Neuroimmunophysiology of the gastrointestinal tract.

Gut physiology is the epicenter of a web of internal communication systems (i.e., neural, immune, hormonal) mediated by cell-cell contacts, soluble factors, and external influences, such as the microbiome, diet, and the physical environment. Together these provide the signals that shape enteric homeostasis and, when they go awry, lead to disease. Faced with the seemingly paradoxical tasks of nutrient uptake (digestion) and retarding pathogen invasion (host defense), the gut integrates interactions between a variety of cells and signaling molecules to keep the host nourished and protected from pathogens. When the system fails, the outcome can be acute or chronic disease, often labeled as "idiopathic" in nature (e.g., irritable bowel syndrome, inflammatory bowel disease). Here we underscore the importance of a holistic approach to gut physiology, placing an emphasis on intercellular connectedness, using enteric neuroimmunophysiology as the paradigm. The goal of this opinion piece is to acknowledge the pace of change brought to our field via single-cell and -omic methodologies and other techniques such as cell lineage tracing, transgenic animal models, methods for culturing patient tissue, and advanced imaging. We identify gaps in the field and hope to inspire and challenge colleagues to take up the mantle and advance awareness of the subtleties, intricacies, and nuances of intestinal physiology in health and disease by defining communication pathways between gut resident cells, those recruited from the circulation, and "external" influences such as the central nervous system and the gut microbiota.

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.

Sinomenine regulates the cholinergic anti-inflammatory pathway to inhibit TLR4/NF-κB pathway and protect the homeostasis in brain and gut in scopolamine-induced Alzheimer's disease mice.

Sinomenine (SIN), an alkaloid extracted from the Chinese herbal medicine Sinomenium acutum, has great potential in anti-inflammatory, immune regulation, analgesic and sedative, and is already a clinical drug for the treatment of rheumatoid arthritis in China. Our previous studies show SIN inhibits inflammation by regulating ɑ7nAChR, a key receptor of cholinergic anti-inflammatory pathway (CAP), which plays an important role in regulating peripheral and central nervous system inflammation. Growing evidence supports the cholinergic dysregulation and inflammatory responses play the key role in the pathogenesis of AD. The intervention effects of SIN on AD by regulating CAP and homeostasis in brain and gut were analyzed for the first time in the present study using scopolamine-induced AD model mice. Behavioral tests were used to assess the cognitive performance. The neurons loss, cholinergic function, inflammation responses, biological barrier function in the mouse brain and intestinal tissues were evaluated through a variety of techniques, and the gut microbiota was detected using 16SrRNA sequencing. The results showed that SIN significantly inhibited the cognitive decline, dysregulation of cholinergic system, peripheral and central inflammation, biological barrier damage as well as intestinal flora disturbance caused by SCOP in mice. More importantly, SIN effectively regulated CAP to suppress the activation of TLR4/NF-κB and protect the homeostasis in brain and gut to alleviate cognitive impairment.

[Effect of electroacupuncture on myocardial fibrosis in spontaneously hypertensive rats based on cholinergic anti-inflammatory pathway].

OBJECTIVE: To observe the effect of electroacupuncture (EA) at "Neiguan" (PC 6) on myocardial fibrosis in spontaneously hypertensive rats (SHR), and explore preliminarily the mediating role of cholinergic anti-inflammatory pathway (CAP) and its downstream nuclear factor κB (NF-κB) signaling pathway. METHODS: Six 12-week-old WKY male rats were employed as the normal group. Eighteen 12-week-old SHR were randomly divided into 3 groups, i.e. a model group, an EA group and a blocking group (EA after blocking α7 nicotinic acetylcholine receptor [α7nAchR]), with 6 rats in each one. In the EA group, EA was delivered at "Neiguan"(PC 6) and the site 0.5 cm from its left side, with disperse-dense wave, 2 Hz/15 Hz in frequency and 1 mA in current intensity. One intervention took 30 min and was given once every 2 days, lasting 8 weeks. In the blocking group, prior to each EA, the α7nAchR specific blocker, α-bungartoxin was injected intravenously in the tails of the rats. After EA intervention, the systolic blood pressure (SBP), the diastolic blood pressure (DBP) and the mean arterial pressure (MAP) were measured with non-invasive blood pressure monitor. Using echocardiogram, the left ventricular (LV) anterior wall end-diastolic thickness (LVAWd) , LV posterior wall end-diastolic thickness (LVPWd) and the LV end-diastolic internal diameter (LVIDd) were measured. The level of hydroxyproline (Hyp) in the myocardial tissue was determined by using alkaline hydrolysis, and that of acetylcholine (Ach) was detected by ELISA. With the real-time PCR adopted, the mRNA expression of NF-κB p65, tumor necrosis factor α (TNF-α), interleukin (IL)-1ß and IL-6 were determined. RESULTS: Compared with the normal group, SBP, DBP, MAP, LVAWd and LVPWd were increased (P<0.01), and LVIDd was decreased (P<0.01) in the rats of the model group. SBP, DBP, MAP and LVAWd were dropped (P<0.01, P<0.05), and LVIDd rose (P<0.01) in the EA group when compared with those in the model group. The differences in the above indexes were not statistically significant between the blocking group and the model group (P>0.05). Compared with the normal group, Hyp level and the mRNA expression of NF-κB p65, TNF-α, IL-1ß and IL-6 in the myocardial tissue increased (P<0.01, P<0.05) and Ach level decreased (P<0.01) in the model group. Hyp level, the mRNA expression of NF-κB p65, TNF-α, IL-1ß and IL-6 in the myocardial tissue were reduced (P<0.05, P<0.01) and Ach level rose (P<0.01) in the EA group when compared with those in the model group. These indexes were not different statistically between the blocking group and the model group (P>0.05). CONCLUSION: CAP may be involved in ameliorating the pathological damage of myocardial fibrosis during EA at "Neiguan"(PC 6). The underlying effect mechanism is associated with up-regulating the neurotransmitter, Ach and down-regulating mRNA expression of NF-κB p65 and pro-inflammatory factors such as TNF-α, IL-1ß and IL-6 in myocardial tissue.

Astragaloside IV alleviates stroke-triggered early brain injury by modulating neuroinflammation and ferroptosis via the Nrf2/HO-1 signaling pathway

Purpose: Stroke is an acute cerebrovascular disease. Astragaloside IV (AS-IV) is an active ingredient extracted from Astragalus membranaceus with an established therapeutic effect on central nervous system diseases. This study examined the neuroprotective properties and possible mechanisms of AS-IV in stroke-triggered early brain injury (EBI) in a rat transient middle cerebral artery occlusion (MCAO) model. Methods: The neurological scores and brain water content were analyzed. 2,3,5-triphenyl tetrazolium chloride (TTC) staining was utilized to determine the infarct volume, neuroinflammatory cytokine levels, and ferroptosis-related genes and proteins, and neuronal damage and molecular mechanisms were evaluated by terminal deoxynucleotidyl transferase dutp nickend labeling (TUNEL) staining, western blotting, and real-time polymerase chain reaction. Results: AS-IV administration decreased the infarct volume, brain edema, neurological deficits, and inflammatory cytokines TNF-α, interleukin-1ß (IL-1ß), IL-6, and NF-κB, increased the levels of SLC7A11 and glutathione peroxidase 4 (GPX4), decreased lipid reactive oxygen species (ROS) levels, and prevented neuronal ferroptosis. Meanwhile, AS-IV triggered the Nrf2/HO-1 signaling pathway and alleviated ferroptosis due to the induction of stroke. Conclusion: Hence, the findings of this research illustrate that AS-IV administration can improve delayed ischemic neurological deficits and decrease neuronal death by modulating nuroinflammation and ferroptosis via the Nrf2/HO-1 signaling pathway.

Cerebellar fastigial nucleus electrostimulation attenuates inflammation in a Post-Infarction rat model by activating cholinergic anti-inflammatory pathway.

There are negative correlations between indices of heart rate variability (HRV) and markers of inflammation. The inflammation plays an important role in myocardial damages after myocardial infarction (MI). Our previous study found that fastigial nucleus electrostimulation (FNS) improved abnormal HRV in a rat model of MI. Whether it can reduce inflammation and improve cardiac function after MI and the underlying mechanisms remain unknown. 66 Sprague Dawley rats were randomly divided into 4 groups as follows: i) Sham group (sham operation); ii) MI group (left anterior descending coronary artery ligation); iii) FNS + MI group (left fastigial nucleus electrostimulation plus MI); iv) FNL + FNS + MI group (left fastigial nucleus lesion plus FNS plus MI). The serum expressions of acetylcholine (ACh), pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), and anti-inflammatory cytokines IL-10 were measured by ELISA. Subsequently, the infarct size, the infiltration of inflammatory cells, the fibrotic area, and cardiac function were also evaluated. Additionally, the expressions of the cholinergic anti-inflammatory pathway (CAP)-related proteins in infarct tissue, such as nuclear factor kappa B (NF-κB) and singal transducers and activators of transcription 3 (STAT3), were determined by Western blot. We found that FNS significantly increased ACh and IL-10 levels in serum, and decreased TNF-α and IL-6 levels. FNS significantly attenuated inflammatory cell infiltration, reduced infarct size, decreased fibrosis, increased left ventricular ejection fraction, and reduced mortality. Besides, the ratios of phosphorylated-STAT3/STAT3 and phosphorylated-NF-κB/NF-κB in infarct tissue significantly elevated after MI. FNS reduced the ratios of p-STAT3/STAT3 and p-NF-κB/NF-κB in infarct tissue. The protective effects of FNS were partially reversed by the fastigial nucleus lesion. Our data suggested that FNS can alleviate the inflammation after MI, and its cardiac neuroprotective mechanism may be achieved by increasing vagal tone, releasing ACh, and further activating the CAP via α7 nicotinic acetylcholine receptor. The precise mechanism remains to be elucidated.

Psychoneuroimmunology in the time of COVID-19: Why neuro-immune interactions matter for mental and physical health.

The brain and immune system are intricately connected, and perturbations in one system have direct effects on the other. This review focuses on these dynamic psychoneuroimmune interactions and their implications for mental and physical health in the context of the COVID-19 pandemic. In particular, we describe how psychological states influence antiviral immunity and the vaccine response, and how immune changes triggered by COVID (either via infection with SARS-CoV-2 or associated stressors) can influence the brain with effects on cognition, emotion, and behavior. We consider negative psychological states, which have been the primary focus of psychological research in the context of COVID-19 (and psychoneuroimmunology more generally). We also consider positive psychological states, including positive affect and eudaimonic well-being, given increasing evidence for their importance as modulators of immunity. We finish with a discussion of interventions that may be effective in improving immune function, the neuro-immune axis, and ultimately, mental and physical health.

Electroacupuncture Ameliorates Intestinal Barrier Destruction in Mice With Bile Duct Ligation-Induced Liver Injury by Activating the Cholinergic Anti-Inflammatory Pathway.

OBJECTIVES: Electroacupuncture (EA) at Zusanli (ST36) can attenuate inflammation in different rodent models. However, the therapeutic mechanisms underlying its action in inhibiting intestinal barrier destruction and liver injury in cholestasis mice have not been clarified. This study aimed at investigating whether EA at ST36 could activate the cholinergic anti-inflammatory pathway to inhibit intestinal barrier destruction and liver injury in cholestasis mice. MATERIALS AND METHODS: Male Hmox1floxp/floxp C57BL/6 mice were randomized and subjected to a sham or bile duct ligation (BDL) surgery. The BDL mice were randomized and treated with, or without (BDL group), sham EA at ST36 (BDL+sham-ST36) or EA at ST36 (BDL+ST36), or received α-bungarotoxin (α-BGT), a specific inhibitor of nicotinic acetylcholine receptor α7 subunit (α7nAChR), before stimulation (BDL+ST36+α-BGT). These mice, together with a group of intestine-specific heme oxygenase-1 (HO-1) knockout (KO) Villin-Cre-HO-1-/- mice, were monitored for their body weights before and 14 days after BDL. The levels of plasma cytokines and liver injury-related alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured by enzyme-linked immunoassay, and pathological changes in the intestinal mucosa and liver fibrosis as well as intestinal barrier permeability in individual mice were examined by histology and immunohistochemistry. The levels of α7nAChR, HO-1, ZO-1, Occludin, Claudin-1, and NF-κBp65 expression and NF-κBp65 phosphorylation in intestinal tissues were quantified. RESULTS: Compared with the sham group, BDL significantly increased the levels of plasma interleukin (IL)-1ß, IL-6, IL-10, tumor necrosis factor α, ALT, and AST and caused intestinal mucosal damages, high permeability, and liver fibrosis in mice, which were remarkably mitigated, except for further increased levels of plasma IL-10 in the BDL+ST36 group of mice. Similarly, EA at ST36 significantly up-regulated α7nAChR and HO-1 expression; mitigated the BDL-decreased ZO-1, Occludin, and Claudin-1 expression; and attenuated the BDL-increased NF-κBp65 phosphorylation in intestinal tissues of mice. The therapeutic effects of EA at ST36 were significantly abrogated by pretreatment with α-BGT or HO-1 KO. CONCLUSION: EA at ST36 inhibits the BDL-induced intestinal mucosal damage and liver fibrosis by activating the HO-1 cholinergic anti-inflammatory pathway in intestinal tissues of mice.

NeuroImmunoEndocrinology: A brief historic narrative.

Although no precise moment or unique event marks its birth, neuroimmunoendocrinology arguably shares a great deal of history with other medical and biologic disciplines. It originated from empirical observations and suppositions that failed to prevail upon the existing axioms. Despite the widespread resistance to embracing novel ideas, the seeming defeats inspired visionary researchers. Those pioneers managed to systematize the emerging knowledge and were able to contribute to science with real foundations. In consequence, new concepts and ideas arose in physiology, anatomy, endocrinology and early immunology. Together, they gave rise to a budding approach on the integration between the nervous, immune and endocrine systems. Then, neuroimmunoendocrinology emerged as a discipline integrating an intricate system with multidirectional functions and interactions that allow for responding to internal and external threats. Such response is mediated by cytokines, hormones and neurotransmitters, involved in different physiologic mechanisms of the organism homeostasis. Neuroimmunoendocrinology is no longer an area of scientific skepticism; on the contrary, it has cemented its position as a biomedical discipline worldwide for the past 70 years. Now, it offers a better understanding of pathologic processes.

Berberine Ameliorates Glucose Metabolism in Diabetic Rats through the alpha7 Nicotinic Acetylcholine Receptor-Related Cholinergic Anti-Inflammatory Pathway.

Berberine is an isoquinoline derivative alkaloid extracted from Chinese herbs. Recent studies have demonstrated the therapeutic effect of berberine on glucose metabolic disorders. However, its specific mechanism is still unclear. Our study aimed to research the glucose-lowering effect of berberine in diabetic rats and to reveal the possible role of the cholinergic anti-inflammatory pathway. Diabetic rats induced by administration of a high-calorie diet and streptozocin tail vein injection were assessed by the oral glucose tolerance test. Then, the diabetic rats were divided into two groups, those with or without the alpha7 nicotinic acetylcholine receptor gene downregulated, respectively, followed by treatment including berberine for 6 weeks. Results of this study show that the administration of berberine downregulated levels of fasting blood glucose and fasting insulin, and ameliorated insulin resistance in diabetic rats. Treatment with berberine inhibited acetylcholinesterase activity, and upregulated acetylcholine levels in the serum and alpha7 nicotinic acetylcholine receptor gene expression in the liver tissue. Meanwhile, berberine reversed elevated expression of cytokines interleukin-1ß and TNF-α in the serum and downregulated nuclear factor κB expression. However, berberine administration showed no glucose-lowering or anti-inflammatory effect in diabetic rats in which alpha7 nicotinic acetylcholine receptor gene expression was downregulated, and acetylcholinesterase activity was also significantly inhibited. In conclusion, berberine may ameliorate glucose metabolism by activating the alpha7 nicotinic acetylcholine receptor-mediated cholinergic anti-inflammatory pathway.

Thymoquinone Lipid Nanoparticles Cut the Gordian Knots of Depression via Neuroprotective BDNF and Downregulation of Neuro-inflammatory NF-κB, IL-6, and TNF-α in LPS Treated Rats.

BACKGROUND: In over 300 million clinical cases, antidepressant drugs seem to provide only symptomatic relief and limited protection in life-threatening depressive events. OBJECTIVES: To compare neuronal-signaling mechanism and neuroprotective roles of Thymoquinone (TQ) suspension and its SLN (TQSLN) against standard antidepressant drug fluoxetine. METHODS: This research investigated in-silico docking at NF-KB p50 active site, CLSM based gut permeation, screening of antidepressant activities and neurosignaling pathways involved. RESULTS: As compared to fluoxetine, TQ reporteda significantly better docking score (-6.83 v/s -6.22) and a better lower free binding energy of (-34.715 Kcal/mol v/s -28.537 Kcal/mol). While poorly oral bioavailable and P-gp substrate TQ reported approximately 250% higher gut permeation if delivered as TQSLN formulation. In locomotor studies, as compared to TQS, TQSLN favored more prominent (p< 0.010) elevation in average time, horizontalactivity, average-velocity, and total-movement with reduced rest time LPS treated groups. However, in the tail suspension test, TQSLN significantly reduced immobility time (p<0.010). Similarly, In the modified force swimming test, TQSLN also significantly reduced immobility time (p<0.010), but swimming time (p<0.010) and climbing time (p<0.050) were significantly elevated. Subsequently, TQSLN reported significantly elevated neuroprotective BDNF (p<0.010) as well as hippocampal 5HT/TRP; accompanied with reduced levels of hippocampal inflammatory markers TNF-α (p<0.001) and IL-6 (p<0.010) as well as lower kynurenine and tryptophan ratio (KYN/TRP). Similarly, the hippocampal CA1 region further revealed TQSL more predominantly attenuated NF-kB nuclear translocation in the brain. CONCLUSION: Despite the poor bioavailability of TQ, TQSLN potentially attenuates neuroinflammatory transmitters and favors BDNF to modulate depressive neurobehavioral states.

Neuroimmune and Mu-Opioid Receptor Alterations in the Mesocorticolimbic System in a Sex-Dependent Inflammatory Pain-Induced Alcohol Relapse-Like Rat Model.

Evidence concerning the role of alcohol-induced neuroinflammation in alcohol intake and relapse has increased in the last few years. It is also proven that mu-opioid receptors (MORs) mediate the reinforcing properties of alcohol and, interestingly, previous research suggests that neuroinflammation and MORs could be related. Our objective is to study neuroinflammatory states and microglial activation, together with adaptations on MOR expression in the mesocorticolimbic system (MCLS) during the abstinence and relapse phases. To do so, we have used a sex-dependent rat model of complete Freund's adjuvant (CFA)-induced alcohol deprivation effect (ADE). Firstly, our results confirm that only CFA-treated female rats, the only experimental group that showed relapse-like behavior, exhibited specific alterations in the expression of phosphorylated NFκB, iNOS, and COX2 in the PFC and VTA. More interestingly, the analysis of the IBA1 expression revealed a decrease of the microglial activation in PFC during abstinence and an increase of its expression in the relapse phase, together with an augmentation of this activation in the NAc in both phases that only occur in female CFA-treated rats. Additionally, the expression of IL1ß also evidenced these dynamic changes through these two phases following similar expression patterns in both areas. Furthermore, the expression of the cytokine IL10 showed a different profile than that of IL1ß, indicating anti-inflammatory processes occurring only during abstinence in the PFC of CFA-female rats but neither during the reintroduction phase in PFC nor in the NAc. These data indicate a downregulation of microglial activation and pro-inflammatory processes during abstinence in the PFC, whereas an upregulation can be observed in the NAc during abstinence that is maintained during the reintroduction phase only in CFA-female rats. Secondly, our data reveal a correlation between the alterations observed in IL1ß, IBA1 levels, and MOR levels in the PFC and NAc of CFA-treated female rats. Although premature, our data suggest that neuroinflammatory processes, together with neural adaptations involving MOR, might play an important role in alcohol relapse in female rats, so further investigations are warranted.

PAC1 Receptor Mediates Electroacupuncture-Induced Neuro and Immune Protection During Cisplatin Chemotherapy.

Platinum-based chemotherapy is an effective treatment used in multiple tumor treatments, but produces severe side effects including neurotoxicity, anemia, and immunosuppression, which limits its anti-tumor efficacy and increases the risk of infections. Electroacupuncture (EA) is often used to ameliorate these side effects, but its mechanism is unknown. Here, we report that EA on ST36 and SP6 prevents cisplatin-induced neurotoxicity and immunosuppression. EA induces neuroprotection, prevents pain-related neurotoxicity, preserves bone marrow (BM) hematopoiesis, and peripheral levels of leukocytes. EA activates sympathetic BM terminals to release pituitary adenylate cyclase activating polypeptide (PACAP). PACAP-receptor PAC1-antagonists abrogate the effects of EA, whereas PAC1-agonists mimic EA, prevent neurotoxicity, immunosuppression, and preserve BM hematopoiesis during cisplatin chemotherapy. Our results indicate that PAC1-agonists may provide therapeutic advantages during chemotherapy to treat patients with advanced neurotoxicity or neuropathies limiting EA efficacy.

Dopaminergic Receptor Targeting in Multiple Sclerosis: Is There Therapeutic Potential?

Dopamine is a neurotransmitter that mediates neuropsychological functions of the central nervous system (CNS). Recent studies have shown the modulatory effect of dopamine on the cells of innate and adaptive immune systems, including Th17 cells, which play a critical role in inflammatory diseases of the CNS. This article reviews the literature data on the role of dopamine in the regulation of neuroinflammation in multiple sclerosis (MS). The influence of dopaminergic receptor targeting on experimental autoimmune encephalomyelitis (EAE) and MS pathogenesis, as well as the therapeutic potential of dopaminergic drugs as add-on pathogenetic therapy of MS, is discussed.

Splenic Nerve Neuromodulation Reduces Inflammation and Promotes Resolution in Chronically Implanted Pigs.

Neuromodulation of the immune system has been proposed as a novel therapeutic strategy for the treatment of inflammatory conditions. We recently demonstrated that stimulation of near-organ autonomic nerves to the spleen can be harnessed to modulate the inflammatory response in an anesthetized pig model. The development of neuromodulation therapy for the clinic requires chronic efficacy and safety testing in a large animal model. This manuscript describes the effects of longitudinal conscious splenic nerve neuromodulation in chronically-implanted pigs. Firstly, clinically-relevant stimulation parameters were refined to efficiently activate the splenic nerve while reducing changes in cardiovascular parameters. Subsequently, pigs were implanted with a circumferential cuff electrode around the splenic neurovascular bundle connected to an implantable pulse generator, using a minimally-invasive laparoscopic procedure. Tolerability of stimulation was demonstrated in freely-behaving pigs using the refined stimulation parameters. Longitudinal stimulation significantly reduced circulating tumor necrosis factor alpha levels induced by systemic endotoxemia. This effect was accompanied by reduced peripheral monocytopenia as well as a lower systemic accumulation of CD16+CD14high pro-inflammatory monocytes. Further, lipid mediator profiling analysis demonstrated an increased concentration of specialized pro-resolving mediators in peripheral plasma of stimulated animals, with a concomitant reduction of pro-inflammatory eicosanoids including prostaglandins. Terminal electrophysiological and physiological measurements and histopathological assessment demonstrated integrity of the splenic nerves up to 70 days post implantation. These chronic translational experiments demonstrate that daily splenic nerve neuromodulation, via implanted electronics and clinically-relevant stimulation parameters, is well tolerated and is able to prime the immune system toward a less inflammatory, pro-resolving phenotype.

Role of Purinergic Signaling in Acupuncture Therapeutics.

Acupuncture is a therapeutic treatment that is well recognized in many countries. However, the initiation mechanisms of acupuncture are not well understood. Purinergic signaling has been considered a key signaling pathway in acupuncture in recent years. Acupuncture-induced ATP is mainly produced by mast cells and fibroblasts, and ATP is gradually hydrolyzed into adenosine. ATP and adenosine further participate in the process of acupuncture information transmission to the nervous and immune systems through specific purine receptors. Acupuncture initiates analgesia via the down-regulation of the expression of P2 receptors or up-regulation of the expression of adenosine A1 receptors on nerve fibers. ATP also promotes the proliferation of immune cells through P2 receptors and A3 receptors, causing inflammation. In contrast, adenosine activates A2 receptors, promotes the production and infiltration of immunosuppressive cells, and causes an anti-inflammatory response. In summary, we described the role of purinergic signaling as a general signaling pathway in the initiation of acupuncture and the influence of purinergic signaling on the neuroimmune network to lay the foundation for future systematic research on the mechanisms of acupuncture therapeutics.

Terpenoids from Abies holophylla Attenuate LPS-Induced Neuroinflammation in Microglial Cells by Suppressing the JNK-Related Signaling Pathway.

We have previously reported that phytochemicals from Abies holophylla exhibit anti-inflammatory and neuroprotective effects by decreasing nitrite production and increasing nerve growth factor production. However, the exact mechanism underscoring these effects has not been revealed. In the present study, we aimed to explore the underlying anti-inflammatory mechanisms of A. holophylla and its phytochemicals. We studied various solvent fractions of A. holophylla and found the chloroform and hexane sub-fractions showed the most significant anti-neuroinflammatory effects in lipopolysaccharide (LPS)-activated murine microglia. Concomitantly, the terpenoids isolated from chloroform and hexane fractions showed similar anti-neuroinflammatory effects with significant inhibition of NO and reactive oxygen species production, and decreased protein expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase. Interestingly, these terpenoids inhibited the phosphorylation of c-Jun N-terminal kinase (JNK), which further inhibited the production of pro-inflammatory mediators, including prostaglandin E2, tumor necrosis factor, and interleukins (IL-6 and IL-1ß), with a potency greater than that of the well-known iNOS inhibitor NG-mono-methyl-L-arginine (L-NMMA). These results suggest that the chloroform- and hexane-soluble fraction mediated the mitogen-activated protein kinase (MAPK) inhibition, in particular the JNK pathway, thereby lowering the inflammatory cascades in LPS-activated murine microglia. Thus, our study suggests that the chloroform and hexane fractions of A. holophylla and their terpenoids may be potential drug candidates for drug discovery against LPS-induced neuroinflammation and neuroinflammatory-related neurodegeneration.

Anti-Inflammatory Effects of Acupuncture at ST36 Point: A Literature Review in Animal Studies.

So far, a number of acupuncture studies have shown anti-inflammatory effects of acupuncture treatment, mostly known at specific point ST36. However, there is no literature that oversaw the inflammation-regulatory effects of acupuncture in each tissue. Therefore, we investigated how acupuncture at specific acupoint ST36 regulates inflammation and its underlying mechanisms. We searched literatures on PubMed until July 2021 using the keywords "animal, acupuncture, ST36, inflammation, immune," and 292 literatures were searched. We ultimately selected 69 studies to determine the anti-inflammatory actions of acupuncture at ST36 and classified the changes of inflammatory mediators according to target regions. Forty-three studies were included in body fluids, 27 studies in the digestive system, 17 studies in the nervous system, and 30 studies in other tissues or organs. In this review, we found that acupuncture at ST36 has clinical benefits in relieving inflammation through several mechanisms such as vagus nerve activation, toll-like receptor 4 (TLR4)/NF-κB signaling, macrophage polarization, mitogen-activated protein kinase (MAPK) signaling pathway, and cholinergic anti-inflammatory pathway. We expect that these data will inform further studies related to ST36 acupuncture on inflammation.

Splenic artery loops: Potential splenic plexus stimulation sites for neuroimmunomodulatory-based anti-inflammatory therapy?

INTRODUCTION: The splenic plexus might represent a novel neuroimmunomodulatory therapeutic target as electrical stimulation of this tissue has been shown to have beneficial anti-inflammatory effects. Tortuous splenic artery segments (splenic artery loops), including their surrounding nerve plexus, have been evaluated as potential stimulation sites in humans. At present, however, our understanding of these loops and their surrounding nerve plexus is incomplete. This study aims to characterize the dimensions of these loops and their surrounding nerve tissue. MATERIALS AND METHODS: Six formaldehyde fixed human cadavers were dissected and qualitative and quantitative macro- and microscopic data on splenic artery loops and their surrounding nerve plexus were collected. RESULTS: One or multiple loops were observed in 83% of the studied specimens. These loops, including their surrounding nerve plexus could be easily dissected free circumferentially thereby providing sufficient space for further surgical intervention. The splenic plexus surrounding the loops contained a significant amount of nerves that contained predominantly sympathetic fibers. CONCLUSION: The results of this study support that splenic artery loops could represent suitable electrical splenic plexus stimulation sites in humans. Dimensions with respect to loop height and width, provide sufficient space for introduction of surgical instruments and electrode implantation, and, the dissected neurovascular bundles contain a substantial amount of sympathetic nerve tissue. This knowledge may contribute to further development of surgical techniques and neuroelectrode interface design.

Psychoneuroimmunology and oncology nursing: a theoretical study / Psiconeuroinmunología y la enfermería oncológica: estudio teórico / Psiconeuroimunologia e a enfermagem oncológica: estudo teórico

ABSTRACT Objective: To discuss the evolution of research in cancer psychoneuroimmunology, the advances in the management of neuropsychological symptom clusters and their interface with mid-range theories, and practical applications in Nursing. Method: This is a theoretical-reflective study anchored in recent literature, as well as in the critical analysis of the authors. Results: This is a promising field of investigation, which emphasizes the complexity and interaction of symptoms, the interrelationships among them, the factors influencing them, and their consequences. Subsidized by mid-range theories in Nursing, such as the Theory of Unpleasant Symptoms and the Theory of Symptom Management, analyses of these interrelationships support Oncology Nursing diagnoses and interventions. Conclusion: An innovative approach is proposed to qualify Oncology Nursing care based on the integration of recent advances in cancer psychoneuroimmunology, Nursing mid-range theories, and practical tools such as health coaching. The approach proposed may strengthen clinical nursing practice in the management of neuropsychological symptom clusters in oncology and shall be integrated into decision-making during cancer treatment, favoring person-centered care.

RESUMEN Objetivo: Discutir la evolución de las investigaciones en psiconeuroinmunología del cáncer, los avances en el manejo de los clusters de síntomas neuropsicológicos y su interface con teorías de rango medio y aplicaciones prácticas por la Enfermería. Método: Estudio teórico-reflexivo ancorado en literatura reciente, así como en el análisis crítico de los autores. Resultados: Este es un campo promisor de investigación, que tiene énfasis en la complejidad y la interacción de los síntomas, las interrelaciones entre ellos, los factores que los influyen y sus consecuencias. Subsidiadas por teorías de rango medio en Enfermería, como la Teoría de los Síntomas Desagradables y la Teoría del Manejo de Síntomas, análisis de estas interrelaciones corroboran los diagnósticos y las intervenciones de Enfermería en Oncología. Consideraciones Finales: Se ha propuesto un abordaje innovador para calificar el cuidado de Enfermería Oncológica a partir de la integración de avances recientes en psiconeuroinmunología del cáncer, teorías de rango medio de Enfermería y herramientas prácticas como coaching de salud. El abordaje propuesto puede fortalecer la práctica clínica de Enfermería en la gestión de los clusters de síntomas neuropsicológicos en oncología y debe ser integrado en las acciones y decisiones durante el tratamiento oncológico que favorezcan el cuidado centrado en las personas.

RESUMO Objetivo: Discutir a evolução das pesquisas em psiconeuroimunologia do câncer, os avanços no manejo dos clusters de sintomas neuropsicológicos e sua interface com teorias de médio alcance e aplicações práticas pela Enfermagem. Método: Estudo teórico-reflexivo ancorado em literatura recente, bem como na análise crítica dos autores. Resultados: Este é um campo promissor de investigação, que enfatiza a complexidade e a interação dos sintomas, as inter-relações entre os mesmos, os fatores que os influenciam e suas consequências. Subsidiadas por teorias de médio alcance em Enfermagem, como a Teoria dos Sintomas Desagradáveis e a Teoria de Gerenciamento de Sintomas, análises destas inter-relações corroboram os diagnósticos e as intervenções de Enfermagem em Oncologia. Conclusão: Propõe-se uma abordagem inovadora para qualificar o cuidado de Enfermagem Oncológica a partir da integração de avanços recentes em psiconeuroimunologia do câncer, teorias de médio alcance de Enfermagem, e ferramentas práticas como coaching de saúde. A abordagem proposta pode fortalecer a prática clínica da Enfermagem no manejo dos clusters de sintomas neuropsicológicos em oncologia e deve ser integrada na tomada de decisões durante o tratamento oncológico, favorecendo o cuidado centrado na pessoa.