Effects of estradiol and progesterone on the proinflammatory cytokine production by mononuclear cells from patients with chronic hepatitis C

AIM:To investigate the effects of estradiol (E2) and progesterone on the unstimulated and oxidative stressstimulated production of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-8, and macrophage chemotactic protein (MCP)-1 by peripheral blood mononuclear cells (PBMCs) from patients with chronic hepatitis C and healthy controls. METHODS:The PBMCs were separated from agematched 72 males and 71 females with and without chronic hepatitis C, who were divided into two groups based on a mean menopausal age of 50 years. Oxidative stress was induced by hydrogen peroxide in the cells incubated in serum-free media. Cytokines in the culture supernatant were measured by an enzyme-linked immunosorbent assay. RESULTS:The highest levels of the spontaneous production of TNF-α, IL-1β, IL-8, and MCP-1 by the unstimulated PBMCs were in the older male patients with chronic hepatitis C and the lowest levels were in the premenopausal female healthy controls. E2 inhibited the cytokine production by the unstimulated PBMCs from the older male and post-menopausal female patients, which was further stimulated by progesterone. The exposure to hydrogen peroxide in the PBMCs from the younger male and pre-menopausal female healthy subjects induced the production of cytokines. The change rates of the hydrogen peroxide-stimulated cytokine production were suppressed by E2 and enhanced by progesterone. CONCLUSION:These findings suggest that E2 may play a favorable role in the course of persistent liver injury by preventing the accumulation of monocytes-macrophages and by inhibiting proinflammatory cytokine production, whereas progesterone may counteract the favorable E2 effects.

Jeju seaweeds suppress lipopolysaccharide-stimulated proinflammatory response in RAW 264.7 murine macrophages

Objective:To investigate the anti-inflammatory effects of Jeju seaweeds on macrophage RAW264.7 cells under lipopolysaccharide(LPS)stimulation.Methods:Ethyl acetate fractions were prepared from five different types of Jeju seaweeds,Dictyopteris divaricata(D.divaricata),Dictyopteris prolifera(D.prolifefa),Prioutis cornea(P.comea,Grateloupia laceolata(G,lanceolate,and Cralcloupia filicina(G.filicina)They were screened for inhibitory effects on proinflammatory mediators and cytokines such as nitric oxide(NO),prostaglandin E,,tumor necrosis factor-a(TNF-a),and interleukin-6(11.-6).Results:Our results revealed that D.divaricata,D.prolifera,P.cornea,G.lanceolata,and G.filicina potently inhibited I.PS-stimulaled NO production(IC_(50),values were 18.0,38.36,38.43,32.81 and 37.14μg/mL,respectively).Consistent with these findings,D.divtricata,D.prolifera,P.cornea,and G.fdicina also reduced the IPS-induced and prostaglandin E,production in a concentration-dependent manner.Expectedly,they suppressed the expression of inducible NO synthase and cyclooxygenase-2 at the protein level in a dose-dependent manner in the RAW264.7 cells,as detennined by western blotting.In addition,the levels of TNF-a and IL-6,released into the medium,were also reduced by D.divaricata,D.prolifera,P.cornea,G,lanceolata,and G.fdicina in a dose-dependent manner(IC_(50)values for TNF-a were 16.11,28.21,84.27,45.52 and74.75μg/mL,respectively;IC_(50),values for IL-6 were 37.35,80.08,103.28,62.53 and 84.28μg/mL,respectively).The total phlorotannin content was measured by the Folin-Ciocalteu method and expressed as phloroglucinol equivalents.The content was 92.0μg/mg for D.divaricata,151.8μg/mg for D.prolifera,57.2μg/mg for P.cornea,53.0 pg/mg for G.lanceolata,and 40.2μg/mg for G.fdicina.Conclusions:Thus,these findings suggest that Jeju seaweed extracts have potential therapeutic applications for inflammatory responses.

Aloe barbadensis Miller peptide/polypeptide fraction alleviates inflammation through inhibition of proinflammatory cytokines and mediators in vitro and in rats with Freund’s adjuvant-induced hind paw edema

Objective:To evaluate the anti-inflammatory potential of peptide/polypeptide fraction of Aloe vera through in vitro and in vivo studies.Methods:The peptide/polypeptide fraction from Aloe vera was obtained through trichloroacetic acid precipitation.The anti-inflammatory property of the peptide/polypeptide fraction was tested by protein denaturation,membrane stabilization assays.The effect of the fraction on RAW 264.7 cell viability was examined by MTT assays.The nitric oxide level was determined through Griess reagent.TNF-αand IL-6 levels were estimated using ELISA kits.In vivo studies were carried out in male Wistar rats through injection of Freund’s adjuvant in the hind paw.Paw edema was measured through the Vernier scale and levels of alanine aminotransferase,aspartate transaminase,TNF-α,IL-6,and secretory phospholipase A2 were estimated through their respective kits after fourteen days of treatment.Graph Pad Prism6 was used for analyzing the results.Results:The peptide/polypeptide extract inhibited protein denaturation with an IC50 value of(218.9±15.6)μg/m L and stabilized the membrane of red blood cells with an IC50 value of(275.9±19.1)μg/m L.The extract showed no changes in cell morphology or cytotoxicity up to the concentration of 20μg/mL in MTT assays.The peptide/polypeptide fraction markedly reduced the levels of proinflammatory markers and mediators in both in vitro and in vivo studies.Conclusions:The results indicate that the peptide/polypeptide fraction of Aloe vera has antiinflammatory property through inhibition of inflammatory markers and mediators responsible for NF-κB and mitogen-activated protein kinase pathways.

Lipid-associated membrane proteins of Mycoplasma penetrans induce production of proinflammatory cytokines in human monocytic cells

The aim of this study is to explore potential pathogenicity of Mycoplasma penetrans, and to investigate whether M. penetrans lipid-associated membrane proteins （LAMPs） could induce human monocytic cell line （THP- 1 ） to produce some proinflammatory cytokines in vitro, including interleukin- 1β （ IL- 1β）, tumor necrosis factor alpha （TNF-α）, and IL-8. THP-1 was stimulated with different concentrations of M.penetrans LAMPs and at different time to analyze the production of human IL-1β, TNF-α and IL-8. The protein levels of human IL-1β, TNF-α and IL-8 were measured by enzyme-linked immunoadsorbent assay （ELISA） and the mRNA levels of these proinflammatory cytokines were detected by reverse transcriptase-PCR （RT-PCR）. It was demonstrated in the present study that the production of IL-1β, TNF-α and IL-8 increased in dose- and time-dependent manner after stimulation with M. penetrans LAMPs in THP-1 cells. M. penetrans LAMPs also induced the expression of IL-1β, TNF-α and IL-8 mRNA. The production of IL-1β, TNF-α and IL-8 and the expression of mRNA were down-regulated by pyrrolidine dithiocarbamate （PDTC）. This study demonstrated that M. penetrans LAMPs can induce the production of proinflammatory cytokines in human monocytic cells in vitro, thus suggesting that it may be an important etiological factor.

Regulation of the expression of proinflammatory cytokines induced by SARS-CoV-2

An outbreak of a novel coronavirus was reported in Wuhan,China,in late 2019.It has spread rapidly through China and many other countries,causing a global pandemic.Since February 2020,over 28 countries/regions have reported confirmed cases.Individuals with the infection known as coronavirus disease-19(COVID-19)have similar clinical features as severe acute respiratory syndrome first encountered 17 years ago,with fever,cough,and upper airway congestion,along with high production of proinflammatory cytokines(PICs),which form a cytokine storm.PICs induced by COVID-19 include interleukin(IL)-6,IL-17,and monocyte chemoattractant protein-1.The production of cytokines is regulated by activated nuclear factor-kB and involves downstream pathways such as Janus kinase/signal transducers and activators transcription.Protein expression is also regulated by post-translational modification of chromosomal markers.Lysine residues in the peptide tails stretching out from the core of histones bind the sequence upstream of the coding portion of genomic DNA.Covalent modification,particularly methylation,activates or represses gene transcription.PICs have been reported to be induced by histone modification and stimulate exudation of hyaluronic acid,which is implicated in the occurrence of COVID-19.These findings indicate the impact of the expression of PICs on the pathogenesis and therapeutic targeting of COVID-19.

Effects of p38 MAPK inhibitor on the rat pain behavior and proinflammatory cytokines in a metastatic bone cancer pain model

Objective： To observe the effects of p38 mitogen activated protein kinase （MAPK） inhibitor SB203580 by intrathecal injection on the pain behavior and the spinal proinflammatory cytokines in a rat model of bone cancer pain induced by breast cancer cells. Methods： Eleven rats were used to establish the models of bone cancer pain, six rats were treated by intrathecal SB203580 injection, and the other 5 were as the controls. The paw withdrawal latency （PWL）, histology and the spinal levels of IL-1β and TNF-α were detected. Results： All the 11 rats presented evident bone destruction and thermal hyperalgesia after intra-tibial injection of breast cancer cells. No effect of SB203580 on the bone destruction was observed. However, following intrathecal injection of SB203580, the left PWLs （12.12± 1.26 s at 16 days and 12.99 ± 1.65 s at 19 days） were significant higher than that of controls （9.05 ± 1.08 s at 16 days and 8.55 ± 1.60 s at 19 days）, P 〈 0.05. Meanwhile, inkathecal injection of SB203580 evidently reduced the levels of spinal IL-1β and TNF-α. Conclusion： Intrathecal injection of SB203580 in a rat model of bone cancer pain cannot prevent the tibial destruction but significantly depress the thermalgia sensitivity, which might result from inhibiting inkacellular p38 MAPK signaling transduction, and thereby reducing the release of the proinflammatory cytokines.

Emodin suppresses LPS-induced proinflammatory responses and nuclear factor-B activation by disruption of lipid rafts and TLR-4 recruitment in endothelial cells

Emodin [1,3,8-Trihydroxy-6-methylanthraquinone] has been reported to exhibit vascular anti-inflammatory properties.However,the relevant anti-inflammatory mechanisms are not well understood.The present study was design to explore the molecular target(s) of emodin

Changes of proinflammatory, fluid balance, vascular permeability and oxidative stress in patients with secretory otitis media

Objective: To investigate the changes of proinflammatory, fluid balance, vascular permeability and oxidative stress in patients with secretory otitis media. Methods: A total of 42 patients with secretory otitis media treated in our hospital from September 2016 to January 2018 were selected as the observation group and 42 healthy people as the control group. The levels of proinflammatory effect [including transforming growth factor beta 1 (TGF-β1), transforming growth factor-beta 2 (TGF-β2)], fluid balance [including aquaporin-1 (AQP-1) and aquaporin-4 (AQP-4)], vascular permeability [including hyaluronic acid (HA), fibronectin (Fn) and platelet activating factor (PAF)] and oxidative stress-related indexes [including malondialdehyde (MDA) and superoxide dismutase (SOD)] were observed and compared between the two groups. Results: The levels of AQP-1, AQP-4 and Fn in the observation group were significantly lower than those in the control group. The expression levels were (4.52±0.39) g/L, (23.06±7.21) g/L and (120.59±13.07) mg/L, respectively. The levels of TGF-β1, TGF-β2, HA, PAF, MDA and SOD were significantly higher than those of the control group and the expression levels were (11.99±4.23) 毺g/L, (4.22±1.66) 毺g/L, (70.54±6.99) 毺g/L, (123.83±20.58) ng/mL, (6.30±0.44) nmol/mL and (15.85±0.78) NU/mL, respectively. The difference was statistically significant. Conclusions: Inflammatory reaction occurs in patients with otitis media with secretory otitis media. It is easy to break the liquid balance in the middle ear cavity and to increase vascular permeability and oxidative stress. The relevant indicators should be strengthened in clinical practice, so as to provide evidence for early diagnosis and treatment of the disease.

The Diagnostic Value of the Investigation of the Proinflammatory and Anti-inflammatory Cytokines Levels in the Immune System of Patients with Breast Cancer

Diagnostic value of serumal levels of proinflammatory(TNF-α,IL-1β,IL-6 and IFN-γ) and anti-inflammatory(IL-4 and IL-10) cytokines of immune system is investigated at 54 mammary glands sick by a cancer.The analysis carried out has allowed to tap the raised concentration of such proinflammatory cytokines,as IL-1β,TNF-α and IL-6 in serum of peripheric blood of MGC patients.The analysis of antiinflammatory cytokines in Serum of peripheric blood of MGC patients also has taped authentically raised value of IL-4 and IL-10.The obtained data testify to presence imbalance cellular and humoral factors of the immune system which studying will serve as the important diagnostic criterion of breast cancer.

Production of proinflammatory cytokines in the human THP-1 monocyte cell line following induction by Tp0751,a recombinant protein of Treponema pallidum

The tissue destruction characteristic of syphilis infection may be caused by inflammation due to Treponema pallidum and the ensuing immune responses to the pathogen.T.pallidum membrane proteins are thought to be potent inducers of inflammation during the early stages of infection.However,the actual membrane proteins that induce inflammatory cytokine production are not known,nor are the molecular mechanisms responsible for triggering and sustaining the inflammatory cascades.In the present study,Tp0751 recombinant protein from T.pallidum was found to induce the production of proinflammatory cytokines,including TNF-α,IL-1βand IL-6,in a THP-1 human monocyte cell line.The signal transduction pathways involved in the production of these cytokines were then further investigated.No inhibition of TNF-a,IL-1β,or IL-6 production was observed following treatment with the SAPK/JNK specific inhibitor SP600125 or with an ERK inhibitor PD98059.By contrast,anti-TLR2 mAb,anti-CD14 mAb,and the p38 inhibitor SB203580 significantly inhibited the production of all three cytokines.In addition,pyrrolidine dithiocarbamate (PDTC),a specific inhibitor of NF-κB,profoundly inhibited the production of these cytokines.Tp0751 treatment strongly activated NF-κB,as revealed by Western blotting.However,NF-κB translocation was significantly inhibited by treatment with PDTC.These results indicated that TLR2,CD14,MAPKs/p38,and NF-κB might be implicated in the inflammatory reaction caused by T.pallidum infection.

Characteristics of Proinflammatory Cytokines and Chemokines in Airways of Asthmatics： Relationships with Disease Severity and Infiltration of Inflammatory Cells

Background：Increased proinflammatory cytokines and chemokines might contribute to infiltration of inflammatory cells and remodeling in airways of asthma.Although these molecules may be associated with asthma,there is lack of systemic evidence showing which and how important these events are in the disease.We aimed to analyze the concentrations of these molecules in the airways and relationships with disease severity and with airway infiltration of inflammatory cells in a large cohort of asthmatics （n =70,including 37 mild and 33 moderate/severe asthmatics） compared with controls （n =30）.Methods：Meso scale discovery system and commercial ELISA kits were used to measure the concentrations ofproinflammatory cytokines interleukin （IL）-1 β;tumor necrosis factor-alpha （TNF-α）;IL-6;and IL-17 and CC and CXC chemokines CCL2,CCL4,CCL 11,CCL 13,CCL17,CCL22,and CCL26 and CXCL8,CXCL9,CXCL10,and CXCL1 1 in bronchoalveolar lavage fluid of asthmatics and controls.Results：The concentrations ofIL-1,TNF-α,IL-6,CXCL8 and CXCL 10,and CCL4,CCL 11,CCL 17,and CCL22 were significantly elevated in asthmatics compared with controls （P 〈 0.05）.The concentrations of TNF-α and CXCL8,but not others,were negatively correlated with severity of disease （lung function forced expiratory volume in 1 s） （TNF-α vs.total：r =-0.359,P =0.002 vs.moderate/severe：r =-0.541,P =0.001;CXCL8 vs.total：r =-0.327,P =0.006 vs.moderate/severe：r =-0.625,P =0.0001,respectively）.In addition,concentrations of these two molecules were also correlated with the absolute numbers of infiltrating eosinophils and neutrophils in asthmatic airways.Conclusions：Increased concentrations of TNF-α and CXCL8 are associated with pathogenesis of asthma.Targeting these molecules might provide an alternative therapeutic for this disease.

Phonopheresis Associated with Nanoparticle Gel from Phyllanthus amarus Relieves Pain by Reducing Oxidative Stress and Proinflammatory Markers in Adults with Knee Osteoarthritis

Objective: To determine the changes in serum levels of inflammatory biomarkers and antioxidant levels among the knee osteoarthritis(OA) patients after treatment with Phyllanthus amarus(PP) by nanoparticle gel phonophoresis. Methods: This study was a randomized, double-blind, placebo-control, parallel-group, clinical trial involving 30 subjects with mild-to-moderate degree of knee OA. The patients were allocated to two groups using a computer-generated random numbers, and received conventional ultrasound therapy(control group, 15 cases) and PP(treatment group, 15 cases) once daily for 10 sessions. The pain was evaluated by visual analogue scale(VAS). Serum levels of tumor necrosis factor-α(TNF-α) were determined by enzyme-linked immunosorbnent assay(ELISA). Nitric oxide(NO) was determined by modified Griess reagent. The antioxidant effects, including superoxide dismutase(SOD) and total antioxidant capacity(TAC), were also measured by ELISA assay. Results: The VAS score was significantly decreased in the treatment group compared with the control group after treatment(P<0.01). The serum concentrations of TNF-α and NO were significantly reduced in the treatment group compared with the control group(P<0.01) after treatment. However, the serum concentrations of SOD and TAC in the treatment group were significantly higher after treatment compared with the control group(P<0.01). Conclusion: PP could alleviate knee pain and significantly reduce systemic antiinflammatory effects in knee OA patients.

Drug-containing serum of Xinfeng capsules protect against H9C2 from death by enhancing miRNA-21 and inhibiting toll-like receptor 4/phosphorylated p-38(p-p38)/p-p65 signaling pathway and proinflammatory cytokines expression

OBJECTIVE: To investigate effect of drug-containing serum of Xinfeng capsules on myocardial cell growth.METHODS: Drug-containing serum of Xinfeng capsules rat models were established by intragastricly administrated Xinfeng capsules. MTT assay wasused to evaluated H9C2 cells viability. H9C2 cells were divided into normal control group, triptolide group, lipopolysaccharide(LPS) group, drug-containing serum group and mi RNA-21 inhibitor group. micro RNA-21(mi RNA-21) inhibitor was structured and transfected into H9C2 cells. Western blot and immunofluorescence assay were applied to examine toll-like receptor 4(TLR4), phosphorylated p-38(p-p38) and p-p65 expression. Quantitative real-time PCR(q RT-PCR) was used to evaluated m RNA levels of mi RNA-21. Enzyme linked immunosorbent(ELISA) was used to measure tumor necrosis factor α(TNF-α), IL-6 and IL-17 levels.RESULTS: Drug-containing serum treatment significantly increased cell viability compared to LPS treated group. q RT-PCR results indicated that mi RNA-21 levels were significantly decreased in drugcontaining serum group compared to LPS group.Early and late apoptosis in drug-containing serum group were significantly decreased compared to LPS group. Western blot and immunofluorescence assay results showed that TLR4, p-p38 and p-p65 levels in drug-containing serum group were significantly decreased compared to LPS group. ELISA findings indicated that drug-containing serum significantly decreased inflammatory cytokine levels of TNF-α, IL-6 and IL-17.CONCLUSION: Drug-containing serum of Xinfeng capsules protect against lipopolysaccharide instructed H9C2 cells from death by enhancing mi RNA-21 and inhibiting TLR4/p-p38/p-p65 signaling pathway and proinflammatory cytokines expression.

Ammonia-induced oxidative stress triggered proinflammatory response and apoptosis in pig lungs

Ammonia,a common toxic gas,is not only one of the main causes of haze,but also can enter respiratory tract and directly affect the health of humans and animals.Pig was used as an animal model for exploring the molecular mechanism and dose effect of ammonia toxicity to lung.In this study,the apoptosis of type II alveolar epithelial cells was observed in high ammonia exposure group using transmission electron microscopy.Gene and protein expression analysis using transcriptome sequencing and western blot showed that low ammonia exposure induced T-cell-involved proinflammatory response,but high ammonia exposure repressed the expression of DNA repair-related genes and affected ion transport.Moreover,high ammonia exposure significantly increased 8-hydroxy-2-deoxyguanosine (8-OHdG) level,meaning DNA oxidative damage occurred.In addition,both low and high ammonia exposure caused oxidative stress in pig lungs.Integrated analysis of transcriptome and metabolome revealed that the up-regulation of LDHB and ND2 took part in high ammonia exposure-affected pyruvate metabolism and oxidative phosphorylation progress,respectively.Inclusion,oxidative stress mediated ammonia-induced proinflammatory response and apoptosis of porcine lungs.These findings may provide new insights for understanding the ammonia toxicity to workers in livestock farms and chemical fertilizer plants.

Reproductive stage associated changes in plasma fatty acid profile and proinflammatory cytokine expression in rat mammary glands

Mastitis is a common disease for mammals all around the world. Figuring out why mastitis mainly occurs around parturition may be helpful for dealing with the disease. Lipolytic activity and oxidative stress take place around parturition, which may leads to alteration in fatty acids profile and proinflammatory cytokine expression. Thus, the aim of the present study was to further our understanding about the high incidence of mastitis around parturition by comparison of plasma fatty acid profile and mammary inflammation indicators at different reproductive stages. A total of 47 female rats were included in the present study. After mating, all the pregnant and non-pregnant rats began to receive the same experimental diet. Blood samples were collected at day 1 and 14 of gestation as well as day 3 postpartum.Mammary samples were collected at day 14 of gestation and day 3 postpartum from pregnant and nonpregnant rats. The results showed that rats at d 3 postpartum had greater(P < 0.05) plasma concentrations of non-esterified fatty acids(NEFA), arachidonic acid(ARA) and docosahexaenoic acid(DHA) as well as ARA: eicosapentaenoic acid(EPA) ratio than those at d 14 of gestation. The mRNA abundances of interleukin-1 β(IL-1β), tumor necrosis factor-α(TNF-α),IL-8 and xanthine oxidoreductase(XOR) in mammary of the pregnant rats were greater(P < 0.05) than those in age-matched non-pregnant rats.Rats at d 3 postpartum had higher(P < 0.05) protein expression levels of IL-1β and TNF-α as well as meloperoxidase(MPO) activity and polymorphonuclear neutrophils(PMN) prevalence than those at d 1 of gestation. The rats at d 3 postpartum also had greater(P < 0.05) IL-1β and MPO activity than those at d 14 of gestation. The results indicated that elevated mammary expression of proinflammatory cytokines and XOR as well as altered fatty acid profile around parturition might facilitate the recruitment of neutrophils into mammary glands.

Antidepressant effects of Yuanzhi (Polygalae Radix) extract on chronic unpredictable mild stress-induced depression in rats: modulation of the NLRP3 inflammasome and NF-κB pathway

Objective To investigate the antidepressant effects of Yuanzhi(Polygalae Radix;PR)aqueous extract on chronic unpredictable mild stress(CUMS)-induced depression rat models and the underlying mechanisms.Methods A total of 40 male Sprague Dawley(SD)rats were randomly divided into control;model;low dose of PR(PR-L;0.5 g/kg);high dose of PR(PR-H;1 g/kg);and fluoxetine(10 mg/kg)groups;with 8 rats in each group.Except for the rats in control group;those in the other four groups underwent CUMS-induced depression modeling.PR and fluoxetine were administered intragastrically once daily;30 min prior to the CUMS procedure;for 14 consecu-tive days until the behavioral tests were performed.After CUMS modeling;the sucrose prefer-ence test(SPT);open field test(OFT);novelty-suppressed feeding test(NSFT);forced swim test(FST);and tail suspension test(TST)were employed to assess the pharmacological ef-fects of PR on the mitigation of depressive-like behaviors in rat models.Additionally;the en-zyme-linked immunosorbent assay(ELISA)was utilized to quantify the serum levels of tumor necrosis factor(TNF)-α;interleukin(IL)-6;and IL-1βin the rats.Western blot analysis was al-so conducted to evaluate the protein expression levels of nuclear factor kappa-B(NF-κB);in-ducible nitric oxide synthase(iNOS);cyclooxygenase-2(COX-2);nucleotide-binding oligomerization domain(NOD)-like receptor family pyrin domain containing 3(NLRP3);apoptosis-associated speck-like protein containing caspase recruitment domain(ASC);and caspase-1 in the hippocampal tissues of the rats.Immunofluorescence staining was per-formed to observe the morphological changes in ionized calcium-binding adapter molecule 1 positive(Iba-1+)cells in the dentate gyrus(DG)of rats with CUMS-induced depression.Results(i)Treatment with PR-H and fluoxetine resulted in significant enhancements in both the total distance and time the rats moved during tests(P<0.01 and P<0.05;respectively).Post-administration of PR-H and fluoxetine also led to statistically significant increase in su-crose preference among rats(P<0.05).Besides;PR-L;PR-H;and fluoxetine treatment markedly decreased the latency of ingestion(P<0.05;P<0.05;and P<0.01;respectively).As observed from the FST;PR-L;PR-H;and fluoxetine presented antidepressant effects on rats with CUMS-induced depression;leading to the reduction in time of their immobility(P<0.05;P<0.01;and P<0.01;respectively).The results of TST indicated reduced immobility time in rats receiving PR-H and fluoxetine treatment as well(P<0.01).(ii)Rats in model group showed an increase in the levels of Iba-1+microglia in their left and right brains in compari-son with control group(P<0.01).However;such increase was negated post PR treatment(P<0.01).Treatment with PR-L;PR-H;and fluoxetine considerably reduced the levels of inflam-matory factors(TNF-α;IL-1β;and IL-6;P<0.01).In addition;treatment of PR-L and PR-H ef-fectively counteracted the elevated levels of NLRP3;ASC;and caspase-1;and markedly down-regulated the expression levels of phosphorylated p65(p-p65);COX-2;and iNOS in rats’hip-pocampus(P<0.01).Conclusion Collectively;these findings indicate that PR exerts an antidepressant effect on rats with CUMS-induced depression partially through the modulation of the NLRP3 and NF-κB signaling pathways.

Interaction between serum inflammatory cytokines and brain-derived neurotrophic factor in cognitive function among first-episode schizophrenia patients

BACKGROUND The pathogenesis of cognitive impairment in schizophrenia(SCZ)remains unclear.Accumulating studies showed that inflammatory-immune dysregulation and altered brain derived neurotrophic factor(BDNF)levels play a crucial role in the psychopathology of SCZ.However,their association with cognitive dysfunction in first-episode SCZ patients has not been thoroughly investigated.AIM To explore the interaction effects between cognitive function and inflammatory cytokines and BDNF in first-episode SCZ.METHODS The current study is a cross-sectional case-control investigation that recruited 84 patients with first-episode SCZ(SCZ group)and 80 healthy controls(HCs group)at the Huzhou Third Municipal Hospital between August 2021 and September 2023.ELISA was employed to measure the serum levels of interleukin(IL)-1β,IL-4,IL-6,IL-10,and BDNF.The Chinese brief cognitive test(C-BCT)and the positive and negative syndrome scales were measured the severity of cognitive impairment and psychiatric symptoms.RESULTS Compared to the HC group,the SCZ group exhibited elevated IL-1βand IL-6 levels,decreased BDNF levels,and reduced C-BCT scores(all P<0.001).In SCZ,BDNF was negatively correlated with IL-6(r=-0.324,P<0.05).Information processing speed was negatively correlated with IL-6(r=-0.315,P<0.05)and positively with BDNF(r=0.290,P<0.05);attention,working memory,comprehensive ability,and executive function were negatively correlated with IL-1βand IL-6(all P<0.05)and positively with BDNF(all P<0.05).Multiple regression analysis showed IL-6 influenced C-BCT dimensions(β=-0.218 to-0.327,all P<0.05);attention and executive ability were influenced by IL-1β(β=-0.199 to-0.261,all P<0.05);comprehensive executive ability was influenced by BDNF(β=0.209,P<0.05).CONCLUSION Our findings suggested that interrelationships between immune dysfunction and neurotrophic deficiency might underlie the pathological mechanisms of cognitive impairments in first-episode SCZ patients.

Clostridium butyricum alleviates intestinal low-grade inflammation in TNBS-induced irritable bowel syndrome in mice by regulating functional status of lamina propria dendritic cells

BACKGROUND Irritable bowel syndrome (IBS) is one of the most common functional gastroenterological diseases characterized by abnormal visceral sensitivity and lowgrade inflammation. The role of Clostridium butyricum (C. butyricum) in reducing intestinal low-grade inflammation via immune pathways has been well defined. However, the detailed mechanisms of the effects of C. butyricum on intestinal mucosal immunity, especially on immune cells of the lamina propria, remain unclear. Dendritic cells (DCs), which are important immune cells, secrete proinflammatory cytokines (IL-1β, IL-6, and others) and express T cell immunoglobulin and mucin domain-3 (TIM3), promoting proliferation and activation of DCs, and mediating Th1 and Th17 inflammatory responses. AIM To investigate the role of DCs in the development of IBS in a rat model and to understand the regulation of DCs after C. butyricum intervention. METHODS An IBS animal model was established using C57BL/6 mice, and C. butyricum was continuously administered via the intragastric route to simulate different intestinal immune states. Intestinal visceral hypersensitivity and histopathology were assessed using the abdominal withdrawal reflex (AWR) test and hematoxylin & eosin (H&E) staining, respectively. The expression of proinflammatory cytokines (IL-1β and IL-6) and TIM3 was analyzed by Western blot analysis and real-time PCR. Flow cytometry was applied to analyze the quantity, function, and membrane molecule TIM3 of the lamina propria dendritic cells (LPDCs). The regulatory effect of C. butyricum was verified in bone marrowderived dendritic cells by in vitro experiments. RESULTS The secretion of proinflammatory cytokines (IL-1β and IL-6) in mice with IBS was significantly increased compared with that of the control group, which suggested that the intestinal mucosa in mice with IBS was in a low-grade inflammatory state. The expression of CD11C+CD80+ and CD11c+TIM3+ in intestinal LPDCs in mice with IBS increased significantly. Meanwhile, the cytokines (IL-1β and IL-6) were significantly reduced after the intervention with probiotic C. butyricum. The amount and function of LPDCs and the TIM3 on the surface of the LPDCs were decreased with the alleviation of the intestinal inflammatory response. CONCLUSION The results suggest that C. butyricum regulates the amount and functional status of LPDCs in the intestinal mucosa of mice with IBS, and therefore modulates the local immune response in the intestine.

Convergence of neuro-endocrine-immune pathways in the pathophysiology of irritable bowel syndrome

Disordered signalling between the brain and the gut are generally accepted to underlie the functional bowel disorder, irritable bowel syndrome(IBS). However, partly due to the lack of disease-defining biomarkers, understanding the aetiology of this complex and multifactorial disease remains elusive. This common gastrointestinal disorder is characterised by alterations in bowel habit such as diarrhoea and/or constipation, bloating and abdominal pain, and symptom exacerbation has been linked with periods of stress, both psychosocial and infection-related. Indeed, a high level of comorbidity exists between IBS and stress-related mood disorders such as anxiety and depression. Moreover, studies have observed alterations in autonomic output and neuro-endocrine signalling in IBS patients. Accumulating evidence indicates that a maladaptive stress response, probably mediated by the stress hormone, corticotropin-releasing factor contributes to the initiation, persistence and severity of symptom flares.Other risk factors for developing IBS include a positive family history, childhood trauma, dietary factors and prior gastrointestinal infection. An emerging role has been attributed to the importance of immune factors in the pathophysiology of IBS with evidence of altered cytokine profiles and increased levels of mucosal immune cells. These factors have also been shown to have direct effects on neural signalling. This review discusses how pathological changes in neural, immune and endocrine pathways, and communication between these systems, contribute to symptom flares in IBS.