Cholinergic Anti-inflammatory Pathway Research Articles

Pyridostigmine to Reduce the duration of postoperative Ileus after Colorectal surgery (PyRICo-RCT): randomized clinical trial.

Postoperative ileus, driven by the cholinergic anti-inflammatory pathway, is the most common complication in patients undergoing colorectal surgery. By inhibiting acetylcholinesterase, pyridostigmine can potentially modulate the cholinergic anti-inflammatory pathway and accelerate gastrointestinal recovery. This study aimed to assess the efficacy of pyridostigmine in improving gastrointestinal recovery after colorectal surgery. This double-blinded RCT enrolled adult patients undergoing elective colorectal surgery at two hospitals in South Australia. Patients were randomized to 60 mg oral pyridostigmine or placebo twice daily starting 6 h after surgery until the first passage of stool. The primary outcome was GI-2, a validated composite measure of time to first stool and tolerance of oral diet. Secondary outcomes included incidence of postoperative ileus (defined as GI-2 greater than 4 days), duration of hospital stay, and 30-day complications, evaluated by intention-to-treat univariate analysis. Of 130 patients recruited (mean(s.d.) age 58.4(16.4) years; 73 men, 56%), 65 were allocated to each arm. The median GI-2 was 1 day shorter with pyridostigmine compared with placebo (2 (i.q.r. 1-3) versus 3 (2-4) days; P = 0.015). However, there were no significant differences in postoperative ileus (17.2 versus 21.5%; P = 0.532) or duration of hospital stay (median 5 (i.q.r. 4-8.75) versus 5 (4-7.5) days; P = 0.921). Similarly, there were no significant differences in overall complications, anastomotic leak, cardiac complications, or patient-reported side effects. Pyridostigmine resulted in a quicker return of GI-2 and was well tolerated. Larger multicentre studies are required to determine the optimal dosing and evaluate the impact of pyridostigmine in different surgical settings. Registration number: ACTRN12621000530820 (https://anzctr.org.au).

Chuanzhitongluo capsule improves cognitive impairment in mice with chronic cerebral hypoperfusion via the cholinergic anti-inflammatory pathway

Vascular cognitive impairment (VCI) has become a common disease-causing cognitive deficit in humans, second only to Alzheimer's Disease (AD). Chuanzhitongluo capsule (CZTL) is a Traditional Chinese Medicine (TCM) preparation known for its effective protection against cerebral ischemia. However, its potential to ameliorate VCI remains unclear. This study aimed to investigate the cognitive improvement effects of CZTL in a mouse model of VCI. Chronic cerebral hypoperfusion (CCH) was induced in mice by bilateral common carotid artery stenosis (BCAS) to simulate the pathological changes associated with VCI. Spatial learning and memory abilities were assessed using the Morris Water Maze (MWM). RNA sequencing (RNA-Seq) was employed to identify differentially expressed genes (DEGs) in the hippocampus. Levels of inflammatory factors were measured through enzyme-linked immunosorbent assay (ELISA), while immunofluorescence (IF) determined the expression intensity of target proteins. Western Blot (WB) confirmed the final action pathway. Results indicated that CZTL significantly improved the spatial learning and memory abilities of CCH mice, along with alterations in gene expression profiles in the hippocampus. It also reduced neuroinflammation in the hippocampus and upregulated the choline acetyltransferase (ChAT) and α7 subunit-containing nicotinic acetylcholine receptor (α7nAChR), which are in synaptic plasticity and neuronal development. Moreover, CZTL inhibited the NF-κB signaling pathway. In conclusion, CZTL may alleviate neuroinflammation induced by CCH and improve cognitive impairment in CCH mice by regulating the cholinergic anti-inflammatory pathway (CAIP) involving ChAT/α7nAChR/NF-κB.

Ratlarda Oluşturulan Renal İskemi Reperfüzyon Hasarında Epibatidinin Etkileri

Objective: The attenuation of renal ischemia reperfusion (I/R) injury by stimulating cholinergic antiinflamatory pathway has been demonstrated in the literature. The purpose of this study is to investigate the protective effects of epibatidine, a non selective nicotinic acethycholine receptor agonist, administered before ischemia on renal ischemia-reperfusion injury. Methods: After Ethics Committee approval, 24 Wistar Albino rats were randomly allocated into 4 groups. Group S: Sham (n=6), Group I/R: Ischemia/reperfusion (n=6), Group I/R-E: Ischemia/ reperfusion-Epibatidine (n=6), Group E: Epibatidine (n=6). All groups underwent laparotomy and bilateral renal artery and vein dissection under anesthesia. No further action was taken in Group S. In Group I/R and Group I/R-E, renal ischemia was applied for 25 minutes and then reperfusion for 24 hours. A single dose of 5 μg kg-1 epibatidine was administered subcutaneously before the laparotomy in Group I/R-E and Group E. At the end of the reperfusion period, blood and urine samples were taken for plasma BUN, creatine, plasma and urinary neutrophil gelatinase associated lipocalin (NGAL) and cystatin C, plasma IL-6 and TNF-α assessment. Results: Plasma BUN, creatine, NGAL, cystatin C, IL-6 and TNF-α levels were significantly higher in Group I/R when compared to Group S (p<0.05). All the levels of the above biomarkers were comparable in Group S and Group I/R-E. Conclusion: These results indicate that epibatidine administration before ischemia has a protective effect on kidney in renal I/R injury induced rats. Keywords: Renal ischemia-reperfusion injury, cholinergic antiinflammatory pathway, n7AchR, epibatidine, NGAL

Cholinergic anti-inflammatory pathway confers protective effects in septic shock rats

Background: Septic shock can lead to multiple organ dysfunction. The cholinergic anti-inflammatory pathway is known to prevent organ damage from infection by modulating the inflammatory response. However, the modulatory capacity of cholinergic anti-inflammatory pathways in septic shock remains unclear. Methods: Cecal ligation and puncture (CLP) was used to establish a rat model of septic shock. Bilateral cervical vagal nerve isolation, dual cervical vagotomy, and vagus nerve stimulation (VNS) were used to inhibit or activate cholinergic anti-inflammatory pathways. Tacrine and α-bungarotoxin groups were used to mimic the activation and shutdown of cholinergic anti-inflammatory pathways. The survival status, hemodynamic indicators, inflammatory cytokine content, and inflammatory response of liver and kidney tissues of the rats were detected. Results: Dual cervical vagotomy significantly exacerbated the hepatic (p < 0.05) and renal (p < 0.05) impairment in septic shock rats relative to the sham-operated group. Tacrine, a cholinergic potentiator, significantly alleviated liver (p < 0.05) and kidney (p < 0.05) damage in septic shock rats. Dual cervical vagotomy significantly promoted the expression of pro-inflammatory factors caused by septic shock in rat liver and kidney tissues (p < 0.05), while Tacrine treatment inhibited the increase of inflammatory factors (p < 0.05). Conclusions: Activation of the cholinergic anti-inflammatory pathway exerts protective effects on multiple organ dysfunction caused by septic shock. The cholinergic enhancer, Tacrine, and VNS effectively ameliorated liver and kidney damage, improved hemodynamic indicators, and enhanced survival rates in septic shock rats.

Vagus nerve signal has an inhibitory influence on the development of peritoneal metastasis in murine gastric cancer

The vagus nerve is the only pathway for transmitting parasympathetic signals between the brain and thoracoabdominal organs, thereby exhibiting anti-inflammatory functions through the cholinergic anti-inflammatory pathway. Despite often being resected during lymph node dissection in upper gastrointestinal cancer surgery, the impact of vagotomy on postoperative outcomes in gastric cancer patients remains unclear. Sub-diaphragmatic vagotomy was performed on C57BL/6 mice. Three weeks later, syngeneic murine gastric cancer cell line YTN16P was injected into the peritoneal cavity, and the number of peritoneal metastases (PM) on the mesentery and omentum compared with control mice. The phenotypes of immune cells in peritoneal lavage and omental milky spots one day after tumor inoculation were analyzed using flow cytometry and immunohistochemistry. Intraperitoneal transfer of 3 × 105 YTN16P significantly increased the number of metastatic nodules on the mesentery in the vagotomy group compared to the control group. The omental metastasis grade was also significantly higher in the vagotomy group. Phenotypic analysis of immune cells in peritoneal lavage did not reveal significant differences after vagotomy. However, vagotomized mice exhibited a notable increase in milky spot area, with a higher presence of cytokeratin(+) tumor cells, F4/80(+) macrophages, and CD3(+) T cells. Vagus nerve signaling appears to regulate the immune response dynamics within milky spots against disseminated tumor cells and inhibits the development of PM. Preserving the vagus nerve may offer advantages in advanced gastric cancer surgery to reduce peritoneal recurrence.

Retrospective evaluation of COVID-19 incidence during smoking cessation treatment with varenicline

Background: Cholinergic anti-inflammatory pathway endogenously controls inflammatory processes through activation of the α7-nicotinic acetylcholine receptor (α7nAChR). Varenicline, used in smoking cessation therapy, is a full α7nAChR agonist with anti-inflammatory effects. In this study, the frequency of coronavirus disease (COVID-19) was evaluated in patients using varenicline as a smoking cessation treatment.
 Methods: In this retrospective cross-sectional study, records of the 111 patients admitted to Smoking Cessation Outpatient Clinic of Dokuz Eylul University Faculty of Medicine during the COVID-19 pandemic were evaluated. The development of COVID-19 disease according to the status of the patients being positive for SARS-COV-2 was evaluated comparatively in patients who received varenicline or not. Additionally, the disease symptoms were questioned. 
 Results: SARS-CoV-2 PCR positivity was not detected in any of 38 patients who regularly used varenicline out of 68 patients evaluated. SARS-CoV-2 PCR positivity was detected in 13 (43.3%) of 30 patients who received other treatments or irregularly used varenicline (p

Modulation of plasmacytoid dendritic cell and CD4+ T cell differentiation accompanied by upregulation of the cholinergic anti-inflammatory pathway induced by enterovirus 71.

Enterovirus 71 (EV71) is a neurotropic enterovirus associated with hand, foot, and mouth disease (HFMD) fatalities. In this study, we investigated the impact of EV71 on plasmacytoid dendritic cells (pDCs) and CD4+ T cells. The results showed that pDCs were promptly activated, secreting interferon (IFN)-α and inducing CD4+ T cell proliferation and differentiation during early EV71 infection. This initiated adaptive immune responses and promoted proinflammatory cytokine production by CD4+ T cells. Over time, viral nucleic acids and proteins were synthesized in pDCs and CD4+ T cells. Concurrently, the cholinergic anti-inflammatory pathway (CAP) was activated, exhibiting an anti-inflammatory role. With constant viral stimulation, pDCs and CD4+ T cells showed reduced differentiation and cytokine secretion. Defects in pDCs were identified as a key factor in CD4+ T cell tolerance. CAP had a more significant regulatory effect on CD4+ T cells than on pDCs and was capable of inhibiting inflammation in these cells.

Osthole Activates the Cholinergic Anti-Inflammatory Pathway via α7nAChR Upregulation to Alleviate Inflammatory Responses.

Osthole (also known as Osthol) is the main anti-inflammatory coumarin found in Cnidium monnieri and severs as the exclusive quality-controlled component according the Chinese Pharmacopoeia. However, its underlying anti-inflammatory mechanism remains unknown. In this study, we demonstrated that Osthole treatment significantly inhibited the generation of TNF-α, but not IL-6 in the classical LPS-stimulated RAW264.7 macrophage model. In addition, LPS induced the activation of both MAPK and NF-κB signalling pathways, of which the former was dose-dependently restrained by Osthole via suppressing the phosphorylation of JNK and P38 proteins, while the phosphorylation of IκB and P65 proteins remained unaffected. Interestingly, Osthole dose-dependently up-regulated the expression of the key cholinergic anti-inflammatory pathway regulator α7nAChR, and the TNF-α inhibition effect of Osthole was also significantly alleviated by the treatment of α7nAChR antagonist methylbetaine. These results demonstrate that Osthole may regulate TNF-α by promoting the expression of α7nAChR, thereby activate the vagus nerve-dependent cholinergic anti-inflammatory pathway.

Direct vagus nerve stimulation: A new tool to control allergic airway inflammation through α7 nicotinic acetylcholine receptor.

Asthma is characterized by airway inflammation, mucus hypersecretion, and airway hyperresponsiveness. The use of nicotinic agents to mimic the cholinergic anti-inflammatory pathway (CAP) controls experimental asthma. Yet, the effects of vagus nerve stimulation (VNS)-induced CAP on allergic inflammation remain unknown. BALB/c mice were sensitized and challenged with house dust mite (HDM) extract and treated with active VNS (5Hz, 0.5ms, 0.05-1mA). Bronchoalveolar lavage (BAL) fluid was assessed for total and differential cell counts and cytokine levels. Lungs were examined by histopathology and electron microscopy. In the HDM mouse asthma model, VNS at intensities equal to or above 0.1mA (VNS 0.1) but not sham VNS reduced BAL fluid differential cell counts and alveolar macrophages expressing α7 nicotinic receptors (α7nAChR), goblet cell hyperplasia, and collagen deposition. Besides, VNS 0.1 also abated HDM-induced elevation of type 2 cytokines IL-4 and IL-5 and was found to block the phosphorylation of transcription factor STAT6 and expression level of IRF4 in total lung lysates. Finally, VNS 0.1 abrogated methacholine-induced hyperresponsiveness in asthma mice. Prior administration of α-bungarotoxin, a specific inhibitor of α7nAChR, but not propranolol, a specific inhibitor of β2-adrenoceptors, abolished the therapeutic effects of VNS 0.1. Our data revealed the protective effects of VNS on various clinical features in allergic airway inflammation model. VNS, a clinically approved therapy for depression and epilepsy, appears to be a promising new strategy for controlling allergic asthma.

Long-COVID-19 autonomic dysfunction: An integrated view in the framework of inflammaging

The recently identified syndrome known as Long COVID (LC) is characterized by a constellation of debilitating conditions that impair both physical and cognitive functions, thus reducing the quality of life and increasing the risk of developing the most common age-related diseases. These conditions are linked to the presence of symptoms of autonomic dysfunction, in association with low cortisol levels, suggestive of reduced hypothalamic-pituitary-adrenal (HPA) axis activity, and with increased pro-inflammatory condition. Alterations of dopamine and serotonin neurotransmitter levels were also recently observed in LC. Interestingly, at least some of the proposed mechanisms of LC development overlap with mechanisms of Autonomic Nervous System (ANS) imbalance, previously detailed in the framework of the aging process. ANS imbalance is characterized by a proinflammatory sympathetic overdrive, and a concomitant decreased anti-inflammatory vagal parasympathetic activity, associated with reduced anti-inflammatory effects of the HPA axis and cholinergic anti-inflammatory pathway (CAP). These neuro-immune-endocrine system imbalanced activities fuel the vicious circle of chronic inflammation, i.e. inflammaging. Here, we refine our original hypothesis that ANS dysfunction fuels inflammaging and propose that biomarkers of ANS imbalance could also be considered biomarkers of inflammaging, recognized as the main risk factor for developing age-related diseases and the sequelae of viral infections, i.e. LC.

Radiation enteropathy-related depression: A neglectable course of disease by gut bacterial dysbiosis.

Radiation enteropathy (RE) is common in patients treated with radiotherapy for pelvic-abdominal cancers. Accumulating data indicate that gut commensal bacteria determine intestinal radiosensitivity. Radiotherapy can result in gut bacterial dysbiosis. Gut bacterial dysbiosis contributes to the pathogenesis of RE. Mild to moderate depressive symptoms can be observed in patients with RE in clinical settings; however, the rate of these symptoms has not been reported. Studies have demonstrated that gut bacterial dysbiosis induces depression. In the state of comorbidity, RE and depression may be understood as local and abscopal manifestations of gut bacterial disorders. The ability of comorbid depression to worsen inflammatory bowel disease (IBD) has long been demonstrated and is associated with dysfunction of cholinergic neural anti-inflammatory pathways. There is a lack of direct evidence for RE comorbid with depression. It is widely accepted that RE shares similar pathophysiologic mechanisms with IBD. Therefore, we may be able to draw on the findings of the relationship between IBD and depression. This review will explore the relationship between gut bacteria, RE, and depression in light of the available evidence and indicate a method for investigating the mechanisms of RE combined with depression. We will also describe new developments in the treatment of RE with probiotics, prebiotics, and fecal microbial transplantation.

Nicotine regulates abnormal macrophage polarization and trophoblast invasion associated with preterm labor via the α7nAChR/SIRT1 axis

IntroductionPreterm birth (PTB) frequently results from the syndrome of preterm labor (PTL). PTL is linked to an atypical maternal inflammatory response, as well as intrauterine inflammation and/or infection. In this study, we explored the mechanisms involved in nicotine-mediated abnormal macrophage polarization and trophoblast invasion associated with PTL. MethodsFirst, THP-1-M0 macrophages were generated by treating the human monocytic leukemia cell line (THP-1) with phorbol 12-myristate 13-acetate for a duration of 24 h. Afterward, nicotine treatment was administered, followed by coculturing with the HTR-8/SVneo trophoblast cell line (HTR-8) at a ratio of 1:1. Next, we transfected sh-α7nAChR and treated THP-1-M0 macrophages and HTR-8 cells with nicotine. In addition, we transfected THP-1-M0 macrophages with sh-NC or sh-SIRT1 or subjected them to 4 nM nicotinamide adenine dinucleotide (NAD) metabolic inhibitor FK866 treatment. Moreover, HTR-8 cells were treated with nicotine, after which THP-1-M0 macrophages were cocultured with HTR-8 cells. Finally, we constructed an in vivo RU486-induced PTL rat model to verify the effect of nicotine and the mechanisms involved. ResultsWe found that nicotine affected polarization and α7nAChR expression in HTR-8 cocultured THP-1-M0 macrophages. Knocking down α7nAChR blocked the effect of nicotine on the proliferation and invasion of HTR-8 cells. Furthermore, nicotine activated the α7nAChR/SIRT1 axis to regulate THP-1-M0 macrophage polarization through the cholinergic anti-inflammatory pathway. Additionally, NAD metabolism mediated the role of the α7nAChR/SIRT1 axis in nicotine-induced polarization of HTR-8 cocultured THP-1-M0 macrophages. In vivo experiments demonstrated that nicotine alleviated inflammation in PTL rats, which involved the α7nAChR/SIRT1 axis. ConclusionNicotine regulated abnormal macrophage polarization and trophoblast invasion associated with PTL via the α7nAChR/SIRT1 axis.

Electroacupuncture targeting the immune system to alleviate sepsis

Sepsis is a life-threatening inflammatory syndrome with high morbidity and mortality rates. However, options for sepsis are still limited to general treatment in intensive care units (ICUs), and effective therapies that improve sepsis survival are required. Immune disturbances play a vital role in the pathology of sepsis and are associated with protracted inflammation, susceptibility to infections, and death. Therefore, many investigators have focused on the potential benefits of immunomodulation therapy for sepsis. Electroacupuncture (EA) has been practiced in clinics for many years and has shown advantages in treating infectious diseases. Over the last few decades, our understanding of the efficacy and mechanisms of EA in sepsis has undergone considerable developments. We searched the literature regarding “CNKI, Wan Fang Data, VIP Database, PubMed, and Ingenta Connect” from 2010 to 2023, using the keywords “sepsis” “septic” and “electroacupuncture” and 336 sources were searched. Finally, we included 82 studies that targeted the immune system to determine EA’s anti-inflammatory and immunomodulatory effects on sepsis. In this review, we found that EA has clinical benefits in relieving septic inflammation, improving immune function, and attenuating related multi-organ injury through several mechanisms, such as activation of the cholinergic anti-inflammatory pathway (CAP), vagal-adrenal axis, inhibition of the nuclear factor Kappa-B (NF-κB) signaling pathway, signal transducers and activators of transcription (STAT) signaling pathway, and improvement of immune cell function. Therefore, EA may be a promising complementary therapy for sepsis treatment. We also expect these data will contribute to further studies on EA in sepsis.

The effects of the cholinergic system on carrageenan-induced arthritis

The cholinergic system has been found to make an anti-inflammatory effect through the cholinergic anti-inflammatory pathway (CAIP), which suppresses the production of pro-inflammatory cytokines by secreting acetylcholine, a major neurotransmitter. However, no studies have been conducted on the effects of CAIP on joint pain and inflammation. In this study, we investigated the effects of muscarinic acetylcholine receptors (mAChRs) in knee arthritis. To examine pain behavioral changes, atropine (or saline for sham control) was pretreated in the joint cavity of rats at 1 % carrageenan + 5, 10, and 30 μL and the dynamic weight-bearing evaluation was performed. Synovial membranes were collected and cyclooxygenase-2 (COX-2) and interleukin-1β (IL-1β) were measured using a western blot. Hematoxylin and eosin staining was performed. Compared to that of the sham group, the weight-bearing of the affected knee joint significantly increased in the 1 % carrageenan + 10 μL atropine group (p < 0.05). However, no significant changes were observed in the 1 % carrageenan + 5 and 30 μL atropine groups. COX-2 and IL-1β and the number of inflammatory cells in synovial membrane significantly increased with 1 % carrageenan + 10 μL of atropine (p < 0.05). These results suggest that cholinergic system is involved in knee joint pain and inflammation and that mAChRs are potential therapeutic targets for knee joint arthritis.

Vagus nerve stimulation: Potential for treating chronic wounds.

Vagus nerve stimulation (VNS) has been approved as a treatment for various conditions, including drug-resistant epilepsy, migraines, chronic cluster headaches and treatment-resistant depression. It is known to have anti-inflammatory, anti-nociceptive and anti-adrenergic effects, and its therapeutic potential for diverse pathologies is being investigated. VNS can be achieved through invasive (iVNS) or non-invasive (niVNS) means, targeting different branches of the vagus nerve. iVNS devices require surgical implantation and have associated risks, while niVNS devices are generally better tolerated and have a better safety profile. Studies have shown that both iVNS and niVNS can reduce inflammation and pain perception in patients with acute and chronic conditions. VNS devices, such as the VNS Therapy System and MicroTransponder Vivistim, have received Food and Drug Administration approval for specific indications. Other niVNS devices, like NEMOS and gammaCore, have shown effectiveness in managing epilepsy, pain and migraines. VNS has also demonstrated potential in autoimmune disorders, such as rheumatoid arthritis and Crohn's disease, as well as neurological disorders like epilepsy and migraines. In addition, VNS has been explored in cardiovascular disorders, including post-operative atrial fibrillation and myocardial ischemia-reperfusion injury, and has shown positive outcomes. The mechanisms behind VNS's effects include the cholinergic anti-inflammatory pathway, modulation of cytokines and activation of specialised pro-resolving mediators. The modulation of inflammation by VNS presents a promising avenue for investigating its potential to improve the healing of chronic wounds. However, more research is needed to understand the specific mechanisms and optimise the use of VNS in wound healing. Ongoing clinical trials may support the use of this modality as an adjunct to improve healing.

The role of the peripheral system dysfunction in the pathogenesis of sepsis-associated encephalopathy.

Sepsis is a condition that greatly impacts the brain, leading to neurological dysfunction and heightened mortality rates, making it one of the primary organs affected. Injury to the central nervous system can be attributed to dysfunction of various organs throughout the entire body and imbalances within the peripheral immune system. Furthermore, central nervous system injury can create a vicious circle with infection-induced peripheral immune disorders. We collate the pathogenesis of septic encephalopathy, which involves microglial activation, programmed cell death, mitochondrial dysfunction, endoplasmic reticulum stress, neurotransmitter imbalance, and blood-brain barrier disruption. We also spotlight the effects of intestinal flora and its metabolites, enterocyte-derived exosomes, cholinergic anti-inflammatory pathway, peripheral T cells and their cytokines on septic encephalopathy.

Differential gene expression during recall of behaviorally conditioned immune enhancement in rats: a pilot study

Background: Behaviorally conditioned immune functions are suggested to be regulated by bidirectional interactions between CNS and peripheral immune system via the hypothalamic-pituitary-adrenal (HPA) axis, sympathetic nervous system (SNS), and the parasympathetic nervous system (PNS). Since the current knowledge about biochemical pathways triggering conditioned immune enhancement is limited, the aim of this pilot study was gaining more insights into that. Methods: Rats were conditioned with camphor smell and poly I:C injection, mimicking a viral infection. Following stimulus re-exposure, animals were sacrificed at different time points, and neural tissues along the HPA axis was analyzed with a rat genome array together with plasma protein using Luminex analysis. Results: In the hypothalamus, we observed a strong upregulation of genes related to Wnt/β-catenin signaling (Otx2, Spp1, Fzd6, Zic1), monoaminergic transporter Slc18a2 and opioid-inhibitory G-protein Gpr88 as well as downregulation of dopaminergic receptors, vasoactive intestinal peptide Vip, and pro-melanin-concentrating hormone Pmch. In the pituitary, we recognized mostly upregulation of steroid synthesis in combination with GABAergic, cholinergic and opioid related neurotransmission, in adrenal glands, altered genes showed a pattern of activated metabolism plus upregulation of adrenoceptors Adrb3 and Adra1a. Data obtained from spleen showed a strong upregulation of immunomodulatory genes, chemo-/cytokines and glutamatergic/cholinergic neurotransmission related genes, as also confirmed by increased chemokine and ACTH levels in plasma. Conclusions: Our data indicate that in addition to the classic HPA axis, there could be additional pathways as e.g. the cholinergic anti-inflammatory pathway (CAIP), connecting brain and immune system, modulating and finetuning communication between brain and immune system.

Cholinergic signaling via the α7 nicotinic acetylcholine receptor regulates the migration of monocyte-derived macrophages during acute inflammation

BackgroundThe involvement of the autonomic nervous system in the regulation of inflammation is an emerging concept with significant potential for clinical applications. Recent studies demonstrate that stimulating the vagus nerve activates the cholinergic anti-inflammatory pathway that inhibits pro-inflammatory cytokines and controls inflammation. The α7 nicotinic acetylcholine receptor (α7nAChR) on macrophages plays a key role in mediating cholinergic anti-inflammatory effects through a downstream intracellular mechanism involving inhibition of NF-κB signaling, which results in suppression of pro-inflammatory cytokine production. However, the role of the α7nAChR in the regulation of other aspects of the immune response, including the recruitment of monocytes/macrophages to the site of inflammation remained poorly understood.ResultsWe observed an increased mortality in α7nAChR-deficient mice (compared with wild-type controls) in mice with endotoxemia, which was paralleled with a significant reduction in the number of monocyte-derived macrophages in the lungs. Corroborating these results, fluorescently labeled α7nAChR-deficient monocytes adoptively transferred to WT mice showed significantly diminished recruitment to the inflamed tissue. α7nAChR deficiency did not affect monocyte 2D transmigration across an endothelial monolayer, but it significantly decreased the migration of macrophages in a 3D fibrin matrix. In vitro analysis of major adhesive receptors (L-selectin, β1 and β2 integrins) and chemokine receptors (CCR2 and CCR5) revealed reduced expression of integrin αM and αX on α7nAChR-deficient macrophages. Decreased expression of αMβ2 was confirmed on fluorescently labeled, adoptively transferred α7nAChR-deficient macrophages in the lungs of endotoxemic mice, indicating a potential mechanism for α7nAChR-mediated migration.ConclusionsWe demonstrate a novel role for the α7nAChR in mediating macrophage recruitment to inflamed tissue, which indicates an important new aspect of the cholinergic regulation of immune responses and inflammation.

VNS improves VSMC metabolism and arteriogenesis in infarcted hearts through m/n-AChR-Akt-SDF-1α in adult male rats

Vagal nerve stimulation (VNS) provides a novel therapeutic strategy for injured hearts by activating cholinergic anti-inflammatory pathways. However, little information is available on the metabolic pattern and arteriogenesis of VSMCs after MI. VNS has been shown to stimulate the expression of CPT1α, CPT1β, Glut1, Glut4 and SDF-1α in coronary VSMCs, decreasing the number of CD68-positive macrophages while increasing CD206-positive macrophages in the infarcted hearts, leading to a decrease in TNF-α and IL-1β accompanied by a reduced ratio of CD68- and CD206-positive cells, which were dramatically abolished by atropine and mecamylamine in vivo. Knockdown of SDF-1α substantially abrogated the effect of VNS on macrophagecell alteration and inflammatory factors in infarcted hearts. Mechanistically, ACh induced SDF-1α expression in VSMCs in a dose-dependent manner. Conversely, atropine, mecamylamine, and a PI3K/Akt inhibitor completely eliminated the effect of ACh on SDF-1α expression. Functionally, VNS promoted arteriogenesis and improved left ventricular performance, which could be abolished by Ad-shSDF-1α. Thus, VNS altered the VSMC metabolism pattern and arteriogenesis to repair the infarcted heart by inducing SDF-1α expression, which was associated with the m/nAChR-Akt signaling pathway.

Effect of physiotherapy on infertility treatment in polycystic ovary syndrome patients.

Polycystic ovary syndrome (PCOS) is a complex hormonal condition associated with psychological, reproductive, and metabolic features. Low-grade inflammation is a recognised factor causing metabolic and reproductive disorders in PCOS, which is why anti-inflammation approaches in PCOS treatment, especially during the COVID pandemic, are considered. A promising therapeutic option is osteopathic manipulative treatment (OMT), which activates the cholinergic anti-inflammatory pathway and can inhibit proinflammatory cytokines, such as TNF, IL-1β, and TNF-β. In our paper we analysed the influence of OMT in women with PCOS. Seventy-three patients, aged 29-46 years, with a history of reproductive failure, who underwent a physiotherapeutic treatment were evaluated. Six months after the end of a physiotherapy session, a follow-up questionnaire was performed. The results show that most women (83.6%) were satisfied with the therapeutic process, and that the sessions met the patient's expectations. Reducing the level of anxiety related to infertility treatment and pregnancy was declared by 60 (82.2%) women, an improvement in well-being was declared by 72 (97.3%) (p = 0.04), and increasing awareness of the body after physiotherapy sessions was declared by 70 (95.9%) women. The physiotherapeutic sessions improved infertility treatment, enhanced quality of life, and had a positive effect on overall health in PCOS women.