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.

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.

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.

Role of inflammatory cytokines in peripheral nerve injury

Inflammatory events occurring in the distal part of an injured peripheral nerve have, nowadays, a great resonance. Investigating the timing of action of the several cytokines in the important stages of Wallerian degeneration helps to understand the regenerative process and design pharmacologic intervention that promotes and expedites recovery. The complex and synergistic action of inflammatory cytokines finally promotes axonal regeneration. Cytokines can be divided into pro- and anti-inflammatory cytokines that upregulate and downregulate, respectively, the production of inflammatory mediators. While pro-inflammatory cytokines are expressed in the first phase of Wallerian degeneration and promote the recruitment of macrophages, anti-inflammatory cytokines are expressed after this recruitment and downregulate the production of all cytokines, thus determining the end of the process. In this review, we describe the major inflammatory cytokines involved in Wallerian degeneration and the early phases of nerve regeneration. In particular, we focus on interleukin-1, interleukin-2, interleukin-6, tumor necrosis factor-β, interleukin-10 and transforming growth factor-β.

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.

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.

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.

Inhibitory Effects of Suppressor of Cytokine Signaling 3 on Inflammatory Cytokine Expression and Migration and Proliferation of IL-6/IFN-γ-induced Vascular Smooth Muscle Cells

Summary： The main pathogenesis of saphenous vein graft neointimal hyperplasia after coronary artery bypass grafting （CABG） is inflammation-caused migration and proliferation of vascular smooth muscle cells （VSMCs）. Janus kinase 2/signal transducer and activators of transcription 3 （JAK2/STAT3） path- way is an important signaling pathway through which VSMCs phenotype conversion occurs. Suppressor of cytokine signaling 3 （SOCS3） is the classic negative feedback inhibitor of JAK2/STAT3 pathway. Growing studies show that SOCS3 plays an important anti-inflammatory role in numerous autoimmune diseases, inflammatory diseases and inflammation-related tumors. However, the effect and mechanism of SOCS3 on vein graft disease is unclear. The purpose of this study was to investigate the effects of SOCS3 on the inflammation, migration and proliferation of VSMCs in vitro and the mechanism. The small interference RNA plasmid targeting rat SOCS3 （SiRNA-rSOCS3） and the recombinant adenovirus vector carrying rat SOCS3 gene （pYrAd-rSOCS3） were constructed, and the empty plamid （SiRNA-control） and vector （pYrAd-GFP） only carrying GFP reported gene were constructed as control. The rat VSMCs were cultured. There were two large groups of A （SOCS3 up-regulated）： control group, IL-6/IFN-γ group, IL-6/IFN-γ＋pYrAd-rSOCS3 group, IL-6/IFN-γ＋pYrAd-GFP group; and B （SOCS3 down-regulated）： control group, IL-6/IFN-γ group, IL-6/IFN-γ＋SiRNA-rSOCS3 group and IL-6/IFN -T＋SiRNA-control group. The pYrAd-rSOCS3 and SiRNA-rSOCS3 were transfected into VSMCs in- duced by IL-6/IFN-γ. After 24 h, real-time reverse transcription polymerase chain reaction （RT-PCR） and Western blotting were used to detect the mRNA and protein expression of SOCS3, STAT3 （only by Western blotting）, P-STAT3 （only by Western blotting）, IL-1β, IL-6, TNF-α, MCP-1 and ICAM-1. The MTT, Transwell assay and flow cytometry were used to examine VSMCs proliferation, migration and cell cycle progression, respectively. As compared with control group, the mRNA and protein expression of SOCS3, STAT3, P-STAT3, IL-1β, IL-6, TNF-α, MCP-1 and ICAM-1 was significantly up-regulated in VSMCs stimulated by IL-6/IFN-γ. However, in VSMCs transfected with pYrAd-rSOCS3 before stimulation with IL-6/IFN-γ, the expression of SOCS3 mRNA and protein was further up-regulated, and that of STAT3, P-STAT3, IL-1β, IL-6, TNF-α, MCP-1 and ICAM-1 was significantly down-regulated as compared with IL-6/IFN-γ group and IL-6/IFN-γ＋pYrAd-GFP group. The expression of those re- lated-cytokines in IL-6/IFN-γ＋SiRNA-rSOCS3 group was markedly increased as compared with IL-6/IFN-γ group and IL-6/IFN-γ＋SiRNA-control group. The absorbance （A） values, the number of cells migrating to the lower chamber, and percentage of cells in the G2/M＋S phase were increased in VSMCs stimulated by IL-6/IFN-γ. In VSMCs incubated with pYrAd-rSOCS3 or SiRNA-rSOCS3 be- fore IL-6/IFN-γ stimulation, the A values, the number of cells migrating to the lower chamber, and the percentage of cells in the G2/M＋S phase were significantly decreased, and increased respectively. These results imply that IL-6/IFN-γ, strong inflammatory stimulators, can promote transformation of VSMCs phenotype form a quiescent contractile state to a synthetic state by activating JAK2/STAT3 pathway. Over-expresssed SOCS3 might inhibit pro-inflammatory effect, migration and growth of VSMCs by blocking STAT3 activation and phosphorylation. These data in vitro confirm that SOCS3 may play a negatively regulatory role in development and progression of vein graft failure. These conclusions can provide a novel strategy for clinical treatment of vein graft diseases and a new theoretic clue for related drug development.

Pretreated Oenan the Javanica extract increases anti-inflammatory cytokines, attenuates gliosis, and protects hippocampal neurons following transient global cerebral ischemia in gerbils

Recently,we have reported that Oenanthe javanica extract(OJE)displays strong neuroprotective effect against ischemic damage after transient global cerebral ischemia.However,neuroprotective mechanisms of OJE have not been fully identified.Thus,this study investigated the neuroprotection of OJE in the hippocampal CA1 area and its anti-inflammatory activity in gerbils subjected to 5 minutes of transient global cerebral ischemia.We treated the animals by intragastrical injection of OJE(100 and 200 mg/kg)once daily for 1 week prior to transient global cerebral ischemia.Neuroprotection of OJE was observed by immunohistochemistry for neuronal nuclear antigen and histofluorescence staining for Fluoro-Jade B.Immunohistochemistry of glial fibrillary acidic protein and ionized calcium-binding adapter molecule 1 was done for astrocytosis and microgliosis,respectively.To investigate the neuroprotective mechanisms of OJE,we performed immunohistochemistry of tumor necrosis factor-alpha and interleukin-2 for pro-inflammatory function and interleukin-4 and interleukin-13 for anti-inflammatory function.When we treated the animals by intragastrical administration of 200 mg/kg of OJE,hippocampal CA1 pyramidal neurons were protected from transient global cerebral ischemia and cerebral ischemia-induced gliosis was inhibited in the ischemic hippocampal CA1 area.We also found that interleukin-4 and-13 immunoreactivities were significantly increased in pyramidal neurons of the ischemic CA1 area after OJE pretreatment,and the increased immunoreactivities were sustained in the CA1 pyramidal neurons after transient global cerebral ischemia.However,OJE pretreatment did not increase interleukin-2 and tumor necrosis factor-alpha immunoreactivities in the CA1 pyramidal neurons.Our findings suggest that pretreatment with OJE can protect neurons and attenuate gliosis from transient global cerebral ischemia via increasing expressions of interleukin-4 and-13.The experimental plan of this study was reviewed and approved by the Institutional Animal Care and Use Committee(IACUC)in Kangwon National University(approval No.KW-160802-1)on August 10,2016.

Omentin-1 prevents inflammation-induced osteoporosis by downregulating the pro-inflammatory cytokines

Osteoporosis is a frequent complication of chronic inflammatory diseases and increases in the pro-inflammatory cytokines make an important contribution to bone loss by promoting bone resorption and impairing bone formation. Omentin-1 is a newly identified adipocytokine that has anti-inflammatory effects, but little is known about the role of omentin-1 in inflammatory osteoporosis. Here we generated global omentin-1 knockout（omentin-1^-/-） mice and demonstrated that depletion of omentin-1 induces inflammatory bone loss-like phenotypes in mice, as defined by abnormally elevated pro-inflammatory cytokines, increased osteoclast formation and bone tissue destruction, as well as impaired osteogenic activities. Using an inflammatory cell model induced by tumor necrosis factor-α（TNF-α）, we determined that recombinant omentin-1 reduces the production of proinflammatory factors in the TNF-α-activated macrophages, and suppresses their anti-osteoblastic and pro-osteoclastic abilities. In the magnesium silicate-induced inflammatory osteoporosis mouse model, the systemic administration of adenoviral-delivered omentin-1 significantly protects from osteoporotic bone loss and inflammation. Our study suggests that omentin-1 can be used as a promising therapeutic agent for the prevention or treatment of inflammatory bone diseases by downregulating the proinflammatory cytokines.

Triptolide Inhibits Expression of Inflammatory Cytokines and Proliferation of Fibroblast-like Synoviocytes Induced by IL-6/sIL-6R-Mediated JAK2/STAT3 Signaling Pathway

Triptolide,a component of the Chinese herb Tripterygium wilfordii Hook F,has been proved to be effective in the treatment of rheumatoid arthritis(RA).However,its underlying mechanisms on RA have not yet been well established.We observed the inhibitory effect of triptolide on the expression of inflammatory cytokines and proliferation of fibroblast-like synoviocytes(FLS)induced by the complex of interleukin-6(IL-6)and the soluble form of the IL-6 receptor(sIL-6R).Furthermore,to clarify the underlying mechanisms,we treated FLS with the Janus-activated kinase 2(JAK2)inhibitor/signal transducer and activator of transcription 3(STAT3)activation blocker AZD1480.In this study,immunohistochemical staining was used to identify vimentin(+)and CD68(−)in FLS.The FLS proliferation was measured by cell proliferation assay,and the cell cycles were analyzed by flow cytometry.Furthermore,ELISA was used to detect the expression of the inflammatory factors in culture solution.The expression levels of p-JAK2,JAK2,p-STAT3 and STAT3 were investigated through Western blotting analysis.The results showed that IL-6/sIL-6R significantly increased the cell proliferation and expression of inflammatory cytokines,including IL-6,interleukin-1β(IL-1β)and vascular endothelial growth factor(VEGF).Triptolide or AZD1480 inhibited the cell proliferation and inflammatory cytokine expression in IL-6/sIL-6R-stimulated FLS by suppressing JAK2/STAT3.The study suggested that the physiological effects of triptolide on RA were due to its contribution to the inhibition of the inflammatory cytokine expression and FLS proliferation by suppressing the JAK2/STAT3 signaling pathway.It may provide an innovative insight into the effect of triptolide in preventing RA pathogenesis.

Unresolved conundrum of the role of physical activity in inflammatory bowel disease:What next?

There is considerable controversy on the role of physical activity in irritable bowel disease(IBD)since published reports are conflicting.It is well known that there is known relapse with specific treatment in IBD.This,in addition to onset of extraintestinal symptoms creates a need to think of alternate approaches.In this context,the current article describes the need of a multi-institutional study with standard protocol of physical activity for documenting its effect on both the primary disease and the extra alimentary manifestations.This paper also points out the possibility of using adjuvant complementary medicine such as yoga,whose effects have been documented in other diseases like irritable bowel syndrome.A third approach could be to focus on the intestinal dysbiosis in IBD and concentrate on research on restoring the microbial flora to normal,to see whether the extraintestinal symptoms are alleviated.

Mutual Effect between Neuropeptides and Inflammatory Cytokines in Neurogenic SMSCs of Human Temporomandibular Joint

In temporomandibular disorders（TMD）, pain takes place when neuropeptides stimulate synovial tissue to produce several cytokines such as interleukin（IL）-1β, IL-6 and tumor necrosis factor（TNF）-α, which activate neurons and glia of synovial membrane at the bilaminar regions of temporomandibular joint（TMJ）. It has been reported that, after neurogenic differentiation, the synovial mesenchymal stem cells（SMSCs）, deriving from TMJ, possess the same cytological features as the neuronal cells. This study examined the ability of substance P（SP） and calcitonin gene-related peptide（CGRP） to stimulate SMSCs and neurogenic SMSCs secreting inflammatory cytokines during TMD, evaluated the mutual effects of inflammatory cytokines and neuropeptides and tested the analgesic effect of hyaluronic acid（HA）. The levels of IL-1β, IL-6 and TNF-α in SMSCs and neurogenic SMSCs in the presence of neuropeptides were measured by ELISA. SP and CGRP produced by SMSCs and neurogenic SMSCs were determined by RT-PCR and Western blotting. The results showed that the expression of SP and CGRP was significantly enhanced in the neurogenic SMSCs in response to IL-1β, IL-6 and TNF-α, and the effect was remarkably inhibited by HA. IL-1β, IL-6 and TNF-α, in return, could be enhanced in the neurogenic SMSCs upon stimulation by SP and CGRP. Neuropeptides and inflammatory cytokines might work mutually on the TMD pain. The HA-mediated analgesic effect may be implicated in the inhibition of SP and CGRP expression in neurogenic SMSCs.

Endothelial cell injury with inflammatory cytokine and coagulation in patients with sepsis

BACKGROUND:Current studies on CD62 P have focused mainly on cardiovascular diseases,while only few studies have evaluated the effects of CD62 P on the development of sepsis and the association between endothelial cell injury with inflammation and coagulation.This study attended to explore the association between endothelial cell injury with inflammation and coagulation by evaluating the expression of soluble CD62P(s-CD62P) in plasma and its mechanism in patients with sepsis,thus to provide the evidence of effective treatment of sepsis with anti-adhesion therapy targeted CD62 P.METHODS:A total of 70 critically ill patients with systemic inflammatory response syndrome(SIRS) admitted to intensive care unit(ICU) between September 2009 and February 2010 were enrolled for a prospective and control study.According to the diagnostic criteria of sepsis/SIRS,the patients were divided into two groups:a sepsis group(n=38) and a SIRS group(n=32).Another 20 healthy volunteers served as a control group.Patients in the sepsis group and SIRS group were matched by clinical signs of high blood pressure,diabetes and its complications.The demographics of the patients including age,sex,body mass index(BMI),smoking and alcohol addict were compared among the groups.Six mL peripheral blood samples were collected within 24-hour admission in ICU for enzymelinked immunosorbent assay(ELISA) to detect the plasma levels of S-CD62 P,TNF-α,and hs-CRP.And variables of coagulation function such as platelet(PLT),prothrombin(PT),activated partial thromboplastin time(APTT),D-dimer and antithrombin-Ⅲ(AT-Ⅲ) were analyzed during 24 hours after admission to ICU.Meanwhile sequential organ failure assessment(SOFA) score of critically ill patients was evaluated.Data were expressed as meanistandard deviation and were statistically analyzed by using SPSS 17.0statistical software.The differences in plasma levels of S-CD62 P of patients in each group were analyzed by ANOVA and the Kruskal-Wallis test.The relations between S-CD62 P and inflammatory cytokines as well as with coagulation were determined by Pearson's product moment correlation coefficient analysis.Changes were considered as statistically significant if P value was less than 0.05.RESULTS:Compared with the control group and SIRS group,the sepsis group demonstrated significantly higher levels of S-CD62 P,TNF-a and highly sensitive C-reactive protein(hs-CRP)(PO.05).The plasma levels of D-dimer,PT,and APTT in the sepsis and SIRS groups were significantly higher than those in the control group,while the platelet count and the activity of AT-Ⅲ were obviously lower(P<0.05).In the sepsis group,the plasma levels of hs-CRP and TNF-a were positively correlated with PT,APTT,and D-dimer,and negatively correlated with AT-Ⅲ and PLT(P<0.05).The plasma levels of S-CD62 P were significantly correlated with the plasma levels of TNF-a,hs-CRP,D-dimer,PT,and APTT,whereas they were correlated negatively well with PLT and AT-Ⅲ(P<0.05).CONCLUSIONS:The concentration of plasma S-CD62 P is elevated as a early biomarker in patients with sepsis,and it serves as one of the pathogenic factors responsible for endothelial cell damage.Coagulation and mediators of inflammation promote each other,aggravating the severity of sepsis.Plasma S-CD62 P may be an important factor for the development of coagulation and inflammatory reaction.

Ghrelin inhibits IKKβ/NF-κB activation and reduces pro-inflammatory cytokine production in pancreatic acinar AR42J cells treated with cerulein

Background: Previous studies have provided conflicting results regarding whether the serum ghrelin concentration can reflect the severity of acute pancreatitis(AP). The present study examined the correlation between the serum ghrelin concentration and AP severity in animal models and investigated whether altered ghrelin expression in pancreatic acinar cells influences IKK β/NF-κ B signaling and pro-inflammatory cytokine production. Methods: Mild or severe AP was induced in rats by intraperitoneal injection of cerulein or retrograde cholangiopancreatic duct injection of sodium taurocholate, respectively. After successful model induction, serum ghrelin, tumor necrosis factor-α(TNF-α), and interleukin-6(IL-6) concentrations were determined by enzyme-linked immunosorbent assay, and IKK β/NF-κ B activation was assessed by immunohistochemistry. Subsequently, stable overexpression or knockdown of ghrelin in AR42 J cells was achieved by lentiviral transfection. After transfected cells and control cells were treated with cerulein for 24 h, the TNF-αand IL-1 β levels in the supernatants were determined by enzyme-linked immunosorbent assay, and the expression levels of p-p65, IKK β, and p-IKK β were detected by Western blotting. Results: In rat AP models, AP severity was correlated with increased IKK β/NF-κ B activation, proinflammatory cytokine production, and ghrelin secretion. The levels of pro-inflammatory cytokines TNF-αand IL-1 β as well as IKK β/NF-κ B signaling activity were increased upon knockdown of ghrelin in the AP acinar cell model and decreased with ghrelin overexpression. Conclusions: Serum ghrelin is related to the severity of AP. Ghrelin may play a protective role in the pathogenesis of AP by inhibiting the pro-inflammatory cytokines and the activation of the IKK β/NF-κ B signaling pathway.

Lipoxin A4 Inhibits Lipopolysaccharide-induced Production of Inflammatory Cytokines in Keratinocytes by Up-regulating SOCS2 and Down-regulating TRAF6

Liopxin A4（LXA4） is considered to be a crucial modulator in the inflammatory responses. In the present study, we aimed to study the effect of LXA4 on the inflammatory cytokines production induced by lipopolysaccharide（LPS） and the possible mechanism in normal human epidermal keratinocytes（NHEKs）. NHEKs were isolated and cultured. The expression of toll-like receptor 4（TLR4）, LXA4 receptor（ALXR） and aryl hydrocarbon receptor（Ah R） in NHEKs was detected by reverse transcription polymerase chain reaction（RT-PCR）. The m RNA and protein levels of tumor necrosis factor-alpha（TNF-α） and interleukin-1β（IL-1β） were determined in NHEKs stimulated by LPS（10 μg/m L） with or without preincubation with LXA4（100 nmol/L） for 30 min by real-time quantitative PCR（real-time q PCR） and enzyme-linked immunosorbent assay（ELISA）, respectively. The expression levels of tumor necrosis factor receptor-associated factor 6（TRAF6） and suppressors of cytokine signaling 2（SOCS2） m RNAs and proteins, and nuclear translocation of NF-k B-p65 were measured by real-time q PCR and Western blotting, respectively. The results showed that NHEKs expressed TLR4, ALXR and Ah R. LXA4 significantly inhibited the m RNA and protein expression levels of TNF-α, IL-1β and TRAF6 induced by LPS in NHEKs, and LXA4 obviously increased the expression of SOCS2 at m RNA and protein levels. The nuclear NF-k B-p65 protein expression induced by LPS was inhibited after preincubation with LXA4 in NHEKs. It was concluded that LXA4 inhibits the LPS-induced production of TNF-α and IL-1β in NHEKs by up-regulating SOCS2 and down-regulating TRAF6.

Effect of propofol on glutamate-induced activation and related inflammatory cytokines of astrocytes from spinal cord dorsal horn

BACKGROUND： Astrocytes participate in central nervous system-mediated physiological or pathological processes, such as pain. Activated dorsal horn astrocytes from the spinal cord produce nerve active substances and proinflammatory cytokines, such as interleukin-lbeta （IL-1 β ）, IL-6, and tumor necrosis factor- α （TNF-α ）, which play important roles in pain transduction and regulation. OBJECTIVE： To investigate the effects of different doses of propofol on activation of cultured spinal cord dorsal horn astrocytes induced by glutamate, as well as changes in IL-1β, IL-6, and TNF- α, and 1L-10 （anti-inflammatory cytokine） expression in rats, and to explore the dose relationship of propofol. DESIGN, TIME AND SETTING： The cellular and molecular biology experiment was performed at the Central Laboratory of Yunyang Medical College between March 2006 and December 2007. MATERIALS： Forty healthy, Wistar rats, aged 2-3 days, were selected. Propofol was provided by Zeneca, UK; glutamate by Sigma, USA; EPICS XL flow cytometry by Beckman culture, USA; rabbit-anti-mouse glial fibrillary acidic protein （GFAP） antibody kit and inflammatory cytokine detection kit were provided by Zhongshan Biotechnology Company Ltd., Beijing; multimedia color pathologic image analysis system was a product of Nikon, Japan. METHODS： Astrocytes were harvested from T11- L6 spinal cord dorsal horn of Wistar rats and incubated for 3 weeks. The cells were divided into seven groups, according to various treatment conditions： control group was cells cultured in Hank＇s buffered saline solution; intralipid group was cells cultured in intralipid （0.2 mL/L）; glutamate group was cells cultured with 100 u mol/L glutamate; propofol group was cells cultured with 250 u mol/L propofol; three glutamate plus propofol groups were cultured in 100 11 mol/L of glutamate, followed by 5, 25, and 250 u mol/L of propofol 10 minutes later. MAIN OUTCOME MEASURES： GFAP-labeled astrocytes were analyzed using a multimedia pathology imaging analysis system to detect area density （AD） and average optical density （AOD） of positive cells. The supernatant concentrations of IL-1β, TNF- α, IL-6, and IL-10 were determined using radioimmune assays. RESULTS： Compared with the control group, cells in the glutamate plus low-dose propofol group were activated and hypertrophic, and AD and AOD were significantly increased （P 〈 0.01 ）. Concentrations of IL-1β, TNF- α, and IL-6 were also significantly increased （P 〈 0.01）, while IL-10 levels remained unchanged （P 〉 0.05）, but still higher than the control and glutamate groups （P 〉 0.05）. Compared with the glutamate group, astrocyte activation was inhibited by moderate and high-dose propotol. In addition, with moderate and high-dose propofol, AD, AOD, IL-1β, TNF- α, and IL-6 concentrations were significantly decreased （P 〈 0.05-0.01）, and IL-10 levels were increased （P 〈 0.01 ）. CONCLUSION： Propofol can effectively inhibit glutamate-induced astrocyte activation in the spinal cord dorsal horn, significantly inhibit production of IL-1 β, TNF- α, and IL-6, and increase IL-10 synthesis and release in a dose-dependent manner.

Meta-analysis of clinical effect of clearing heat and cooling blood on psoriasis and its effect on inflammatory cytokines

Objective:To evaluate the effect of Qingreliangxue method compared with Acitretin Capsules on clinical efficacy of psoriasis and serum inflammatory cytokines.Methods:The computer searches databases such as CNKI,Wanfang,VIP,PubMed,Embase and Cochrane Library.The search time is from the time the library is built until December 2019.According to the criteria for screening and selection of studies,extract data,use risk assessment tools for quality evaluation,and use Revman 5.3 software to perform meta-analysis on the outcome indicators of the included studis.Results:Finally,20 studies were included,with a total of 1592 patients.The analysis results showed that the total effective rate(OR=3.70,95%CI[2.58,5.30],P<0.00001)and cure rate(OR=2.40,95%CI[1.86,3.10],P<0.00001),PASI score(OR=-2.65,95%CI[-3.60,-1.70],P<0.00001),serum inflammatory cytokines(OR=-8.84,95%CI[-10.52,-7.16],P<0.00001),adverse reactions(OR=0.25,95%CI[0.11,0.57],P=0.001)are superior to Acitretin Capsules.Statistics of the top 10 Chinese medicines in clinical used frequency are,in order,habitat,red peony root,paeonol,honeysuckle,comfrey,soil tuckahoe,salvia miltiorrhiza,buffalo horn,heliotrope,angelica.Conclusion:Based on the current evidence,the treatment of psoriasis with clearing heat and cooling blood as the mainstay of Chinese medicine alone or in combination with Acitretin Capsules can better improve the efficacy,and its mechanism may be related to reducing inflammation.Due to the limitation of the included literature,this conclusion needs to be further verified.

The Profile of the Serum Levels of Inflammatory Cytokines TNF-a,IL-6,IL-10 and Captopril Intervention in Reno-hypertensive Rats

Objectives To observe the profile of the serum levels of inflammatory cytokines interleukin-6（IL-6）, tumor necrosis factor（TNF-α）and interleukin-10 （IL-10） and evaluate the effects of angiotensin- converting enzyme inhibitor-Captopril on them in renohypertensive rats. Methods Using reformed two-kidney-one-clip （2K 1C） method, renal hypertensive rats （RHR） were obtained by ligating abdominal aorta. 30 Wistar rats were randomized into three groups： sham-operation group （A）, model control group （ B ） and captopril group （C）. All rats were killed after being given the trial drugs 5 weeks, ELISA assays were used to detect the levels of IL-6 and IL-10, the levels of TNF-alpha were measured with radioimmunoassays. Results ①compared with group A, the left ventricular hypertrophy was aggravated in group B significantly, the ratio of left ventricle and body weight（LV/BW） was 0.00318 ±0.00030 （B）and 0.00256 ±0.00040 （A） respectively（P 〈 0.001 ）, the levels of IL-6 and TNF-α increased significantly （P 〈 0.001 and P 〈 0.002 respectively）, whereas the levels of IL-10 were not changed between the two groups （P 〉 0.05）; ② compared with group B, the LV/BW was 0.00266 ± 0.00018 （C） and 0.00318±0.00030 （B） respectively（P 〈 0.001）, the levels of IL-6 and TNF-α decreased significantly （ P 〈 0.01）, whereas the levels of IL-10 were not changed between the two groups （P 〉 0.05） ; Condusions Angiotensin converting enzyme inhibitor-captopril can lower the serum levels of proinflammatory cytokines IL-6 and TNF-α effectively, but can not increase the levels of anti-inflammatory cytokine feature IL-10, it suggests that captopril may have to prevent or slow development hypertensive complications by means of levels of pro-inflammatory cytokines a of lowering the but not by increasing anti-inflammatory cytokine IL-10.