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Journal of Clinical Medicine Jun 2023Marginal ulcer (MU) is a potential complication following Roux-en-Y gastric bypass (RYGB), with a mean prevalence of 4.6%. Early identification and prompt intervention... (Review)
Review
Marginal ulcer (MU) is a potential complication following Roux-en-Y gastric bypass (RYGB), with a mean prevalence of 4.6%. Early identification and prompt intervention are crucial to mitigating further complications. The pathophysiology of MU is complex and involves multiple factors, including smoking, infection, non-steroidal anti-inflammatory drug (NSAID) use, and larger pouch size. Patients with MU may experience acute or chronic abdominal pain. Rarely, they may present with a complication from the ulceration, such as bleeding, perforation, or strictures. Following diagnosis by endoscopy, management of MU typically involves modification of risk factors and medical therapy focused on proton pump inhibitors. In case of complicated ulcers, surgical intervention is often required for the repair of the perforation or resection of the stricture. For recurrent or recalcitrant ulcers, endoscopic coverage of the ulcer bed, resection of the anastomosis, and abdominal or thoracoscopic truncal vagotomy may be considered. This review aims at providing an overview of the etiology, diagnosis, and management of MU after RYGB.
PubMed: 37445371
DOI: 10.3390/jcm12134336 -
IScience Feb 2021Tumors comprise cancer cells and the associated stromal and immune/inflammatory cells, i.e., tumor microenvironment (TME). Here, we identify a metabolic signature of...
Tumors comprise cancer cells and the associated stromal and immune/inflammatory cells, i.e., tumor microenvironment (TME). Here, we identify a metabolic signature of human and mouse model of gastric cancer and show that vagotomy in the mouse model reverses the metabolic reprogramming, reflected by metabolic switch from glutaminolysis to OXPHOS/glycolysis and normalization of the energy metabolism in cancer cells and TME. We next identify and validate SNAP25, mTOR, PDP1/α-KGDH, and glutaminolysis as drug targets and accordingly propose a therapeutic strategy to target the nerve-cancer metabolism. We demonstrate the efficacy of nerve-cancer metabolism therapy by intratumoral injection of BoNT-A (SNAP25 inhibitor) with systemic administration of RAD001 and CPI-613 but not cytotoxic drugs on overall survival in mice and show the feasibility in patients. These findings point to the importance of neural signaling in modulating the tumor metabolism and provide a rational basis for clinical translation of the potential strategy for gastric cancer.
PubMed: 33598644
DOI: 10.1016/j.isci.2021.102091 -
NeuroImage Nov 2022Interactions between the brain and the stomach shape both cognitive and digestive functions. Recent human studies report spontaneous synchronization between brain...
Interactions between the brain and the stomach shape both cognitive and digestive functions. Recent human studies report spontaneous synchronization between brain activity and gastric slow waves in the resting state. However, this finding has not been replicated in any animal models. The neural pathways underlying this apparent stomach-brain synchrony is also unclear. Here, we performed functional magnetic resonance imaging while simultaneously recording body-surface gastric slow waves from anesthetized rats in the fasted vs. postprandial conditions and performed a bilateral cervical vagotomy to assess the role of the vagus nerve. The coherence between brain fMRI signals and gastric slow waves was found in a distributed "gastric network", including subcortical and cortical regions in the sensory, motor, and limbic systems. The stomach-brain coherence was largely reduced by the bilateral vagotomy and was different between the fasted and fed states. These findings suggest that the vagus nerve mediates the spontaneous coherence between brain activity and gastric slow waves, which is likely a signature of real-time stomach-brain interactions. However, its functional significance remains to be established.
Topics: Humans; Rats; Animals; Stomach; Vagus Nerve; Brain; Vagotomy; Neural Pathways
PubMed: 36113737
DOI: 10.1016/j.neuroimage.2022.119628 -
Molecular Medicine (Cambridge, Mass.) May 2022Severe COVID-19 is characterized by pro-inflammatory cytokine release syndrome (cytokine storm) which causes high morbidity and mortality. Recent observational and...
BACKGROUND
Severe COVID-19 is characterized by pro-inflammatory cytokine release syndrome (cytokine storm) which causes high morbidity and mortality. Recent observational and clinical studies suggest famotidine, a histamine 2 receptor (H2R) antagonist widely used to treat gastroesophageal reflux disease, attenuates the clinical course of COVID-19. Because evidence is lacking for a direct antiviral activity of famotidine, a proposed mechanism of action is blocking the effects of histamine released by mast cells. Here we hypothesized that famotidine activates the inflammatory reflex, a brain-integrated vagus nerve mechanism which inhibits inflammation via alpha 7 nicotinic acetylcholine receptor (α7nAChR) signal transduction, to prevent cytokine storm.
METHODS
The potential anti-inflammatory effects of famotidine and other H2R antagonists were assessed in mice exposed to lipopolysaccharide (LPS)-induced cytokine storm. As the inflammatory reflex is integrated and can be stimulated in the brain, and H2R antagonists penetrate the blood brain barrier poorly, famotidine was administered by intracerebroventricular (ICV) or intraperitoneal (IP) routes.
RESULTS
Famotidine administered IP significantly reduced serum and splenic LPS-stimulated tumor necrosis factor (TNF) and IL-6 concentrations, significantly improving survival. The effects of ICV famotidine were significantly more potent as compared to the peripheral route. Mice lacking mast cells by genetic deletion also responded to famotidine, indicating the anti-inflammatory effects are not mast cell-dependent. Either bilateral sub-diaphragmatic vagotomy or genetic knock-out of α7nAChR abolished the anti-inflammatory effects of famotidine, indicating the inflammatory reflex as famotidine's mechanism of action. While the structurally similar H2R antagonist tiotidine displayed equivalent anti-inflammatory activity, the H2R antagonists cimetidine or ranitidine were ineffective even at very high dosages.
CONCLUSIONS
These observations reveal a previously unidentified vagus nerve-dependent anti-inflammatory effect of famotidine in the setting of cytokine storm which is not replicated by high dosages of other H2R antagonists in clinical use. Because famotidine is more potent when administered intrathecally, these findings are also consistent with a primarily central nervous system mechanism of action.
Topics: Animals; Anti-Inflammatory Agents; COVID-19; Cytokine Release Syndrome; Famotidine; Histamine; Histamine H2 Antagonists; Lipopolysaccharides; Mice; Reflex; Vagus Nerve; alpha7 Nicotinic Acetylcholine Receptor
PubMed: 35578169
DOI: 10.1186/s10020-022-00483-8 -
Life Sciences May 2021The aim of this study was to explore the potential effect of electroacupuncture (EA) at ST36 on mice bearing breast tumors by regulating inflammatory cytokines to...
AIMS
The aim of this study was to explore the potential effect of electroacupuncture (EA) at ST36 on mice bearing breast tumors by regulating inflammatory cytokines to enhance antitumor immunity via vagus nerve.
MATERIALS AND METHODS
Female BALB/c mice were implanted with 4T1-luc2 breast tumor cells to establish a murine mammary cancer model. Tumor growth was evaluated by tumor volume, weight and bioluminescence imaging. Inflammatory conditions in serum and tumor tissue were assessed by cytokines (IL-1β, TNF-α and IL-10) and HE staining. Proportions and functions of CD8 T cells, NK cells and MDSCs were identified by flow cytometry and western blot. Involvement of vagal efferent components was confirmed by ChAT and c-Fos double labeling immunohistochemistry in dorsal motor nucleus of vagus (DMV). Subdiaphragmatic vagotomy was employed to determine if the effect of EA was mediated by vagus nerve.
KEY FINDINGS
EA at ST36 reduced the volume and weight of tumors within 22 days after implantation. Proinflammatory cytokines IL-1β and TNF-α in serum, tumor and local inflammatory infiltration were obviously attenuated after EA. Meanwhile, EA intervention significantly augmented the proportion and cytolytic function of CD8 T cells and NK cells, along with a decline in the accumulation and immunosuppressive activities of MDSCs. Finally, c-Fos expression in ChAT neurons in DMV increased following EA, and the ameliorating effect of EA was obviously blocked by subdiaphragmatic vagotomy.
SIGNIFICANCE
EA intervention relieved tumor progression in breast tumor-bearing mice by alleviating inflammation and enhancing antitumor immunity, which was mediated by eliciting efferent vagus nerve activity.
Topics: Animals; Breast Neoplasms; CD8-Positive T-Lymphocytes; China; Cytokines; Electroacupuncture; Female; Inflammation; Interleukin-1beta; Mice; Mice, Inbred BALB C; Tumor Necrosis Factor-alpha; Vagus Nerve
PubMed: 33636172
DOI: 10.1016/j.lfs.2021.119259 -
Journal of Internal Medicine Sep 2019Excessive chronic inflammation is linked to many diseases and considered a stress factor in humans (Robbins Pathologic Basis of Disease. Philadelphia: W.B. Saunders Co.,... (Review)
Review
Excessive chronic inflammation is linked to many diseases and considered a stress factor in humans (Robbins Pathologic Basis of Disease. Philadelphia: W.B. Saunders Co., 1999, Proc Natl Acad Sci USA, 2008, 105: 17949, Immunity, 44, 2016, 44: 463, N Engl J Med, 2011, 364: 656). Today, the resolution of inflammation is widely recognized as a cellular biochemically active process involving biosynthesis of a novel superfamily of endogenous chemical signals coined specialized pro-resolving mediators (SPMs; Nature, 2014, 510:92). Herein, we review recent evidence, indicating a role for the vagus nerve and vagotomy in the regulation of lipid mediators. Vagotomy reduces pro-resolving mediators, including the lipoxins, resolvins, protectins and maresins, delaying resolution in mouse peritonitis. Vagotomy also delays resolution of Escherichia coli infection in mice. Specifically, right vagus regulates peritoneal Group 3 innate lymphoid cell (ILC-3) number and peritoneal macrophage responses with lipid mediator profile signatures with elevated pro-inflammatory eicosanoids and reduced resolvins, including the novel protective immunoresolvent agonist protectin conjugate in tissue regeneration1 (PCTR1). Acetylcholine upregulates PCTR biosynthesis, and administration of PCTR1 to vagotomized mice restores tissue resolution and host responses to E. coli infections. Results obtained with human vagus ex vivo indicate that vagus can produce both pro-inflammatory eicosanoids, such as prostaglandins and leukotrienes, as well as the SPM. Electrical stimulation of human vagus in vitro reduces both prostaglandins and leukotrienes and enhances resolvins and the other SPM. These results elucidate a host protective mechanism mediated by vagus stimulation of SPM that includes resolvins and PCTR1 to regulate myeloid antimicrobial functions and resolution of infection. Moreover, they define a new pro-resolution of inflammation reflex operative in mice and human tissue that involves a vagus SPM circuit.
Topics: Acute Disease; Animals; CD59 Antigens; Docosahexaenoic Acids; Exudates and Transudates; Fatty Acids, Essential; Inflammation; Inflammation Mediators; Leukocytes; Lipid Metabolism; Mice; Neuroprotection; Signal Transduction; Vagotomy; Vagus Nerve
PubMed: 30565762
DOI: 10.1111/joim.12871 -
Frontiers in Physiology 2021Cirrhosis and hepatic encephalopathy (HE) are linked with an altered gut-liver-brain axis, however, the relative contribution of hepatic vagal innervation is unclear. We...
BACKGROUND
Cirrhosis and hepatic encephalopathy (HE) are linked with an altered gut-liver-brain axis, however, the relative contribution of hepatic vagal innervation is unclear. We aimed to determine the impact of hepatic vagotomy on the gut microbiome, brain, and liver in murine cirrhosis.
METHODS
10-15-week-old male C57BL/6 mice with and without hepatic vagotomy underwent carbon tetrachloride (CCl4) gavage for 8 weeks. Frontal cortex [inflammation, glial/microglial activation, BDNF (brain-derived neurotrophic factor)], liver [histology including inflammation and steatosis, fatty acid synthesis (sterol-responsive binding protein-1) SREBP-1, insulin-induced gene-2 (Insig2) and BDNF], and colonic mucosal microbiota (16srRNA microbial sequencing) were evaluated on sacrifice. Conventional mice with and without cirrhosis were compared to vagotomized counterparts.
RESULTS
: Cirrhosis resulted in dysbiosis, hepatic/neuro-inflammation with glial/microglial activation, and low brain BDNF vs. controls. Vagotomized control mice had a lower colonic dysbiosis than conventional mice but the rest of the hepatic/brain parameters were similar. After vagotomy + cirrhosis, we found lower dysbiosis but continuing neuroinflammation in the absence of glial/microglial activation vs. conventional cirrhosis. Vagotomy + Cirrhosis groups showed higher hepatic steatosis due to higher SREBP1 and low Insig2 protein and altered activation of key genes involved in hepatic lipid metabolism and inflammation. BDNF levels in the brain were higher but low in the liver in vagotomy + cirrhosis, likely a protective mechanism.
CONCLUSIONS
Hepatic vagal innervation affects the gut microbial composition, hepatic inflammation and steatosis, and cortical inflammation and BDNF expression and could be a critical modulator of the gut-liver-brain axis with consequences for HE development.
PubMed: 34248683
DOI: 10.3389/fphys.2021.702646 -
Virologica Sinica Jun 2023Erythroleukemia belongs to acute myeloid leukemia (AML) type 6 (M6), and treatment remains difficult due to the poor prognosis of the disease. Friend virus (FV) is a...
Erythroleukemia belongs to acute myeloid leukemia (AML) type 6 (M6), and treatment remains difficult due to the poor prognosis of the disease. Friend virus (FV) is a complex of two viruses: Friend murine leukemia virus (F-MuLV) strain along with a defective spleen focus-forming virus (SFFV), which can induce acute erythroleukemia in mice. We have previously reported that activation of vagal α7 nicotinic acetylcholine receptor (nAChR) signaling promotes HIV-1 transcription. Whether vagal muscarinic signaling mediates FV-induced erythroleukemia and the underlying mechanisms remain unclear. In this study, sham and vagotomized mice were intraperitoneally injected with FV. FV infection caused anemia in sham mice, and vagotomy reversed this change. FV infection increased erythroblasts ProE, EryA, and EryB cells in the spleen, and these changes were blocked by vagotomy. In bone marrow, FV infection reduced EryC cells in sham mice, an effect that was counteracted by vagotomy. FV infection increased choline acetyltransferase (ChAT) expression in splenic CD4 and CD8 T cells, and this change was reversed by vagotomy. Furthermore, the increase of EryA and EryB cells in spleen of FV-infected wild-type mice was reversed after deletion of ChAT in CD4 T cells. In bone marrow, FV infection reduced EryB and EryC cells in sham mice, whereas lack of ChAT in CD4 T cells did not affect this change. Activation of muscarinic acetylcholine receptor 4 (mAChR4) by clozapine N-oxide (CNO) significantly increased EryB in the spleen but decreased the EryC cell population in the bone marrow of FV-infected mice. Thus, vagal-mAChR4 signaling in the spleen and bone marrow synergistically promotes the pathogenesis of acute erythroleukemia. We uncover an unrecognized mechanism of neuromodulation in erythroleukemia.
Topics: Mice; Animals; Leukemia, Erythroblastic, Acute; Friend murine leukemia virus; CD8-Positive T-Lymphocytes; Signal Transduction; Leukemia, Experimental
PubMed: 37172825
DOI: 10.1016/j.virs.2023.05.005 -
Annals of the New York Academy of... Oct 2019With few effective treatments available, the global rise of metabolic diseases, including obesity, type 2 diabetes mellitus, and cardiovascular disease, seems... (Review)
Review
With few effective treatments available, the global rise of metabolic diseases, including obesity, type 2 diabetes mellitus, and cardiovascular disease, seems unstoppable. Likely caused by an obesogenic environment interacting with genetic susceptibility, the pathophysiology of obesity and metabolic diseases is highly complex and involves crosstalk between many organs and systems, including the brain. The vagus nerve is in a key position to bidirectionally link several peripheral metabolic organs with the brain and is increasingly targeted for neuromodulation therapy to treat metabolic disease. Here, we review the basics of vagal functional anatomy and its implications for vagal neuromodulation therapies. We find that most existing vagal neuromodulation techniques either ignore or misinterpret the rich functional specificity of both vagal efferents and afferents as demonstrated by a large body of literature. This lack of specificity of manipulating vagal fibers is likely the reason for the relatively poor beneficial long-term effects of such therapies. For these therapies to become more effective, rigorous validation of all physiological endpoints and optimization of stimulation parameters as well as electrode placements will be necessary. However, given the large number of function-specific fibers in any vagal branch, genetically guided neuromodulation techniques are more likely to succeed.
Topics: Animals; Electric Stimulation; Humans; Metabolic Diseases; Nerve Block; Obesity; Vagus Nerve
PubMed: 31268181
DOI: 10.1111/nyas.14182 -
BioRxiv : the Preprint Server For... May 2023The vagus nerve plays an important role in neuroimmune interactions and in the regulation of inflammation. A major source of efferent vagus nerve fibers that contribute...
BACKGROUND
The vagus nerve plays an important role in neuroimmune interactions and in the regulation of inflammation. A major source of efferent vagus nerve fibers that contribute to the regulation of inflammation is the brainstem dorsal motor nucleus of the vagus (DMN) as recently shown using optogenetics. In contrast to optogenetics, electrical neuromodulation has broad therapeutic implications, but the anti-inflammatory efficacy of electrical DMN stimulation (eDMNS) was not previously investigated. Here, we examined the effects of eDMNS on heart rate (HR) and cytokine levels in murine endotoxemia as well as the cecal ligation and puncture (CLP) model of sepsis.
METHODS
Anesthetized male 8-10-week-old C57BL/6 mice on a stereotaxic frame were subjected to eDMNS using a concentric bipolar electrode inserted into the left or right DMN or sham stimulation. eDMNS (50, 250 or 500 μA and 30 Hz, for 1 min) was performed and HR recorded. In endotoxemia experiments, sham or eDMNS utilizing 250 μA or 50 μA was performed for 5 mins and was followed by LPS (0.5 mg/kg) i.p. administration. eDMNS was also applied in mice with cervical unilateral vagotomy or sham operation. In CLP experiments sham or left eDMNS was performed immediately post CLP. Cytokines and corticosterone were analyzed 90 mins after LPS administration or 24h after CLP. CLP survival was monitored for 14 days.
RESULTS
Either left or right eDMNS at 250 μA and 500 μA decreased HR, compared with pre- and post-stimulation. This effect was not observed at 50 μA. Left side eDMNS at 50 μA, compared with sham stimulation, significantly decreased serum and splenic levels of the pro-inflammatory cytokine TNF and increased serum levels of the anti-inflammatory cytokine IL-10 during endotoxemia. The anti-inflammatory effect of eDMNS was abrogated in mice with unilateral vagotomy and were not associated with serum corticosterone alterations. Right side eDMNS suppressed serum TNF levels but had no effects on serum IL-10 and on splenic cytokines. In mice with CLP, left side eDMNS suppressed serum TNF and IL-6, as well as splenic IL-6 and increased splenic IL-10 and significantly improved the survival rate of CLP mice.
CONCLUSIONS
For the first time we show that a regimen of eDMNS which does not cause bradycardia alleviates LPS-induced inflammation and these effects require an intact vagus nerve and are not associated with corticosteroid alterations. eDMNS also decreases inflammation and improves survival in a model of polymicrobial sepsis. These findings are of interest for further studies exploring bioelectronic anti-inflammatory approaches targeting the brainstem DMN.
PubMed: 37292846
DOI: 10.1101/2023.05.17.541191