution, it can aggravate specific responses related to inflammation, oxidative stress, and remodeling.
PubMed: 38961398
DOI: 10.1186/s12950-024-00399-6 -
EBioMedicine Jul 2024The clinical heterogeneity of myasthenia gravis (MG), an autoimmune disease defined by antibodies (Ab) directed against the postsynaptic membrane, constitutes a...
BACKGROUND
The clinical heterogeneity of myasthenia gravis (MG), an autoimmune disease defined by antibodies (Ab) directed against the postsynaptic membrane, constitutes a challenge for patient stratification and treatment decision making. Novel strategies are needed to classify patients based on their biological phenotypes aiming to improve patient selection and treatment outcomes.
METHODS
For this purpose, we assessed the serum proteome of a cohort of 140 patients with anti-acetylcholine receptor-Ab-positive MG and utilised consensus clustering as an unsupervised tool to assign patients to biological profiles. For in-depth analysis, we used immunogenomic sequencing to study the B cell repertoire of a subgroup of patients and an in vitro assay using primary human muscle cells to interrogate serum-induced complement formation.
FINDINGS
This strategy identified four distinct patient phenotypes based on their proteomic patterns in their serum. Notably, one patient phenotype, here named PS3, was characterised by high disease severity and complement activation as defining features. Assessing a subgroup of patients, hyperexpanded antibody clones were present in the B cell repertoire of the PS3 group and effectively activated complement as compared to other patients. In line with their disease phenotype, PS3 patients were more likely to benefit from complement-inhibiting therapies. These findings were validated in a prospective cohort of 18 patients using a cell-based assay.
INTERPRETATION
Collectively, this study suggests proteomics-based clustering as a gateway to assign patients to a biological signature likely to benefit from complement inhibition and provides a stratification strategy for clinical practice.
FUNDING
CN and CBS were supported by the Forschungskommission of the Medical Faculty of the Heinrich Heine University Düsseldorf. CN was supported by the Else Kröner-Fresenius-Stiftung (EKEA.38). CBS was supported by the Deutsche Forschungsgemeinschaft (DFG-German Research Foundation) with a Walter Benjamin fellowship (project 539363086). The project was supported by the Ministry of Culture and Science of North Rhine-Westphalia (MODS, "Profilbildung 2020" [grant no. PROFILNRW-2020-107-A]).
PubMed: 38959848
DOI: 10.1016/j.ebiom.2024.105231 -
Transfusion and Apheresis Science :... Jul 2024Autoimmune autonomic ganglionopathy (AAG) is characterized by various autonomic and extra-autonomic symptoms and is caused by autoantibodies against nicotinic... (Review)
Review
Autoimmune autonomic ganglionopathy (AAG) is characterized by various autonomic and extra-autonomic symptoms and is caused by autoantibodies against nicotinic acetylcholine receptors present in the autonomic ganglia (ganglionic acetylcholine receptor, gAChR), requiring immediate and aggressive intervention to prevent the exacerbation of symptoms. However, there is currently no internationally accepted standard of care for the immunotherapy of AAG, including apheresis. Although the rationale for the use of plasma exchange (PLEX) in AAG is strong, whereby pathogenic gAChR antibodies are removed, its overall impact on patient outcomes is not well-established. Based on previous case reports and small case series studies, we provide a comprehensive overview of the challenges and uncertainties surrounding the use of PLEX for the management of AAG and provide current practice recommendations to guide treatment decisions.
PubMed: 38959810
DOI: 10.1016/j.transci.2024.103967 -
Journal of Agricultural and Food... Jul 2024Root-knot nematodes pose a serious threat to crops by affecting production and quality. Over a period of time, substantial work has been done toward the development of...
Root-knot nematodes pose a serious threat to crops by affecting production and quality. Over a period of time, substantial work has been done toward the development of effective and environmentally benign nematicidal compounds. However, due to the inefficiencies of previously reported synthetics in achieving the target of safe, selective, and effective treatment, it is necessary to develop new efficacious and safer nematicidal agents considering human health and environment on top priority. This work aims to highlight the efficient and convenient l-proline catalyzed synthesis of pyrano[3,2-]pyridone and their use as potential nematicidal agents. results of larval mortality and egg hatching inhibition revealed maximum nematicidal activity against from compounds , , and with LC values of 28.8, 46.8, and 49.18 μg/mL at 48 h, respectively. Under similar conditions, pyrano[3,2-]pyridones derivatives (LC = 28.8 μg/mL) was found at par with LC (26.92 μg/mL) of commercial nematicide carbofuran. The results were further validated with studies with the most active compound nematicidal within the binding to the pocket of acetylcholine esterase (AChE). In docking, binding free energy values for compound were found to be -6.90 kcal/mol. Results indicated that pyrano[3,2-]pyridone derivatives have the potential to control .
PubMed: 38959331
DOI: 10.1021/acs.jafc.4c00103 -
High Altitude Medicine & Biology Jul 2024Autoimmune myasthenia gravis (MG) is a condition commonly caused by the production of antibodies that block acetylcholine receptors. Until recently, gastrointestinal...
Autoimmune myasthenia gravis (MG) is a condition commonly caused by the production of antibodies that block acetylcholine receptors. Until recently, gastrointestinal (GI) symptoms were considered rare in myasthenia gravis, but are now being proposed as an early identification tool. Presented here is a case study that exemplifies GI symptoms in MG, exacerbated by low barometric pressure at altitude. This illustrates the need to identify GI symptoms earlier in MG patients, as well as the need for providers at high altitude to be aware of these manifestations of MG.
PubMed: 38957962
DOI: 10.1089/ham.2023.0132 -
Physiological Research Jul 2024One element, potassium, can be identified as the connecting link in the research of Czech neurophysiologist Prof. František Vyskočil. It accompanied him from the first...
One element, potassium, can be identified as the connecting link in the research of Czech neurophysiologist Prof. František Vyskočil. It accompanied him from the first student experiments on the frog muscle (Solandt effect) via sodium-potassium pump and quantum and non-quantum release of neurotransmitters (e.g. acetylcholine) to the most appreciated work on the reversible leakage of K+ from brain neurons during the Leao´s spreading cortical depression, often preceding migraine. He used a wide range of methods at the systemic, cellular and genetic levels. The electrophysiology and biochemistry of nerve-muscle contacts and synapses in the muscles and brain led to a range of interesting findings and discoveries on normal, denervated and hibernating laboratory mammals and in tissue cultures. Among others, he co-discovered the facilitating effects of catecholamines (adrenaline in particular) by end-plate synchronization of individual evoked quanta. This helps to understand the general effectiveness of nerve-muscle performance during actual stress. After the transition of the Czech Republic to capitalism, together with Dr. Josef Zicha from our Institute, he was an avid promoter of scientometry as an objective system of estimating a scientist´s success in basic research (journal Vesmír, 69: 644-645, 1990 in Czech).
PubMed: 38957950
DOI: No ID Found -
Toxicology Research Aug 2024Improving the quality of life in elderly patients and finding new treatment options for neurological diseases such as Alzheimer's has become one of the priorities in the...
Improving the quality of life in elderly patients and finding new treatment options for neurological diseases such as Alzheimer's has become one of the priorities in the scientific world. In recent years, the beneficial effects and therapeutic properties of natural foods on neurological health have become a very remarkable issue. Walnut oil (WO) is a promising nutraceutical, with many phytochemicals and polyunsaturated fatty acids and is thought to be promising in the treatment of many neurological diseases and cognitive deficits, such as Alzheimer's disease (AD). Polyphenolic compounds found in WO enhance intraneuronal signaling and neurogenesis and improve the sequestration of insoluble toxic protein aggregates. The objective of this study was to investigate the potential protective and therapeutic effects of WO in a model of AD induced by retinoic acid (RA) and brain-derived neurotrophic factor (BDNF). In order to achieve this, the experimental groups were formed as follows: Control group, WO group, Alzheimer's disease (AD) group, AD + WO applied group (AD + WO). WO supplementation almost significantly reduced oxidative stress in the ad model, providing 2-fold protection against protein oxidation. Additionally, WO showed a significant reduction in tau protein levels (2-fold), increased acetylcholine (ACh) levels (12%), and decreased acetylcholine esterase (AChE) activity (~50%). Since it has been known for centuries that WO does show any adverse effects on human health and has neuroprotective properties, it may be used in the treatment of AD as an additional nutraceutical to drug treatments.
PubMed: 38957781
DOI: 10.1093/toxres/tfae097 -
BMC Pulmonary Medicine Jul 2024Myasthenia gravis (MG) is the most common paraneoplastic disorder associated with thymic neoplasms. MG can develop after thymectomy, and this condition is referred to...
BACKGROUND
Myasthenia gravis (MG) is the most common paraneoplastic disorder associated with thymic neoplasms. MG can develop after thymectomy, and this condition is referred to post-thymectomy myasthenia gravis (PTMG). Diffuse panbronchiolitis (DPB), is a rare form of bronchiolitis and is largely restricted to East Asia, has been reported in association with thymic neoplasms. Only three cases of combined MG and DPB have been reported in the literature.
CASE PRESENTATION
A 45-year-old Taiwanese woman presented to our hospital with productive cough, rhinorrhea, anosmia, ear fullness, shortness of breath, and weight loss. She had a history of thymoma, and she underwent thymectomy with adjuvant radiotherapy 7 years ago. Chest computed tomography scan revealed diffuse bronchitis and bronchiolitis. DPB was confirmed after video-assisted thoracoscopic surgery lung biopsy, and repeated sputum cultures grew Pseudomonas aeruginosa. She has been on long-term oral azithromycin therapy thereafter. Intravenous antipseudomonal antibiotics, inhaled amikacin, as well as oral levofloxacin were administered. Three months after DPB diagnosis, she developed ptosis, muscle weakness, and hypercapnia requiring the use of noninvasive positive pressure ventilation. MG was diagnosed based on the acetylcholine receptor antibody and repetitive stimulation test results. Her muscle weakness gradually improved after pyridostigmine and corticosteroid therapies. Oral corticosteroids could be tapered off ten months after the diagnosis of MG. She is currently maintained on azithromycin, pyridostigmine, and inhaled amikacin therapies, with intravenous antibiotics administered occasionally during hospitalizations for respiratory infections.
CONCLUSIONS
To our knowledge, this might be the first case report of sequential development of DPB followed by PTMG. The coexistence of these two disorders poses a therapeutic challenge for balancing infection control for DPB and immunosuppressant therapies for MG.
Topics: Humans; Female; Myasthenia Gravis; Middle Aged; Bronchiolitis; Thymectomy; Thymus Neoplasms; Tomography, X-Ray Computed; Haemophilus Infections; Thymoma; Anti-Bacterial Agents; Taiwan
PubMed: 38956567
DOI: 10.1186/s12890-024-03134-2 -
Scientific Reports Jul 2024Coronary artery bypass surgery can result in endothelial dysfunction due to ischemia/reperfusion (IR) injury. Previous studies have demonstrated that DuraGraft helps...
Coronary artery bypass surgery can result in endothelial dysfunction due to ischemia/reperfusion (IR) injury. Previous studies have demonstrated that DuraGraft helps maintain endothelial integrity of saphenous vein grafts during ischemic conditions. In this study, we investigated the potential of DuraGraft to mitigate endothelial dysfunction in arterial grafts after IR injury using an aortic transplantation model. Lewis rats (n = 7-9/group) were divided in three groups. Aortic arches from the control group were prepared and rings were immediately placed in organ baths, while the aortic arches of IR and IR + DuraGraft rats were preserved in saline or DuraGraft, respectively, for 1 h before being transplanted heterotopically. After 1 h after reperfusion, the grafts were explanted, rings were prepared, and mounted in organ baths. Our results demonstrated that the maximum endothelium-dependent vasorelaxation to acetylcholine was significantly impaired in the IR group compared to the control group, but DuraGraft improved it (control: 89 ± 2%; IR: 24 ± 1%; IR + DuraGraft: 48 ± 1%, p < 0.05). Immunohistochemical analysis revealed decreased intercellular adhesion molecule-1, 4-hydroxy-2-nonenal, caspase-3 and caspase-8 expression, while endothelial cell adhesion molecule-1 immunoreactivity was increased in the IR + DuraGraft grafts compared to the IR-group. DuraGraft mitigates endothelial dysfunction following IR injury in a rat bypass model. Its protective effect may be attributed, at least in part, to its ability to reduce the inflammatory response, oxidative stress, and apoptosis.
Topics: Animals; Rats; Endothelium, Vascular; Reperfusion Injury; Rats, Inbred Lew; Male; Coronary Artery Bypass; Oxidative Stress; Intercellular Adhesion Molecule-1; Disease Models, Animal; Aldehydes; Caspase 3; Vasodilation; Apoptosis; Acetylcholine
PubMed: 38956161
DOI: 10.1038/s41598-024-66056-3