Dexmedetomidine attenuates inflammation and pancreatic injury in a rat model of experimental severe acute pancreatitis via cholinergic anti-inflammatory pathway

Background:Excessive inflammatory responses play a critical role in the development of severe acute pancreatitis(SAP),and controlling such inflammation is vital for managing this often fatal disease.Dexmedetomidine has been reported to possess protective properties in inflammatory diseases.Therefore,this study aimed to investigate whether dexmedetomidine pre-treatment exerts an anti-inflammatory effect in rats with SAP induced by sodium taurocholate,and if so,to determine the potential mechanism.Methods:SAP was induced with sodium taurocholate.Rats received an intraperitoneal injection of dexmedetomidine 30 min before sodium taurocholate administration.α-bungarotoxin,a selective alpha-7 nicotinic acetylcholine receptor(α7nAchR)antagonist,was injected intra-peritoneally 30 min before dexmedetomidine administration.The role of the vagus nerve was evaluated by performing unilateral cervical vagotomy before the administration of dexmedetomidine.Efferent discharge of the vagal nerve was recorded by the BL-420F Data Acquisition&Analysis System.Six hours after onset,serum pro-inflammatory cytokine(tumor necrosis factorα[TNF-α]and interleukin 6[IL-6])levels and amylase levels were determined using an enzyme-linked immunosorbent assay and an automated biochemical analyzer,respectively.Histopathological changes in the pancreas were observed after hematoxylin and eosin staining and scored according to Schmidt criteria.Results:Pre-treatment with dexmedetomidine significantly decreased serum levels of TNF-α,IL-6,and amylase,strongly alleviating pathological pancreatic injury in the rat model of SAP(TNF-α:174.2±30.2 vs.256.1±42.4 pg/ml;IL-6:293.3±46.8 vs.421.7±48.3 pg/ml;amylase:2102.3±165.3 vs.3186.4±245.2 U/L).However,the anti-inflammatory and pancreatic protective effects were abolished after vagotomy or pre-administration ofα-bungarotoxin.Dexmedetomidine also significantly increased the discharge frequency and amplitude of the cervical vagus nerve in the SAP rat model(discharge frequency:456.8±50.3 vs.332.4±25.1 Hz;discharge amplitude:33.4±5.3 vs.20.5±2.9μV).Conclusions:Dexmedetomidine administration attenuated the systemic inflammatory response and local pancreatic injury caused by SAP in rats through the cholinergic anti-inflammatory pathway involving vagus-andα7nAChR-dependent mechanisms.

Impairment of the nerve growth factor pathway driving amyloid accumulation in cholinergic neurons the incipit of the Alzheimer's disease story?

The current idea behind brain pathology is that disease is initiated by mild disturbances of common physiological processes. Overtime, the disruption of the neuronal homeostasis will determine irreversible degeneration and neuronal apoptosis. This could be also true in the case of nerve growth factor(NGF) alterations in sporadic Alzheimer's disease(AD), an age-related pathology characterized by cholinergic loss, amyloid plaques and neurofibrillary tangles. In fact, the pathway activated by NGF, a key neurotrophin for the metabolism of basal forebrain cholinergic neurons(BFCN), is one of the first homeostatic systems affected in prodromal AD. NGF signaling dysfunctions have been thought for decades to occur in AD late stages, as a mere consequence of amyloid-driven disruption of the retrograde axonal transport of neurotrophins to BFCN. Nowadays, a wealth of knowledge is potentially opening a new scenario: NGF signaling impairment occurs at the onset of AD and correlates better than amyloid load with cognitive decline. The recent acceleration in the characterization of anatomical, functional and molecular profiles of early AD is aimed at maximizing the efficacy of existing treatments and setting novel therapies. Accordingly, the elucidation of the molecular events underlying APP metabolism regulation by the NGF pathway in the septo-hippocampal system is crucial for the identification of new target molecules to slow and eventually halt mild cognitive impairment(MCI) and its progression toward AD.

MicroRNA-124 mediates the cholinergic anti-inflammatory action through inhibiting the production of pro-inflammatory cytokines

The vagus nerve can control inflammatory response through a ＇ cholinergic anti-inflammatory pathway＇, which is mediated by the α7-nicotinic acetylcholine receptor （α7nAChR） on macrophages. However, the intracel- lular mechanisms that link α7nAChR activation and pro-inflammatory cytokine production remain not well under- stood. In this study, we found that miR-124 is upregulated by cholinergic agonists in LPS-exposed cells and mice. Utilizing miR-124 mimic and siRNA knockdown, we demonstrated that miR-124 is a critical mediator for the cho- linergic anti-inflammatory action. Furthermore, our data indicated that miR-124 modulates LPS-induced cytokine production by targeting signal transducer and activator of transcription 3 （STAT3） to decrease IL-6 production and TNF-α converting enzyme （TACE） to reduce TNF-ot release. These results also indicate that miR-124 is a potential therapeutic target for the treatment of inflammatory diseases.

Selenium-enriched oolong tea(Camellia sinensis)extract exerts anti-inflammatory potential via targeting NF-κB and MAPK pathways in macrophages

Both tea polyphenols and selenium(Se)have been suggested to exert the health benefits via the regulatory capacities of chronic inflammation,which make Se-enriched oolong tea a promising beverage as an anti-inflammatory diet.The aim of this study is to investigate the anti-inflammatory effects of Se-enriched oolong tea extract(Se-TE)and underlying mechanism in lipopolysaccharide(LPS)-induced RAW264.7 cells.Se-TE treatments(50 and 150μg/m L)significantly suppressed the over-production of nitric oxide(NO)and prostaglandin E2(PGE2)in LPS-stimulated macrophages via downregulating the expression of nitric oxide synthase(i NOS)and cyclooxygenase-2(COX-2).Moreover,Se-TEs also effectively inhibited the productions of inflammatory cytokines,such as tumor necrosis factor-α(TNF-α),interleukin-6(IL-6),and interleukin-1β(IL-1β).Furthermore,Se-TE could block mitogen-activated protein kinase(MAPK)and nuclear factor-kappa B(NF-κB)signaling pathways through the inhibition of the phosphorylation of key proteins(IκB-α,p65,p38,ERK,and JNK)and the translocation of the p65 subunit into the nucleus.Collectively,our results indicated that Se-TE may have the potential to be used as a novel food ingredient for the development of various anti-inflammatory foods and the treatment and prevention of chronic inflammation-related diseases.

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),vagaladrenal 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.

Effect of the Monocyte Locomotion Inhibitory Factor (MLIF) a Natural Anti-Inflammatory Produced by E. Histolytica on Apoptosis in Human CD4 + T Lymphocytes

Apoptosis prevents the extravasation of intracellular material and the subsequent inflammatory response. Currently, it is not known whether Monocyte Locomotion Inhibitor Factor (MLIF), an anti-inflammatory pentapeptide, induces programmed cell death. We evaluated the effect of MLIF on extrinsic and intrinsic apoptosis pathways human CD4 + T lymphocytes. Cells were cultured for 24 h in RPMI-1640 medium alone (control) or in RPMI medium containing MLIF alone, PMA alone, PMA + MLIF or actinomycin D. Annexin V/propidium iodide-stained cells in early apoptosis showed that cells treated with MLIF or PMA + MLIF were not significantly different from control cells in medium;in contrast, cells treated with PMA or PMA + MLIF demonstrated significant differences from the control in delayed apoptosis. Cytochrome c and caspase 3 levels in cells treated with MLIF showed no significant differences from control cells, however, compared to the control, cells treated with PMA and PMA + MLIF exhibited a significant increase in cytochrome c and caspase 3 levels, which demonstrates that this weak induction of cell death is regulated by the intrinsic pathway of apoptosis. The Fas receptor was not detected in cell culture with any of the treatments employed, suggesting that the extrinsic pathway of apoptosis is not involved. The MLIF per se does not induce apoptosis in human CD4 + T lymphocytes;there may be an additional effect of PMA + MLIF producing the low levels of cell death recorded in the late apoptosis phase. MLIF acts as a natural, biological anti-inflammatory compound produced in axenic cultures of E. histolytica that does not cause apoptosis or elicit an immune response due to its small size, which could make it a strong candidate for future clinical applications.

Comparative study of anti-inflammatory effects of different processed products through the COX-2/PGE2 signaling pathway: based on network pharmacology and molecular docking

Background:Radix Aconiti Lateralis Preparata(Fu-zi)is a traditional Chinese medicinal herb,which has been widely used in the clinic and has potent anti-inflammatory activities.we aimed to explore the mechanisms of extract containing alkaloids from different Fu-zi Processed Products(FPP)in treating inflammation,especially rheumatoid arthritis(RA).Methods:Firstly,using network pharmacology technology,the ingredients,and targets of Fu-zi were obtained by searching and screening,the targets involving RA were acquired,the intersection targets were constructed a"component-target-pathway"network.A comprehensive investigation was conducted on the anti-rheumatoid arthritis mechanisms of 5 FPPs in lipopolysaccharide(LPS)induced RAW264.7 cells,which serve as a model for RA.The production of NO and inflammatory cytokines were measured by ELISA kit.Quantitative Real-time PCR(qRT-PCR)was utilized to measure the mRNA levels.COX-2/PGE2 signaling pathway-associated proteins were determined by western blot.Results:According to a network pharmacological study,16 chemical components and 43 common targets were found in Fu-zi and 6 key targets including PTGS2 were closely related to the mechanism of Fu-zi in treating RA.The in vitro study revealed that the levels of NO,TNF-α,and IL-1βwere substantially decreased by the 5 FPPs.The 5 FPPs significantly suppressed the expression of proteins COX-2,iNOS,and NF-κB,with particularly notable effects observed for PFZ and XFZ.Conclusion:Altogether,these results demonstrated that the 5 PPS containing alkaloids have a good anti-RA-related inflammatory effect,and the mechanism may be related to COX-2/PGE2 signaling pathway,particularly,Fu-zi prepared utilizing a traditional Chinese technique.

The role of microglia in depression

According to studies,neuroinflammation is increasingly being linked to the development of major depressive disorder(MDD).In response to inflammatory stimuli,brain microglia,which are immune cells,can change into reactive states.Because of this,microglia play an essentiall role in the early stages of neuroinflammation.Experiments have shown that microglia are able to detect infected or damaged cells,which then activates a cytotoxic response that further exacerbates the harm to brain cells.It has been proven that microglia are quite good at recognizing infections and damaged cells.Microglia,on the other hand,have been found to respond in a number of ways to injury and may even help regenerate damaged tissues.Chronic activation of microglia has been observed in persons with MDD.Deficits in neuroplasticity have been linked to depression,and recent studies show that this may be related to changes in microglia shape and function brought on by either excessive inflammatory activity or the natural aging process.Changing the phenotype of microglia by regulation of inflammatory pathways may be necessary for harnessing neuroinflammation in MDD.Recent research has linked several microglial phenotypes to individual metabolic pathways,showing that energy metabolism plays a pivotal role in coordinating microglial activity.In this study,we investigate whether or not traditional pro-inflammatory,anti-inflammatory,and metabolic pathways in microglia can be used as novel therapeutic routes for regulating neuroinflammation in brain diseases.The focus of this essay is on MDD,although we will also discuss related mental health issues.

TaVNS reduces inflammatory responses in a L-NAME-induced rat model of pre-eclampsia

Pre-eclampsia is characterized by an excessive maternal inflammatory response.The cholinergic antiinflammatory pathway(CAP)has been shown as the efferent arm of a vagal reflex with the potential to limit inflammatory responses.Therefore,in this study,the CAP regulation through the nervous vagal stimulation(VNS)reduced the severity of NG-nitro-L-arginine methyl ester(L-NAME)-induced pre-eclampsia was determined in a rat model.Rats were given 125 mg/kg/day of L-NAME via subcutaneous injection on gestational day(GD)10–16.In addition,the rats were treated by active or sham electrical stimulation once a day during GD 13–19.Systolic blood pressure(SBP),urinary albumin,and pregnancy outcomes were documented for each rat.The average fetal weights and crown-rump length(CRL)as well as the placental weights of rats in both control and experimental groups were recorded onthe 13th day,16th day and 20th day of gestation.Subsequently,placentas were collected from the rats on GD20 to measure the level of cytokines.In addition,qRT-PCR and Western blot analysis were used to detect the mRNA and protein expression ofα7 nicotinic acetylcholine receptor(α7nAChR)and nuclear factor-κB(NF-κB),respectively.Immunohistochemistry assays were also carried out to determine the location and level ofα7nAChR and NF-κB in placentas.CAP regulation through the transcutaneous auricular nerve stimulation alleviated the clinical symptoms in the rats after L-NAME induction,including hypertension,proteinuria,fetal growth retardation and fetal death.In addition,TaVNS also increasedα7nAChR expression,reduced NF-κB p65 expression,and reversed LNAME-induced proinflammatory cytokines in the placenta tissues,including tumor necrosis factor-alpha(TNF-α),high mobility group box 1(HMGB-1)and interleukin-6(IL-6).The findings of this study showed that TaVNS might be used as a promising tool to attenuate pre-eclampsia-like symptoms.In addition,the protective effect of TaVNS was associated with the improvement ofα7nAChR expression and the inhibition of inflammatory reactions at the maternal-fetal interface through activating cholinergic anti-inflammation pathway.

Medicinal nicotine in COVID-19 acute respiratory distress syndrome,the new corticosteroid

The cholinergic anti-inflammatory pathway(CAP)refers to the anti-inflammatory effects mediated by the parasympathetic nervous system.Existence of this pathway was first demonstrated when acetylcholinesterase inhibitors showed benefits in animal models of sepsis.CAP functions via the vagus nerve.The systemic antiinflammatory effects of CAP converges on theα7 nicotinic acetylcholine receptor on splenic macrophages,leading to suppression of pro-inflammatory cytokines and simultaneous stimulation of anti-inflammatory cytokines,including interleukin 10.CAP offers a novel mechanism to mitigate inflammation.Electrical vagal nerve stimulation has shown benefits in patients suffering from rheumatoid arthritis.Direct agonists like nicotine and GTS-1 have also demonstrated antiinflammatory properties in models of sepsis and acute respiratory distress syndrome,as have acetylcholinesterase inhibitors like Galantamine and Physostigmine.Experience with coronavirus disease 2019(COVID-19)induced acute respiratory distress syndrome indicates that immunomodulators have a protective role in patient outcomes.Dexamethasone is the only medication currently in use that has shown to improve clinical outcomes.This is likely due to the suppression of what is referred to as a cytokine storm,which is implicated in the lethality of viral pneumonia.Nicotine transdermal patch activates CAP and harvests its anti-inflammatory potential by means of an easily administered depot delivery mechanism.It could prove to be a promising,safe and inexpensive additional tool in the currently limited armamentarium at our disposal for management of COVID-19 induced acute hypoxic respiratory failure.

Qingfei Xiaoyan Wan,a traditional Chinese medicine formula, ameliorates Pseudomonas aeruginosa–induced acute lung inflammation by regulation of PI3K/AKT and Ras/MAPK pathways

Gram-negative pathogen–induced nosocomial infections and resistance are a most serious menace to global public health. Qingfei Xiaoyan Wan(QF), a traditional Chinese medicine(TCM)formula, has been used clinically in China for the treatment of upper respiratory tract infections, acute or chronic bronchitis and pulmonary infection. In this study, the effects of QF on Pseudomonas aeruginosa–induced acute pneumonia in mice were evaluated. The mechanisms by which four typical antiinflammatory ingredients from QF, arctigenin(ATG), cholic acid(CLA), chlorogenic acid(CGA) and sinapic acid(SPA), regulate anti-inflammatory signaling pathways and related targets were investigated using molecular biology and molecular docking techniques. The results showed that pretreatment with QF significantly inhibits the release of cytokines(TNF-α and IL-6) and chemokines(IL-8 and RANTES),reduces leukocytes recruitment into inflamed tissues and ameliorates pulmonary edema and necrosis. In addition, ATG was identified as the primary anti-inflammatory agent with action on the PI3K/AKT and Ras/MAPK pathways. CLA and CGA enhanced the actions of ATG and exhibited synergistic NF-κB inactivation effects possibly via the Ras/MAPK signaling pathway. Moreover, CLA is speculated to target FGFR and MEK firstly. Overall, QF regulated the PI3K/AKT and Ras/MAPK pathways to inhibit pathogenic bacterial infections effectively.

New cyclopiane diterpenes with anti-inflammatory activity from the sea sediment-derived fungus Penicillium sp.TJ403-2

Three new rare cyclopiane diterpenes(1-3),together with thirteen known compounds(4-16),were isolated and identified from a sea sediment-derived fungus Penicillium sp.TJ403-2.The planar and relative structures of compounds 1-3 were elucidated by HRESIMS,one-and two-dimensional NMR analyses,and their absolute configurations were further established by X-ray crystallography experiment.Compounds 1-3 were evaluated for the anti-inflammatory activity against LPS-induced NO production,and compound 1 showed notable inhibitory potency with an IC50 value of2.19±0.25μmol/L,which was three fold lower than the positive control indomethacin(IC50=8.76±0.92μmol/L).Further Western blot and immunofluorescence experiments demonstrated its mechanism of action to be that 1 inhibited the NF-κB-activated pathway,highlighting it as a promising starting point for the development of new anti-inflammatory agents.

Inflammation-associated ectopic mineralization

Ectopic mineralization refers to the deposition of mineralized complexes in the extracellular matrix of soft tissues.Calcific aortic valve disease,vascular calcification,gallstones,kidney stones,and abnormal mineralization in arthritis are common examples of ectopic mineralization.They are debilitating diseases and exhibit excess mortality,disability,and morbidity,which impose on patients with limited social or financial resources.Recent recognition that inflammation plays an important role in ectopic mineralization has attracted the attention of scientists from different research fields.In the present review,we summarize the origin of inflammation in ectopic mineralization and different channels whereby inflammation drives the initiation and progression of ectopic mineralization.The current knowledge of inflammatory milieu in pathological mineralization is reviewed,including how immune cells,pro-inflammatory mediators,and osteogenic signaling pathways induce the osteogenic transition of connective tissue cells,providing nucleating sites and assembly of aberrant minerals.Advances in the understanding of the underlying mechanisms involved in inflammatory-mediated ectopic mineralization enable novel strategies to be developed that may lead to the resolution of these enervating conditions.

Interacting with α7 nAChR is a new mechanism for AChE to enhance the inflammatory response in macrophages

Acetylcholine(ACh)regulates inflammation viaα7 nicotinic acetylcholine receptor(α7 nAChR).Acetylcholinesterase(AChE),an enzyme hydrolyzing ACh,is expressed in immune cells suggesting non-classical function in inflammatory responses.Here,the expression of PRiMA-linked G4 AChE was identified on the surface of macrophages.In lipopolysaccharide-induced inflammatory processes,AChE was upregulated by the binding of NF-κB onto the ACHE promotor.Conversely,the overexpression of G4 AChE inhibited ACh-suppressed cytokine release and cell migration,which was in contrast to that of applied AChE inhibitors.AChEmt,a DNA construct without enzymatic activity,was adopted to identify the protein role of AChE in immune system.Overexpression of G4 AChEmt induced cell migration and inhibited ACh-suppressed cell migration.The co-localization ofα7 nAChR and AChE was found in macrophases,suggesting the potential interaction ofα7 nAChR and AChE.Besides,immunoprecipitation showed a close association ofα7 nAChR and AChE protein in cell membrane.Hence,the novel function of AChE in macrophage by interacting withα7 nAChR was determined.Together with hydrolysis of ACh,AChE plays a direct role in the regulation of inflammatory response.As such,AChE could serve as a novel target to treat age-related diseases by antiinflammatory responses.