Nε-carboxymethyl-lysine and inflammatory cytokines,markers and mediators of coronary artery disease progression in diabetes

This editorial refers to the article“Comparative analysis of Nε-carboxymethyllysine and inflammatory markers in diabetic and non-diabetic coronary artery disease patients”,published in the recent issue of the World Journal of Diabetes 2023 is based on glucose metabolism,advanced glycation end products(AGEs),inflammation and adiposity on diabetes and coronary artery disease(CAD).This study has included CAD patients who were stratified according to glycosylated hemoglobin higher than 6.5 and sex-matched.A higher prevalence of hypertension,dyslipidemia,and non-vegetarian diet were found in the diabetic group.These risk factors might influence body weight and adiposity and explain the increment of the left atrium.Although this data was not supported by the study.The diet can also explain the non-enzymatic reactions on lipids,proteins,or nucleic acids and consequently an increment of AGEs.These molecules can emit fluorescence.However,one of the non-fluorescent and most abundant AGEs is Nε-carboxymethyl-lysine(CML).Its association with coronary artery stenosis and severity in the diabetic group might suggest its role as a player in CAD progression.Thus,CML,after binding with its receptor(RAGE),can induce calcification cascade through reactive oxygen species and mitogen-activated protein kinase.Moreover,this interaction AGE-RAGE can cause activation of the transcription nuclear factor-kb and induce inflammatory cytokines.It might explain the relationship between CML and pro-inflammatory cytokines in diabetic and CAD patients.Although this is a population from one center,the determination of CML and inflammatory cytokines might improve the diagnosis of severe and progressive CAD.Future and comparative studies among glycosylated hemoglobin,CML,and other AGE levels according to diagnosis and prognosis value might modify the clinical practice.Although these molecules are irreversible,they can act through a specific receptor inducing a signal transduction that might be modulated by inhibitors,antibodies,or siRNA.Further mechanistic studies might improve the development of future preventive therapies for diabetic patients.

Predictive effect of lipopolysaccharide-stimulated inflammatory cytokines on symptoms of generalized anxiety disorder

BACKGROUND Generalized anxiety disorder(GAD)is a relatively common mental disorder.Recently,inflammation,an important factor for the development of depression,has attracted increasing attention.Several studies have shown that inflammatory cytokines can affect the pathophysiological processes of several nervous system diseases.We hypothesized that there is a correlation between the levels of lipopolysaccharide(LPS)-stimulated inflammatory cytokines and the clinical symptoms of GAD.AIM To investigate the predictive effect of LPS-stimulated inflammatory cytokines on symptoms of GAD.METHODS This was a cross-sectional study in which 89 patients with GAD diagnosed at The First Hospital of Hebei Medical University from January 2022 to December 2022 and 70 individuals without anxiety and depression(controls)during the same period were included.Fasting venous blood was collected from all the subjects in heparin tubes,and another 3 ml of blood was supplemented with LPS(10 ng/ml).The plasma levels of 12 cytokines[Interleukin(IL)-1β,IL-2,IL-4,IL-5,IL-6,IL-8,IL-10,tumor necrosis factor(TNF)-α,interferon(IFN)-γ,IL-17A,IL-12p70,and IFN-α]were detected.RESULTS Post-LPS stimulation,the levels of IL-1β,IL-6,IL-8,IL-10,and TNF-αin both the control and GAD groups were significantly elevated above those in the nonstimulated groups,with IL-6 and IL-8 showing marked increases.Increases in IL-8 and TNF-αwere statistically significant in the GAD group(P<0.05).IL-1β,IL-6,IL-8,IL-10,and TNF-αwere found to be significantly correlated with Hamilton Anxiety Rating Scale(HAMA)scores(P<0.05).A negative correlation was observed between IL-10 levels and HAMA scores.Further analysis revealed that TNF-αwas associated with mental anxiety,whereas IL-1β,IL-8,and IL-10 were associated with physical anxiety symptoms,with IL-10 showing a negative correlation with physical anxiety.IL-6 was associated with both mental and physical aspects of anxiety.CONCLUSION The physical symptoms of GAD are related to inflammatory factors.IL-1β,IL-8,IL-10,and TNF-a can be used as predictors of physical or mental anxiety in patients with GAD.

Lentivirus Transduced T Cell Lines Response to Pro-Inflammatory and Antiviral Cytokines in the Presence of HIV

Various studies have attempted to understand HIV infection under a diverse range of stimulants including cytokine stimulation. Pro-inflammatory cytokines, such as TNF-α, have been shown to reactivate HIV latency by inducing NF-κB mediated activation of the HIV LTR (long terminal repeats) that contain κB transcriptional binding sites. Interferon-alpha (IFN-α), an anti-viral cytokine, is not well studied as an inducer of HIV activation. However, previous work from our group has shown that HIV can block IFN-α signaling in CD4+ T cells presumably to allow for further viral replication. Initially using HEK 293T cells, we moved to CD4+ T cells lines to develop a system to determine how stimulation with different cytokines impacts signaling within T cell lines. We confirmed that in our system TNF-α triggers activation of NF-κB driven reporters but not in the presence of HIV. In addition, we show that the presence of HIV blocks IFN-α signaling. Taken together, our system demonstrates that HIV by TNF-α, will continue to block IFN-α signaling preventing it from impacting HIV activation. This system can now be used to screen for cytokine based and other molecule activators that may be influenced by the presence of HIV.

Association of Cytokines with Clinical Indicators in Patients with Drug-Induced Liver Injury

Objective To explore characteristics of clinical parameters and cytokines in patients with drug-induced liver injury(DILI)caused by different drugs and their correlation with clinical indicators.Method The study was conducted on patients who were up to Review of Uncertainties in Confidence Assessment for Medical Tests(RUCAM)scoring criteria and clinically diagnosed with DILI.Based on Chinese herbal medicine,cardiovascular drugs,non-steroidal anti-inflammatory drugs(NSAIDs),antiinfective drugs,and other drugs,patients were divided into five groups.Cytokines were measured by Luminex technology.Baseline characteristics of clinical biochemical indicators and cytokines in DILI patients and their correlation were analyzed.Results 73 patients were enrolled.Age among five groups was statistically different(P=0.032).Alanine aminotransferase(ALT)(P=0.033)and aspartate aminotransferase(AST)(P=0.007)in NSAIDs group were higher than those in chinese herbal medicine group.Interleukin-6(IL-6)and tumor necrosis factor alpha(TNF-α)in patients with Chinese herbal medicine(IL-6:P<0.001;TNF-α:P<0.001)and cardiovascular medicine(IL-6:P=0.020;TNF-α:P=0.001)were lower than those in NSAIDs group.There was a positive correlation between ALT(r=0.697,P=0.025),AST(r=0.721,P=0.019),and IL-6 in NSAIDs group.Conclusion Older age may be more prone to DILI.Patients with NSAIDs have more severe liver damage in early stages of DILI,TNF-αand IL-6 may partake the inflammatory process of DILI.

Differential expression of plasma cytokines in sepsis patients and their clinical implications

BACKGROUND Sepsis,which is characterized by acute systemic inflammation and is associated with high rates of morbidity and mortality,presents a significant challenge in health care.Some scholars have found that the sequential organ failure assessment(SOFA)and quick SOFA scores are not ideal for predicting severe sepsis and mortality.Microbial culture takes a long time(2-3 d)and provides no information for early diagnosis and treatment.Therefore,new diagnostic methods for sepsis need to be explored.AIM To assess cytokine levels in the plasma of sepsis patients and identify potential biomarkers for diagnosing sepsis.METHODS Ten sepsis patients admitted to the emergency department within 24 h of onset were enrolled as the observation group,whereas ten noninfected patients served as the control group.Of the 10 noninfected patients,9 hypertension combined with cerebral infarction,1 patients with vertiginous syndrome.Plasma Cytokines were measured using the Bio-Plex Pro^(TM)Human Chemokine Panel 40-plex.Differentially expressed cytokines in plasma of sepsis and nonsepsis patients were analyzed using Gene Ontology(GO)functional enrichment and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analyses.RESULTS Interleukin(IL)-16,granulocyte-macrophage granulocyte-macrophage colony-stimulating factor(GM-CSF),CX3CL1,CXCL9,CXCL16,CCL25,and CCL23 plasma levels were significantly increased in sepsis patients.GO analysis revealed that these cytokines were mainly associated with cellular structures such as intermediates,nuclear plaques,adhesion plaques,lateral plasma membranes,and cell matrix junctions.These genes were involved in various molecular functions,such as cytokine activity,receptor ligand activity,and signal receptor activator activity,contributing to various biological functions,such as leukocyte chemotaxis,migration,and chemotaxis.KEGG analysis indicated involvement in cytokine cytokine receptor interactions,chemokine signaling pathways,virus–protein interactions with cytokines and cytokine receptors,and the tumor necrosis factor signaling pathway.CONCLUSION Elevated serum levels of IL-16,GM-CSF,CX3CL1,CXCL9,CXCL16,CCL25,and CCL23 in sepsis patients suggest their potential as diagnostic biomarkers for sepsis.

DNA Damage-driven Inflammatory Cytokines:Reprogramming of Tumor Immune Microenvironment and Application of Oncotherapy

DNA damage occurs across tumorigenesis and tumor development.Tumor intrinsic DNA damage can not only increase the risk of mutations responsible for tumor generation but also initiate a cellular stress response to orchestrate the tumor immune microenvironment(TIME)and dominate tumor progression.Accumulating evidence documents that multiple signaling pathways,including cyclic GMP-AMP synthase-stimulator of interferon genes(cGAS-STING)and ataxia telangiectasia-mutated protein/ataxia telangiectasia and Rad3-related protein(ATM/ATR),are activated downstream of DNA damage and they are associated with the secretion of diverse cytokines.These cytokines possess multifaced functions in the anti-tumor immune response.Thus,it is necessary to deeply interpret the complex TIME reshaped by damaged DNA and tumor-derived cytokines,critical for the development of effective tumor therapies.This manuscript comprehensively reviews the relationship between the DNA damage response and related cytokines in tumors and depicts the dual immunoregulatory roles of these cytokines.We also summarize clinical trials targeting signaling pathways and cytokines associated with DNA damage and provide future perspectives on emerging technologies.

Indications of pro-inflammatory cytokines in laparoscopic and open liver resection for early-stage hepatocellular carcinoma

Background:Our clinical practice of laparoscopic liver resection(LLR)had achieved better short-term and long-term benefits for patients with hepatocellular carcinoma(HCC)over open liver resection(OLR),but the underlying mechanisms are not clear.This study was to find out whether systemic inflammation plays an important role.Methods:A total of 103 patients with early-stage HCC under liver resection were enrolled(LLR group,n=53;OLR group,n=50).The expression of 9 inflammatory cytokines in patients at preoperation,postoperative day 1(POD1)and POD7 was quantified by Luminex Multiplex assay.The relationships of the cytokines and the postoperative outcomes were compared between LLR and OLR.Results:Seven of the circulating cytokines were found to be significantly upregulated on POD1 after LLR or OLR compared to their preoperative levels.Compared to OLR,the POD1 levels of granulocytemacrophage colony-stimulating factor(GM-CSF),interleukin-6(IL-6),IL-8,and monocyte chemoattractant protein-1(MCP-1)in the LLR group were significantly lower.Higher POD1 levels of these cytokines were significantly correlated with longer operative time and higher volume of blood loss during operation.The levels of these cytokines were positively associated with postoperative liver injury,and the length of hospital stay.Importantly,a high level of IL-6 at POD1 was a risk factor for HCC recurrence and poor disease-free survival after liver resection.Conclusions:Significantly lower level of GM-CSF,IL-6,IL-8,and MCP-1 after liver resection represented a milder systemic inflammation which might be an important mechanism to offer better short-term and long-term outcomes in LLR over OLR.

Effects of Lycium barbarum polysaccharide on cytokines in adolescents with subthreshold depression:a randomized controlled study

Strong evidence has accumulated to show a correlation between depression symptoms and inflammatory responses.Moreover,anti-inflammatory treatment has shown partial effectiveness in alleviating depression symptoms.Lycium barbarum polysaccharide(LBP),derived from Goji berries,exhibits notable antioxidative and anti-inflammatory properties.In our recent double-blinded randomized placebo-controlled trial,we found that LBP significantly reduced depressive symptoms in adolescents with subthreshold depression.It is presumed that the antidepressant effect of LBP may be associated with its influence on inflammatory cytokines.In the double-blinded randomized controlled trial,we enrolled 29 adolescents with subthreshold depression and randomly divided them into an LBP group and a placebo group.In the LBP group,adolescents were given 300 mg/d LBP.A 6-week follow up was completed by 24 adolescents,comprising 14 adolescents from the LBP group(15.36±2.06 years,3 men and 11 women)and 10 adolescents from the placebo group(14.9±1.6 years,2 men and 8 women).Our results showed that after 6 weeks of treatment,the interleukin-17A level in the LBP group was lower than that in the placebo group.Network analysis showed that LBP reduced the correlations and connectivity between inflammatory factors,which were associated with the improvement in depressive symptoms.These findings suggest that 6-week administration of LBP suppresses the immune response by reducing interleukin-17A level,thereby exerting an antidepressant effect.

Expression and Clinical Significance of Various Cytokines in Otitis Media

The expression and clinical significance of relevant cytokines in otitis media (OM) are discussed, and the alterations to the pathological state of the otitis media mucosa are further understood through the study of cytokine transduction pathways. More and more studies have shown that relevant cell proliferation and inflammation progression pathways play a role in the development of otitis media, such as the Jun amino-terminal protein kinase (JNK) mitogen-activated protein kinase (MAPK) signaling pathway, the NF-κB signaling pathway, and the PI3K/AKT/PTEN pathway, which are involved in the proliferation of the middle ear mucosa during otitis media, which affects the mucosal cilia, motor function, Eustachian tube function, and the mucosal ciliary function. These studies provide new ideas for the treatment of otitis media and further explore the feasibility of immunotherapy in the future treatment of otitis media. In this paper, we present a review of the latest research progress on the expression of various cytokines in otitis media.

Cytokines,synaptic plasticity and network dynamics:a matter of balance

The modern view of the immune system as a sensitizing and modulating machinery of the central nervous system is now well recognized.However,the specific mechanisms underlying this fine crosstalk have yet to be fully disentangled.To control cognitive function and behavior,the two systems are engaged in a subtle interacting act.In this scenario,a dual action of pro-inflammatory cytokines in the modulation of brain network connections is emerging.Pro-inflammatory cytokines are indeed required to express physiological plasticity in the hippocampal network while being detrimental when over-expressed during uncontrolled inflammatory processes.In this dynamic equilibrium,synaptic functioning and the performance of neural networks are ensured by maintaining an appropriate balance between pro-and anti-inflammatory molecules in the central nervous system microenvironment.

Serum level changes of inflammatory cytokines in patients with moderate to severe acne vulgaris treated with dual-wavelength laser

Background:Acne vulgaris(AV)is a common inflammatory skin disease.Although various mechanisms have been indicated in the etiopathogenesis of AV,the exact pathophysiology remains unknown.Various lasers have been used to treat AV;however,the serum level changes of inflammatory cytokines after laser therapy have not been elucidated.We aimed to investigate the relationship between inflammatory changes and remission on the opposite side in patients with moderate to severe AV after treating half of the face with 595-and 1064-nm dualwavelength laser.Methods:In total,18 patients(9 male and 9 female)between 16 and 35 years of age with moderate to severe AV were evaluated in the study.Disease severity was classified according to the Pillsbury grading system of acne.Patients were randomized to receive a series of two treatment sessions at intervals of 2 weeks and followed up at 2 weeks after the final treatment.A 3 mL blood sample was drawn from every subject each time,and serum levels of inflammatory cytokines such as interleukin(IL)-6,IL-8,and IL-22 were determined using enzyme-linked immunosorbent assay at baseline and 2 weeks after each treatment.Improvement was determined by a blinded assessment of photographs taken before and after the final evaluation.Results:Inflammation was significantly reduced on both the treated and untreated sides,and symptoms of AV lesions were alleviated.All patients showed a significant increase in serum IL-22 levels after the first laser therapy,with no significant difference in serum IL-6 and IL-8 levels.After the second laser therapy,serum IL-6,IL-8,and IL-22 levels were significantly decreased.No significant side effects such as bruising,edema,hyperpigmentation,hypopigmentation,or scarring were reported.Conclusion:Half-face treatment with 595-and 1064-nm dual-wavelength laser for moderate and severe AV showed a significant effect of full-face remission,which was associated with a gradual decrease in IL-6,IL-8,and IL-22 levels after half-face topical treatment.This suggests that reducing inflammatory cytokine levels in the serum can relieve inflammation in non-therapeutic sites.This laser treatment is effective,economical,and painless.

Conbercept combined with laser photocoagulation in the treatment of diabetic macular edema and its influence on intraocular cytokines

BACKGROUND The prevalence of diabetes mellitus(DM)in China is high,and the base is broad.Diabetic retinopathy(DR)is a critical condition affecting the life and health of a nation and its economic development.DR is a common complication of DM.AIM To investigate the efficacy of laser photocoagulation combined with intravitreal injection of conbercept for treating macular edema.METHODS Overall,130 patients with diabetic macular edema(DME)hospitalized in The Third People’s Hospital of Changzhou from January 2019 to June 2022 were retrospectively included.According to the treatment plan,130 patients with DME were categorized into an observation and a control group,with 65 patients in each group.The control group received laser photocoagulation,and the observation group received laser photocoagulation with intravitreal injection of conbercept.Observe changes in vision,cytokines in the eye and so on.RESULTS The total efficacy rate in the observation group(93.85%)was higher than that in the control group(78.46%)(P<0.05).In both groups,the best corrected visual acuity correction effect improved after treatment,and the observation group was superior to the control group(P<0.05).Retinal thickness and central macular thickness improved after treatment,and the observation group was superior to the control group(P<0.05).The levels of vascular endothelial growth factor,interleukin-6,soluble intercellular adhesion molecule-1,and basic fibroblast growth factor in both groups improved after treatment,and the observation group was superior to the control group(P<0.05).CONCLUSION In patients with macular edema,combining laser photocoagulation and intravitreal injections of conbercept for DME is a more effective and safer strategy to improve vision,and lower intraocular cytokine levels.

Perspective on inflammatory cytokines in open spinal dysraphism

Myelomeningocele(MMC)is a severe form of spinal dysraphism.Due to the failure of neural tube closure during early embryonic development,the affected part of the spinal cord is left open like a book at the back of the affected child.This malformed part of the spinal cord is not covered by its protective mesodermal and ectodermal derived layers.Consequently,the exposed neural tissue(i.e.,the neural placode)is prone to injuryduring further intra-uterine development.

The secondary injury cascade after spinal cord injury:an analysis of local cytokine/chemokine regulation

After spinal cord injury,there is an extensive infiltration of immune cells,which exacerbates the injury and leads to further neural degeneration.Therefore,a major aim of current research involves targeting the immune response as a treatment for spinal cord injury.Although much research has been performed analyzing the complex inflammatory process following spinal cord injury,there remain major discrepancies within previous literature regarding the timeline of local cytokine regulation.The objectives of this study were to establish an overview of the timeline of cytokine regulation for 2 weeks after spinal cord injury,identify sexual dimorphisms in terms of cytokine levels,and determine local cytokines that significantly change based on the severity of spinal cord injury.Rats were inflicted with either a mild contusion,moderate contusion,severe contusion,or complete transection,7 mm of spinal cord centered on the injury was harvested at varying times post-injury,and tissue homogenates were analyzed with a Cytokine/Chemokine 27-Plex assay.Results demonstrated pro-inflammatory cytokines including tumor necrosis factorα,interleukin-1β,and interleukin-6 were all upregulated after spinal cord injury,but returned to uninjured levels within approximately 24 hours post-injury,while chemokines including monocyte chemoattractant protein-1 remained upregulated for days post-injury.In contrast,several anti-inflammatory cytokines and growth factors including interleukin-10 and vascular endothelial growth factor were downregulated by 7 days post-injury.After spinal cord injury,tissue inhibitor of metalloproteinase-1,which specifically affects astrocytes involved in glial scar development,increased more than all other cytokines tested,reaching 26.9-fold higher than uninjured rats.After a mild injury,11 cytokines demonstrated sexual dimorphisms;however,after a severe contusion only leptin levels were different between female and male rats.In conclusion,pro-inflammatory cytokines initiate the inflammatory process and return to baseline within hours post-injury,chemokines continue to recruit immune cells for days post-injury,while anti-inflammatory cytokines are downregulated by a week post-injury,and sexual dimorphisms observed after mild injury subsided with more severe injuries.Results from this work define critical chemokines that influence immune cell infiltration and important cytokines involved in glial scar development after spinal cord injury,which are essential for researchers developing treatments targeting secondary damage after spinal cord injury.

Future applications of exosomes delivering resolvins and cytokines in facilitating diabetic foot ulcer healing

Type 2 diabetes mellitus(T2DM)increases the risk of many lethal and debilitating conditions.Among them,foot ulceration due to neuropathy,vascular disease,or trauma affects the quality of life of millions in the United States and around the world.Physiological wound healing is stalled in the inflammatory phase by the chronicity of inflammation without proceeding to the resolution phase.Despite advanced treatment,diabetic foot ulcers(DFUs)are associated with a risk of amputation.Thus,there is a need for novel therapies to address chronic inflammation,decreased angiogenesis,and impaired granulation tissue formation contributing to the non-healing of DFUs.Studies have shown promising results with resolvins(Rv)and anti-inflammatory therapies that resolve inflammation and enhance tissue healing.But many of these studies have encountered difficulty in the delivery of Rv in terms of efficiency,tissue targetability,and immunogenicity.This review summarized the perspective of optimizing the therapeutic application of Rv and cytokines by pairing them with exosomes as a novel strategy for targeted tissue delivery to treat non-healing chronic DFUs.The articles discussing the T2DM disease state,current research on Rv for treating inflammation,the role of Rv in enhancing wound healing,and exosomes as a delivery vehicle were critically reviewed to find support for the proposition of using Rv and exosomes in combination for DFUs therapy.The literature reviewed suggests the beneficial role of Rv and exosomes and exosomes loaded with antiinflammatory agents as promising therapeutic agents in ulcer healing.

Cytokine release syndrome triggered by programmed death 1 blockade(sintilimab)therapy in a psoriasis patient:A case report

BACKGROUND In recent years,immune checkpoint inhibitors(ICIs)have demonstrated remarkable efficacy across diverse malignancies.Notably,in patients with advanced gastric cancer,the use of programmed death 1(PD-1)blockade has significantly prolonged overall survival,marking a pivotal advancement comparable to the impact of Herceptin over the past two decades.While the therapeutic benefits of ICIs are evident,the increasing use of immunotherapy has led to an increase in immune-related adverse events.CASE SUMMARY This article presents the case of a patient with advanced gastric cancer and chronic plaque psoriasis.Following sintilimab therapy,the patient developed severe rashes accompanied by cytokine release syndrome(CRS).Fortunately,effective management was achieved through the administration of glucocorticoid,tocilizumab,and acitretin,which resulted in favorable outcomes.CONCLUSION Glucocorticoid and tocilizumab therapy was effective in managing CRS after PD-1 blockade therapy for gastric cancer in a patient with chronic plaque psoriasis.

Oligodendrocytes in central nervous system diseases:the effect of cytokine regulation

Cytokines including tumor necrosis factor, interleukins, interferons, and chemokines are abundantly produced in various diseases. As pleiotropic factors, cytokines are involved in nearly every aspect of cellular functions such as migration, survival, proliferation, and differentiation. Oligodendrocytes are the myelin-forming cells in the central nervous system and play critical roles in the conduction of action potentials, supply of metabolic components for axons, and other functions. Emerging evidence suggests that both oligodendrocytes and oligodendrocyte precursor cells are vulnerable to cytokines released under pathological conditions. This review mainly summarizes the effects of cytokines on oligodendrocyte lineage cells in central nervous system diseases. A comprehensive understanding of the effects of cytokines on oligodendrocyte lineage cells contributes to our understanding of central nervous system diseases and offers insights into treatment strategies.

Cytotoxic synergism of Clostridioides difficile toxin B with proinflammatory cytokines in subjects with inflammatory bowel diseases

Clostridioides difficile(C.difficile)is progressively colonizing humans and animals living with humans.During this process,hypervirulent strains and mutated toxin A and B of C.difficile(TcdA and TcdB)are originating and developing.While in healthy subjects colonization by C.difficile becomes a risk after the use of antibiotics that alter the microbiome,other categories of people are more susceptible to infection and at risk of relapse,such as those with inflammatory bowel disease(IBD).Recent in vitro studies suggest that this increased susceptibility could be due to the strong cytotoxic synergism between TcdB and proinflammatory cytokines the tumor necrosis factor-alpha and interferon-gamma(CKs).Therefore,in subjects with IBD the presence of an inflammatory state in the colon could be the driver that increases the susceptibility to C.difficile infection and its progression and relapses.TcdB is internalized in the cell via three receptors:chondroitin sulphate proteoglycan 4;poliovirus receptor-like 3;and Wnt receptor frizzled family.Chondroitin sulphate proteoglycan 4 and Wnt receptor frizzled family are involved in cell death by apoptosis or necrosis depending on the concentration of TcdB and cell types,while poliovirus receptor-like 3 induces only necrosis.It is possible that cytokines could also induce a greater expression of receptors for TcdB that are more involved in necrosis than in apoptosis.Therefore,in subjects with IBD there are the conditions:(1)For greater susceptibility to C.difficile infection,such as the inflammatory state,and abnormalities of the microbiome and of the immune system;(2)for the enhancement of the cytotoxic activity of TcdB+Cks;and(3)for a greater expression of TcdB receptors stimulated by cytokines that induce cell death by necrosis rather than apoptosis.The only therapeutic approach currently possible in IBD patients is monitoring of C.difficile colonization for interventions aimed at reducing tumor necrosis factor-alpha and interferon-gamma levels when the infection begins.The future perspective is to generate bacteriophages against C.difficile for targeted therapy.

Pro-inflammatory cytokines levels in tears and dry eye disease in Parkinson’s disease

Background:Neuroinflammation is an essential event in Parkinson’s disease(PD).Identifying affordable and less invasive biomarkers to make an early diagnosis and monitor therapeutic strategies should be a priority among researchers.The study’s objective was to measure tear levels of cytokines in subjects with PD and their association with motor features and the presence of dry eye symptoms.Methods:A total of 16 subjects with PD and 16 age-and sex-matched controls were included.Movement Disorders Society-Unified Parkinson’s Disease Rating Scale(MDS-UPDRS),Hoehn and Yahr(HY)stage scale,Montreal Cognitive Assessment(MoCA),tear break-up time(TBUT),blink rate(BR),Dry Eye Questionnaire 5(DEQ-5)were examined,and pro-inflammatory cytokines[interleukin(IL)-1β,IL-6,IL-8,IL-10,IL-12p70 and tumor necrosis factor-alpha(TNF-α)]were quantified in tears using the BD Cytometric Bead Array Human Inflammatory Cytokine Kit.Results:Higher tear TNF-αwere quantified in PD compared to controls(2.94±3.95 vs.0.33±0.49 pg/mL,P=0.008).According to DEQ-5,50.0%(n=8)of PD subjects and 12.5%(n=2)controls had dry eye disease(DED).No differences were found in cytokines concentrations between PD patients with DED compared to those without DED.IL-8 was associated with the HY stage,TBUT,DEQ-5,and a better MoCA score.A higher BR correlated moderately with a lower HY stage(r=−0.645,P=0.007),and DED patients have lower BR in PD(12.14±2.54 vs.9.0±2.06 blinks/minute,P=0.031).Conclusions:PD patients have higher levels of TNF-αin tears than age-and sex-matched HC.IL-8 in tears may be both involved in the severity of the disease and in the development of DED in PD.In addition,our findings suggest that as HY stage increases,indicating a more advanced stage,BR decreases,indicating greater motor impairment.Conversely,the presence of DED is associated with higher levels of bradykinesia in PD patients,suggesting a potential relationship between DED and motor impairment severity.

Effect of acupuncture on acupoint "Yingxiang-Hegu" on Th1, Th2 cytokines and T-bet/GATA-3 of allergic rhinitis rats

Objective:To explore the effect of"Yingxiang-Hegu"on Th1,Th2-related cytokines and[2]transcription factors T-bet and GATA-3 in rats with allergic rhinitis.Methods:Rats were randomly divided into three groups:blank group,model group and acupoint group.The rat model of ovalbumin(OVA)AR was established,and the general condition of the rats was observed and scored.Acupuncture intervention was performed on the acupoint group on the second day after successful modeling,once per day for 20 min for 10 d.After intervention,the general behavior,behavioral score and histomorphological changes of nasal mucosa were observed.Eosinophils(EOS)were counted under microscope after nasal lavage smear staining,and the contents of total IgE,IFN-γ,IL-12,IL-4 and IL-5 in serum were detected by ELISA.Westernblot and IHC were used to detect the protein level and positive protein expression of specific transcription factors T-bet and GATA-3 in rat nasal mucosa.Results:After the establishment of the model,except for the blank group,the behavioral observation scores of rats in the model group and acupoint group were more than 5 points,indicating that the model was successful.After acupuncture intervention on acupoint"Yingxiang-Hegu",the behavioral score of rats in the acupoint group and western medicine group was significantly lower than that in the model group(P<0.05).Microscopic examination showed that the structure of nasal mucosa in the model group was obviously damaged,cilia were arranged discontinuously,uneven,local congestion and swelling,a large number of epithelial cells exfoliated and necrotic,goblet cell proliferation,obvious inflammatory cell infiltration.The pathological degree of nasal mucosa in the pair point group was significantly less than that in the model group.Compared with the model group,the levels of IFN-γ,IL-2 and IL-12 in serum were significantly increased,while IgE,IL-4,IL-5 and IL-6 were significantly decreased,GATA-3 protein and positive expression in nasal mucosa were significantly decreased and T-bet was significantly increased after acupuncture.Conclusion:Acupuncture at"Yingxiang-Hegu"can effectively improve the nasal sensitive symptoms and control nasal inflammation in AR rats.The mechanism may be that acupuncture at Yingxiang-Hegu can up-regulate the expression of T-bet,decrease the level of GATA-3,promote the production of Th1 cytokines and inhibit the synthesis and secretion of Th2 cells,thus restoring the immune balance of Th1 and Th2.