Concentrations Of Inflammatory Cytokines Research Articles

Effects of combustible cigarettes and electronic nicotine delivery systems on the development and progression of chronic lung inflammation in mice.

Although detrimental effects of combustible cigarettes (CCs) on the progression of lung inflammatory diseases are well known, changes in electronic nicotine delivery systems (ENDS)-exposed lung-infiltrated immune cells are still unrevealed. The analysis of blood gas parameters, descriptive and quantitative histology of lung tissues, determination of serum cytokines, intracellular staining and flow cytometry analysis of lung-infiltrated immune cells were used to determine the differences in the extent of lung injury and inflammation between mice from experimental (CC and ENDS-exposed animals) and control group (Air-exposed mice). Continuous exposition to either CCs or ENDS induced severe systemic inflammatory response, increased activation of NLRP3 inflammasome in neutrophils and macrophages and enhanced dendritic cell-dependent activation of Th1 and Th17 cells in the lungs. ENDS induced less severe immune response than CCs. Serum concentrations of inflammatory cytokines were significantly lower in the samples of ENDS-exposed mice. Compared to CCs, ENDS recruited lower number of circulating leukocytes in injured lungs and had less capacity to induce CD14/TLR-2-dependent activation of NLRP3 inflammasome in lung-infiltrated neutrophils and macrophages. ENDS-primed dendritic cells had reduced capacity for the generation of Th1 and Th17 cell-driven lung inflammation. Accordingly, extensive immune cell-driven lung injury resulted in severe respiratory dysfunction in CCs-exposed mice, while ENDS caused moderate respiratory dysfunction in experimental animals. Continuous exposition to either CCs or ENDS induced immune cell-driven lung damage in mice. ENDS triggered immune response which was less potent than inflammatory response elicited by CCs and, therefore, caused less severe lung injury and inflammation. This is the first study that compared the effects of CCs and ENDS on lung-infiltrated immune cells. Although both CCs and ENDS elicited systemic inflammatory response, immune cell-driven lung injury and inflammation were less severe in ENDS-exposed than in CC-exposed animals. Continuous exposition to ENDS-sourced aerosols was less harmful for respiratory function of experimental animals than CC-derived smoke.

CD33-Deleted Hematopoietic Cells (Trem-Cel) Are Protected from CD33xCD3 Bispecific Antibody Treatment and Produce Significantly Reduced Levels of Inflammatory Cytokines in Preclinical Studies

INTRODUCTION: Acute myeloid leukemia (AML) is the most common form of adult acute leukemia. Currently, allogeneic hematopoietic stem cell transplant (HCT) is the standard of care for high-risk patients yet ~40% patients will relapse, emphasizing the need for new therapeutic approaches. Effective targeted therapy in AML has been hampered by a lack of cancer specific targets. One described AML target is CD33, a glycoprotein expressed predominantly on normal myeloid cells and the majority of AML cells. However, CD33-directed therapies have been challenged by cytopenias due to on-target, off-tumor toxicity and, in the case of bispecific antibodies, cytokine release syndrome (CRS). Tremtelectogene empogeditemcel (trem-cel) is a gene-edited hematopoietic stem and progenitor cell (HSPC) transplant product currently in clinical trial (NCT04849910) whereby CD33, shown to be dispensable for normal hematopoiesis and function, is deleted to allow for post-HCT treatment with CD33-directed immunotherapies with reduced myelotoxicity as the reconstituted hematopoietic compartment lacks CD33. JNJ-67571244, a bispecific antibody that binds to both CD3 and CD33, is capable of inducing T cell recruitment for CD33-directedtumor cytotoxicity. This study examines whether CD33 neg hematopoietic cells are protected from JNJ-67571244 and if CD33 neg human HSPC (hHSPC) xenotransplanted mice have reduced levels of inflammatory cytokines associated with CRS when treated with JNJ-67571244. METHODS: In vitro proof-of-concept (POC) studies were carried out using CD3 + T cells co-cultured with JNJ-67571244 and AML target cell lines. Further studies were conducted with CD34 + hHSPCs that were either CRISPR/Cas9 gene edited to delete CD33 or treated with a non-targeting gRNA control (gCtrl) followed by differentiation towards the monocytic lineage. These in vitro differentiated monocytes (MIVD) were assayed for editing frequency, CD33protein expression and myeloid phenotype by flow cytometry prior to co-culture with donor matched T cells and JNJ-67571244 ranging from 0.5 pM to 500 nM. Cytotoxicity was analyzed using flow cytometry at 48 and 72 hr and cytokine concentrations in the supernatants were measured using Luminex. For in vivo POC studies, CD33 or gCtrl-edited CD34 + hHSPCs were xenotransplanted into NSG-SGM3 mice followed by treatment with either control bispecific (CD3xNull) or JNJ-67571244 at 0.5 mg/kg. Plasma cytokine concentration were measured via Luminex and hematopoietic tissues were analyzed by flow cytometry to measure protection from JNJ-67571244 cytotoxic killing. RESULTS: Annexin V and Live/Dead staining showed that JNJ-67571244 was able to induce AML target cell killing by human T cells. Importantly CD33 neg MIVD cells co-cultured with T cells and JNJ-67571244 were significantly more viable at all doses compared to gCtrl cells. The EC 50 of gCtrl MIVD was 0.0208 nM whereas the CD33 neg MIVD EC 50 was at least 20,000-fold higher (>430.8 nM). T cell activation, measured by CD25 and CD69 positivity, and release of cytokines that are associated with CRS such as IFN-γ, TNF-α, IL-2, IL-6 and IL-10, were all significantly decreased in the CD33 neg MIVD cells treated with JNJ-67571244 compared to the gCtrl group at all doses. Analysis of blood and bone marrow from xenotransplant studies revealed that JNJ-67571244 was effective at killing CD33 + cells as well as CD14 + monocytes in the gCtrl group treated with JNJ-67571244. Conversely, CD14 + monocytes and CD15 + neutrophils derived from CD33-edited hHSPCs, were not significantly reduced in cell number when treated with JNJ-67571244 suggesting that they were protected from JNJ-67571244 specific killing. IFN-γ, TNF-α, IL-2, IL-6 and IL-10, were all significantly decreased in mice transplanted with CD33-edited hHSPCs compared to gCtrl group in response to JNJ-67571244. CONCLUSIONS: Taken together, these studies demonstrate that CD33 deleted hematopoietic compartment is protected from the CD33 directed immuno-therapy JNJ-67571244 both in in vitro cytotoxicity assays and preclinical xenotransplantation studies, with decreased concentrations of inflammatory cytokines associated with CRS. These findings enable the development of a next-generation AML treatment strategy by pairing trem-cel transplant with a subsequent CD33-directed bispecific compound to potentially improve safety and efficacy while minimizing myelotoxicity.

High throughput sequencing technology reveals alteration of lower respiratory tract microbiome in severe aspiration pneumonia and its association with inflammation

BackgroundAspiration pneumonia is a common and severe clinical condition. The microbiome present in the lower respiratory tract plays a crucial role in regulating human inflammatory response. However, the relationship between the altered lower respiratory tract microbiome and inflammation in aspiration pneumonia remains inadequately explored. PurposeTo investigate the alteration of the lower respiratory tract microbiome in severe aspiration pneumonia patients and explore the potential correlation between microbiome components and inflammatory response. MethodPatients in the severe aspiration pneumonia group and control group were enrolled from the intensive care unit of Jinshan Hospital, Fudan University between December 31, 2020 and August 19, 2021. Sputum specimens were collected from all participants and subsequently subjected to 16S rDNA high throughput sequencing technology. The concentration of inflammatory cytokines in serum was measured using enzyme-linked immunosorbent assay (ELISA) kits, and collected data including patients' demographic information, clinical data, and laboratory examination results were recorded for further analysis. ResultsAlteration in the lower respiratory tract microbiome was observed in severe aspiration pneumonia. Compared to the control group, a significant decrease in the relative abundance of Firmicutes was found at the phylum level (P < 0.01). At the family level, the relative abundance of Corynebacteriaceae, Enterobacteriaceae and Enterococcaceae increased significantly (P < 0.001, P < 0.05, P < 0.01). There were no significant differences in community diversity of the lower respiratory tract between the two groups. Patients in the severe aspiration pneumonia group exhibited significantly higher levels of inflammation compared to those in the control group. Correlation analysis showed that the relative abundance of Corynebacteriaceae was positively correlated with the expression level of IL-1β and IL-18 (P = 0.002, P = 0.02); the relative abundance of Enterobacteriaceae was negatively correlated with IL-4 (P = 0.011); no other significant correlations have been identified between microbiome and inflammatory indicators thus far (P > 0.05). ConclusionsAlteration of the lower respiratory tract microbiome is critically involved in inflammation and disease progression in severe cases of aspiration pneumonia. The potential inflammation regulation properties of the microbiome hold promising value for developing novel therapeutic approaches aimed at mitigating the severity of the disease.

Immunotherapeutic treatment of inflammation in mice exposed to methamphetamine.

Currently, there are no FDA-approved medications to treat methamphetamine addiction, including the inflammatory, neurotoxic, and adverse neuropsychiatric effects. We have shown that partial (p)MHC class II constructs (i.e., Recombinant T-cell receptor Ligand - RTL1000), comprised of the extracellular α1 and β1 domains of MHC class II molecules linked covalently to myelin oligodendrocyte glycoprotein (MOG)-35-55 peptide, can address the neuroimmune effects of methamphetamine addiction through its ability to bind to and down-regulate CD74 expression, block macrophage migration inhibitory factor (MIF) signaling, and reduce levels of pro-inflammatory chemokine ligand 2 (CCL2). The present study evaluated the effects of our third-generation pMHC II construct, DRmQ, on cognitive function and concentration of inflammatory cytokines in the frontal cortex, a region critical for cognitive functions such as memory, impulse control, and problem solving. Female and male C57BL/6J mice were exposed to methamphetamine (or saline) via subcutaneous (s.c.) injections administered four times per day every other day for 14 days. Following methamphetamine exposure, mice received immunotherapy (DRmQ or ibudilast) or vehicle s.c. injections daily for five days. Cognitive function was assessed using the novel object recognition test (NORT). To evaluate the effects of immunotherapy on inflammation in the frontal cortex, multiplex immunoassays were conducted. ANOVA was used to compare exploration times on the NORT and immune factor concentrations. Post hoc analysis revealed increased novel object exploration time in MA-DRmQ treated mice, as compared to MA-VEH treated mice (non-significant trend). One-way ANOVA detected a significant difference across the groups in the concentration of macrophage inflammatory protein-2 (MIP-2) (p = 0.03). Post hoc tests indicated that mice treated with methamphetamine and DRmQ or ibudilast had significantly lower levels of MIP-2 in frontal cortex, as compared to mice treated with methamphetamine and vehicle (p > 0.05). By specifically targeting CD74, our DRQ constructs can block the signaling of MIF, inhibiting the downstream signaling and pro-inflammatory effects that contribute to and perpetuate methamphetamine addiction.

Association of inflammation with shock severity, 30-day mortality and therapy response in patients with cardiogenic shock

Abstract Background Elevated concentrations of C-reactive protein (CRP) and other circulating cytokines are often found in cardiogenic shock (CS). The role of systemic inflammation in the pathogenesis of cardiogenic shock remains unclear. To address this, associations between elevated plasma CRP concentrations upon admission with shock severity, 30-day mortality, and therapy response were analysed in patients with CS. Methods Plasma CRP concentrations were identified in a large data base containing unselected patients admitted with cardiogenic shock. The association between plasma CRP concentrations and CS severity (SCAI stage, reference SCAI B) was analyzed using adjusted linear and logistic regression models. The association between plasma CRP concentrations and 30-day mortality was analyzed using adjusted Cox regression models. The interaction between plasma CRP concentrations and treatment response was assessed by fitting an interaction term between plasma CRP concentrations and the use of mechanical circulatory support (MCS) in the above described Cox regression models. Results A total of 1116 patients were analysed. Median age was 70 years [interquartile range 58-78.6 years], 71.3% were male, 47.7% presented with CS due to acute myocardial infarction, and 58.3% with prior cardiac arrest. The median plasma CRP concentration was 17 mg/dl [interquartile range 5.0-71.0 mg/dl]. Plasma CRP concentrations were equally distributed among patients with higher vs. lower shock severity (higher SCAI stage). After adjustment for CS severity and other cofounders, higher plasma CRP concentrations were associated with higher 30-day mortality [8% relative risk increase per 50 mg/dl increase in plasma CRP, range 3-13%, adjusted p&amp;lt;0.001]. The association of plasma CRP concentration and 30-day mortality was abolished in patients treated with MCS [HR for CRP&amp;gt;median: MCS use 0.92 (95%-CI: 0.67-1.26; p=0.59)], while plasma CRP concentration was associated with 30-day mortality in patients not treated with MCS [HR for CRP&amp;gt;median 1.50 (95%-CI: 1.21-1.86; p&amp;lt;0.001); p-interaction=0.01]. Conclusion Increased concentrations of inflammatory cytokines are associated with a higher 30-day mortality regardless of shock severity. This association is abolished when mechanical circulatory support systems are used, potentially by providing sufficient end-organ perfusion. This interaction calls for further research on this topic.

Neurological manifestations with jugular vein thrombosis linked to an inflammatory profile may be a sequela of long COVID

AbstractMore than 670 million cases of coronavirus disease 2019 (COVID‐19) have been recorded worldwide in the 3 years since the start of the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) pandemic. About 45% of survivors of COVID‐19 develop a syndrome known as long‐term COVID, in which symptoms persist even months after the acute infection. About 76% of patients with long COVID experience neurological manifestations. Moreover, patients who have survived COVID‐19 have an increased risk of cerebral venous thrombosis. This case report describes a 41‐year‐old woman who developed neurological manifestations associated with jugular vein thrombosis 24 h after administration of the Oxford–AstraZeneca (ChAdOx1 nCoV‐19) vaccine (AstraZeneca‐Serum Institute of India). She had been infected with SARS‐CoV‐2 three months before vaccination. Although initially suspected to be a case of vaccine‐induced immune thrombotic thrombocytopenia (VITT) in view of her recent vaccination, the patient did not have any hallmarks of VITT, such as thrombocytopenia, an increased d‐dimer level, or antibodies against platelet factor‐4. Moreover, the neurological manifestations were associated with a high concentration of inflammatory cytokines, including interleukin (IL)‐6, IL‐17A, and IL‐21, and elevated neutrophil levels in cerebrospinal fluid, suggesting that inflammatory immune components had a role in the development of thrombotic events and pointing to an alternative diagnosis. In this case, the laboratory results indicated that the neurological manifestations associated with jugular vein thrombosis were not associated with VITT. Therefore, we propose that the thrombosis of the left jugular vein was a sequela of SARS‐CoV‐2 infection.

LONG-TERM COVID-19 EFFECT TO ENDOTHELIAL DAMAGE TROUGH EXTRINSIC APOPTOSIS LED TO CARDIOVASCULAR DISEASE PROGRESSION: AN UPDATE REVIEW

COVID-19 can involve persistence, sequelae, and other medical complications that last weeks to months after initial recovery; these prolonged symptoms called as long-term covid-19 effect. Symptoms, signs, or abnormal clinical parameters persisting two or more weeks after COVID-19 onset that do not return to a healthy baseline can potentially be long-term effects of the disease. SARS-CoV-2 affects the cardiovascular system and causes conditions such as myocarditis, arrhythmias, and myocardial injury. Vascular damage from COVID-19 has been affected directly by the SARS-CoV-2 virus infection and indirectly by systemic inflammatory cytokine storm. This damage can be long-lasting and lead to various cardiovascular complications. Fas ligand (FasL)-Fas complex is a death factor that induces cell apoptosis. Fas and FasL have been detected in the endothelial wall, and it has been proposed that Fas-mediated apoptosis has a role in physiological and pathological cell turnover in the endothelial wall. High concentrations of inflammatory cytokines, such as cytokines storm induced by SARS-CoV-2 infection, are thought to increase the expression of FasL, which leads to an increase in the regulation of extrinsic apoptosis in endothelial cells leading to endothelial damage. This article summarises the current understanding of the long-term covid-19 effect on endothelial damage through extrinsic apoptosis Fas-FasL complex.

PSI-1 Assessing the Impact of Hempseed Meal Supplementation on Inflammatory Cytokine Concentrations in Boer X Spanish Intact Male Goats

Abstract This study aimed to evaluate the effect of hempseed meal (HSM) supplementation on the concentrations of inflammatory cytokines in intact male goats. Effect on the concentration of pro-inflammatory cytokines, interleukin (IL) 2 , IL-6, tumor necrosis factor-alpha (TNF-α), and interferon-gamma (INF-γ) and anti-inflammatory cytokines,; IL-4 and IL10, were evaluated via chicken-ovalbumin challenge. Thirty-six Boer x Spanish intact male goats, 10 to 11 months of age and bodyweights of 44.1 ± 3.8 kg, were randomly assigned to one of the four experimental diets (n = 9 goats/diet): 0% (control), 10%, 20%, and 30% HSM diets and fed ad libitum for 60 days. Experimental diets were formulated as total mixed ration (TMR), and the nutrient content of each diet was formulated to be iso-nitrogenous (18% crude protein) and to meet or exceed the nutrient requirement of breeding male goats. On day 46, goats were injected subcutaneously with chicken ovalbumin (2.5 mg) prepared in saline solution and alhydrogel as an adjuvant. On 14 days of post-injection, serum samples were collected and analyzed for cytokines concentrations using an indirect enzyme-linked immunosorbent assay. Data were analyzed using one-way ANOVA and Kruskal-Wallis test using R version 4.2.1. Results show no significant difference (P &amp;gt; 0.05) among the experimental groups in terms of studied pro-inflammatory cytokines (IL-2, IL-6, TNF-α, and INF-γ) as well as anti-inflammatory cytokines (IL-4 and IL-10) concentrations (Table 1). Results indicate that the inclusion of HSM up to 30 % in the diet does not affect the production of pro-inflammatory and anti-inflammatory cytokines in intact male goats. This study provides valuable insights into the impact of HSM supplementation on inflammatory response in goats.

Excessive Glucose and Fructose Intake Aggravates the Pathogenesis of Rat Experimental Colitis

Ulcerative colitis (UC) is a relapsing and remitting disease that causes chronic inflammation and ulceration of colonic tissue, especially in the rectum region. Although sugars are rapidly digested and absorbed and can be efficiently utilized as energy in the body, they are also known to promote inflammation. Herein, we aimed to examine the effects of special diets containing excess glucose (Glu) or fructose (Fru) on the pathogenesis of dextran sulfate sodium (DSS)-induced UC in Wistar rats. The model rats (termed UC rats or UCR) were divided into three groups: DSS group, UCR fed a regular diet; DSS + Glu group, UCR fed a special diet mixed with glucose at 63% calories; DSS + Fru group, UCR fed a special diet mixed with fructose at 63% calories. The DSS + Glu and DSS + Fru groups exhibited a lower weight and colon length than the DSS group. The DSS + Fru group had a lower diet and DSS intake than the other two groups. The microscopic findings revealed that the DSS + Glu and DSS + Fru groups tended to have higher severity scores than the DSS group. The DSS + Fru group tended to have higher serum and colonic tissue concentrations of inflammatory cytokines than the DSS + Glu group. Collectively, these findings suggest that excessive glucose and fructose intake can aggravate intestinal inflammation.

Clinical Trial Protocol for BEACH: A Phase 2a Study of MW189 in Patients with Acute Nontraumatic Intracerebral Hemorrhage

Patients with acute spontaneous intracerebral hemorrhage (ICH) develop secondary neuroinflammation and cerebral edema that can further damage the brain and lead to increased risk of neurologic complications. Preclinical studies in animal models of acute brain injury have shown that a novel small-molecule drug candidate, MW01-6-189WH (MW189), decreases neuroinflammation and cerebral edema and improves functional outcomes. MW189 was also safe and well tolerated in phase 1 studies in healthy adults. The proof-of-concept phase 2a Biomarker and Edema Attenuation in IntraCerebral Hemorrhage (BEACH) clinical trial is a first-in-patient, multicenter, randomized, double-blind, placebo-controlled trial. It is designed to determine the safety and tolerability of MW189 in patients with acute ICH, identify trends in potential mitigation of neuroinflammation and cerebral edema, and assess effects on functional outcomes. A total of 120 participants with nontraumatic ICH will be randomly assigned 1:1 to receive intravenous MW189 (0.25 mg/kg) or placebo (saline) within 24 h of symptom onset and every 12 h for up to 5 days or until hospital discharge. The 120-participant sample size (60 per group) will allow testing of the null hypothesis of noninferiority with a tolerance limit of 12% and assuming a “worst-case” safety assumption of 10% rate of death in each arm with 10% significance and 80% power. The primary outcome is all-cause mortality at 7 days post randomization between treatment arms. Secondary end points include all-cause mortality at 30 days, perihematomal edema volume after symptom onset, adverse events, vital signs, pharmacokinetics of MW189, and inflammatory cytokine concentrations in plasma (and cerebrospinal fluid if available). Other exploratory end points are functional outcomes collected on days 30, 90, and 180. BEACH will provide important information about the utility of targeting neuroinflammation in ICH and will inform the design of future larger trials of acute central nervous system injury.

Timing of anti–PD-L1 antibody initiation affects efficacy/toxicity of CD19 CAR T-cell therapy for large B-cell lymphoma

AbstractMore than half of the patients treated with CD19-targeted chimeric antigen receptor (CAR) T-cell immunotherapy for large B-cell lymphoma (LBCL) do not achieve durable remission, which may be partly due to PD-1/PD-L1–associated CAR T-cell dysfunction. We report data from a phase 1 clinical trial (NCT02706405), in which adults with LBCL were treated with autologous CD19 CAR T cells (JCAR014) combined with escalating doses of the anti–PD-L1 monoclonal antibody, durvalumab, starting either before or after CAR T-cell infusion. The addition of durvalumab to JCAR014 was safe and not associated with increased autoimmune or immune effector cell–associated toxicities. Patients who started durvalumab before JCAR014 infusion had later onset and shorter duration of cytokine release syndrome and inferior efficacy, which was associated with slower accumulation of CAR T cells and lower concentrations of inflammatory cytokines in the blood. Initiation of durvalumab before JCAR014 infusion resulted in an early increase in soluble PD-L1 (sPD-L1) levels that coincided with the timing of maximal CAR T-cell accumulation in the blood. In vitro, sPD-L1 induced dose-dependent suppression of CAR T-cell effector function, which could contribute to inferior efficacy observed in patients who received durvalumab before JCAR014. Despite the lack of efficacy improvement and similar CAR T-cell kinetics early after infusion, ongoing durvalumab therapy after JCAR014 was associated with re-expansion of CAR T cells in the blood, late regression of CD19+ and CD19– tumors, and enhanced duration of response. Our results indicate that the timing of initiation of PD-L1 blockade is a key variable that affects outcomes after CD19 CAR T-cell immunotherapy for adults with LBCL.

Sevoflurane suppresses ALG13 transcription in a CREBBP-dependent manner to induce hippocampal damage and cognitive impairment

BackgroundSevoflurane (Sev) is a common clinical anesthetic but may lead to cognitive impairment. This study aims to deconstruct the underpinning molecular mechanism involved in Sev-induced neurological damage. MethodsBioinformatics analyses was conducted to investigate candidate cognitive impairment-related physiological targets of Sev. C57BL/6 mice and SH-SY5Y cells were exposed to Sev to generate animal and cellular models, respectively. Neurological impairment in mice was evaluated by Morris water maze test, modified Longa scoring, and pathological changes and cell apoptosis in the hippocampal tissues. In vitro, viability, apoptosis, and inflammatory cytokine concentration in SH-SY5Y cells were measured. Gain- or loss-of-function studies of CREB binding protein (CREBBP) and its predicted target asparagine-linked glycosylation 13 (ALG13) were performed in mice and in SH-SY5Y cells to investigate their roles in neural damage. ResultsSev treatment induced neurological deficit in mice and damage on SH-SY5Y cells, and it reduced protein level of CREBBP in both models. CREBBP overexpression restored learning and memory ability of mice, reduced neurological deficit score, and reduced cell apoptosis while enhancing neuronal viability in the hippocampus. In vitro, the CREBBP overexpression increased viability while suppressing apoptosis and inflammation in SH-SY5Y cells. CREBBP bound to the ALG13 promoter to increase its transcription. Further knockdown of ALG13 negated the neuro-protective functions of CREBBP in vivo and in vitro. ConclusionThis study demonstrates that Sev targets CREBBP to inhibit ALG13 transcription to induce hippocampal damage and cognitive impairment.

10-hydroxy-2-decenoic acid alleviates lipopolysaccharide-induced intestinal mucosal injury through anti-inflammatory, antioxidant, and gut microbiota modulation activities in chickens.

This study aimed to investigated the effects of 10-hydroxy-2-decenoic acid (10-HDA) on the growth performance, intestinal barrier, inflammatory response, oxidative stress, and gut microbiota of chickens challenged with lipopolysaccharide (LPS). A total of 240 one-day-old chickens were randomly assigned to five treatment groups: (1) control group (basal diet + saline); (2) LPS group (basal diet + LPS); (3) Chlortetracycline (CTC) group (basal diet containing 75 mg/kg CTC + LPS); (4) 0.1% 10-HDA group (basal diet containing 1 g/kg 10-HDA + LPS); and (5) 0.5% 10-HDA group (basal diet containing 5 g/kg 10-HDA + LPS). All chickens were injected intraperitoneally with 0.5 mg/kg body weight of either LPS or saline at 17, 19, and 21 days of age. The results showed that dietary 10-HDA supplementation attenuated the loss in growth performance caused by the LPS challenge (p < 0.05). 10-HDA effectively alleviated LPS-induced intestinal mucosal injury, as evidenced by reduced bleeding, decreased serum diamine oxidase levels (p < 0.05), and increased villus/crypt ratios of the jejunum and ileum (p < 0.05). Dietary treatment with 0.1% 10-HDA reduced the concentrations of inflammatory cytokines (TNF-α, IL-1β, IL-6; p < 0.05), and increased immunoglobulin (IgA, IgG) and antioxidant enzyme levels (CAT, GSH-px, T-SOD) in the serum of LPS-challenged chickens (p < 0.05). These effects were similar to those observed in the CTC group. Moreover, 0.1% 10-HDA treatment reversed the LPS-induced variations in the mRNA expression of genes related to inflammation, antioxidant capacity, and intestinal tight junctions (p < 0.05). 16S rRNA analysis revealed that 10-HDA supplementation increased the relative abundance of Faecalibacterium and Clostridia_UCG-014 (p < 0.05). Additionally, it decreased the abundance of Clostridia_vadinBB60_group, Eubacterium_nodatum_group, and UC5-1-2E3 (p < 0.05). These changes were correlated with reduced inflammation and improved antioxidant capacity in the LPS-challenged chickens. Collectively, dietary 10-HDA supplementation alleviated LPS-induced intestinal mucosal injury and the loss of growth performance through anti-inflammatory, antioxidant, and gut microbiota modulation activities in chickens. Moreover, 0.1% 10-HDA supplementation had comparable or even better protection for LPS-challenged chickens than supplementation with antibiotics or 0.5% 10-HDA. 10-HDA has the potential to be used as an alternative to antibiotics in protecting the intestinal health and improving the performance of poultry.

Protective effect of zerumbone on sepsis-induced acute lung injury through anti-inflammatory and antioxidative activity via NF-κB pathway inhibition and HO-1 activation.

Sepsis is a systemic illness for which there are no effective preventive or therapeutic therapies. Zerumbone, a natural molecule, has anti-oxidative and anti-inflammatory properties that may help to prevent sepsis. In the present study, we have assessed the protective effect of zerumbone against sepsis-induced acute lung injury (ALI) and its underlying mechanisms. During the experiment, mice were divided into five groups: a sham group, a sepsis-induced ALI group, and three sepsis groups that are pre-treated with zerumbone at different concentrations. We found that zerumbone greatly decreased the sepsis-induced ALI using histological investigations. Also, zerumbone treatment reduced the sepsis-induced inflammatory cytokine concentrations as well as the number of infiltrating inflammatory cells in BALF compared to non-treated sepsis animals. The zerumbone-pretreated sepsis groups had reduced pulmonary myeloperoxidase (MPO) activity than the sepsis groups. Moreover, the mechanism underlying the protective action of zerumbone on sepsis is accomplished by the activation of antioxidant genes such as nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), superoxide dismutase (SOD), and heme oxygenase 1 (HO-1). The obtained results revealed that zerumbone inhibited the sepsis-induced ALI through its anti-inflammatory and antioxidative activity via inhibition of the NF-κB pathway and activation of HO-1 pathway. Our findings demonstrate that zerumbone pretreatment suppresses sepsis-induced ALI via antioxidative activities and anti-inflammatory, implying that zerumbone could be a viable preventive agent for sepsis-induced ALI.

Association between inflammatory cytokines and oxidative stress levels in aqueous humor with axial length in human myopia

This study investigated the content of inflammatory cytokines and oxidative stress levels in the aqueous humor (AH) of patients with high myopia (HM) and explored the relationship between these factors and the axial length (AL) of the eye, to explore the roles of mild intraocular inflammation and oxidative stress imbalance in the occurrence and development of myopia. AH samples from 40 patients (70 eyes) were collected during implantable collamer lens (ICL-V4c) surgery. The subjects were divided into three groups according to AL: group A (AL ≤ 26 mm), group B (26 < AL ≤ 28 mm), and group C (AL ≥ 28 mm). The concentrations of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), matrix metalloproteinase-2 (MMP-2), and interleukin-1β (IL-1β) in the AH of the three groups were measured using the Luminex system. Oxidative stress levels were measured using reagent kits targeting total antioxidant capacity (T-AOC), catalase (CAT), and nitric oxide (NO) and malonaldehyde (MDA) content. The results showed compared with group A, IL-1β, MMP-2, and IL-6 concentrations were significantly higher and T-AOC levels were significantly lower in group C. There were no significant differences in CAT, NO, MDA, or TNF-α levels among the groups. The concentrations of IL-6 (r = 0.379, p = 0.016), MMP-2 (r = 0.469, p = 0.002), and MDA (r = 0.354, p = 0.025) in AH were positively correlated with the AL, whereas T-AOC (r = −0.678, p = 0.000) was negatively correlated with AL. These results suggest that mild intraocular inflammation and oxidative stress imbalance may be associated with myopia. Further experiments are needed to confirm the role of mild intraocular inflammation and oxidative stress imbalance in the occurrence and development of myopia.

Impact of autologous platelet-rich plasma therapy vs. hyaluronic acid on synovial fluid biomarkers in knee osteoarthritis: a randomized controlled clinical trial.

Observe the effects of platelet-rich plasma (PRP) therapy on inflammatory cytokines in the synovial fluid of the knee joint of patients with KOA, and explore the effects of PRP intra-articular injection on the inflammation of the knee joint environment and the possible mechanism of action. Seventy patients were randomized to undergo three blinded weekly intra-articular injections of PRP or hyaluronic acid (HA). The concentrations of inflammatory cytokines, including interleukin (IL)-6, IL-1β, tumor necrosis factor (TNF)-α, IL-8, IL-17A, IL-17F, IL-4, IL-5, and IL-10, in the synovial fluid were evaluated before the intervention and 1 month after the third injection. The Western Ontario and McMaster University (WOMAC) and visual analog scale (VAS) scores were used to assess pain and functional status of the knee joints in both groups before the intervention, immediately post-intervention, and 1, 3, 6, and 12 months after the intervention. Baseline characteristics were similar in both groups with no statistical difference. The IL-6, IL-1β, TNF-α, IL-17A, and IL-10 levels in the synovial fluid of the observation group decreased significantly after, vs. before, the intervention (p < 0.05), whereas the IL-8, IL-17F, and IL-4 levels decreased (p > 0.05) and IL-5 levels increased (p > 0.05). There was no statistically significant difference between inflammatory cytokine levels in the synovial fluid of the samples from the control group before and after the intervention (p > 0.05). There were no statistically significant differences between the two groups immediately after intervention (p > 0.05). At 1, 3, 6, and 12 months after intervention, the WOMAC and VAS scores were significantly better in the observation group than in the control group (p < 0.05). Platelet plasma therapy can reduce the concentrations of inflammatory cytokines IL-6, IL-1β, TNF-α, IL-17A, and IL-10 in the synovial fluid of KOA patients, reduce the expression levels of IL-8, IL-17F, and IL-4, clear the pro-inflammatory factors, improve the inflammatory environment of the affected knee joint, and alleviate pain caused by inflammation. Thus, alleviating pain and improving knee function in patients with KOA.

Substantial heterogeneity of inflammatory cytokine production and its inhibition by a triple cocktail of toll-like receptor blockers in early sepsis.

Early sepsis is a life-threatening immune dysregulation believed to feature a "cytokine storm" due to activation of pattern recognition receptors by pathogen and danger associated molecular patterns. However, treatments with single toll-like receptor (TLR) blockers have shown no clinical benefit. We speculated that sepsis patients at the time of diagnosis are heterogeneous in relation to their cytokine production and its potential inhibition by a triple cocktail of TLR blockers. Accordingly, we analyzed inflammatory cytokine production in whole blood assays from early sepsis patients and determined the effects of triple TLR-blockade. Whole blood of 51 intensive care patients sampled within 24h of meeting Sepsis-3 criteria was incubated for 6h without or with specific TLR2, 4, and 7/8 stimuli or suspensions of heat-killed S. aureus or E. coli bacteria as pan-TLR challenges, and also with a combination of monoclonal antibodies against TLR2 and 4 and chloroquine (endosomal TLR inhibition), subsequent to dose optimization. Concentrations of tumor necrosis factor (TNF), Interleukin(IL)-6, IL-8, IL-10, IL-1α and IL-1β were measured (multiplex ELISA) before and after incubation. Samples from 11 sex and age-matched healthy volunteers served as controls and for dose-finding studies. Only a fraction of sepsis patient samples revealed ongoing cytokine production ex vivo despite sampling within 24h of first meeting Sepsis-3 criteria. In dose finding studies, inhibition of TLR2, 4 and endosomal TLRs reliably suppressed cytokine production to specific TLR agonists and added bacteria. However, inflammatory cytokine production ex vivo was only suppressed in the high cytokine producing samples but not in the majority. The suppressive response to TLR-blockade correlated both with intraassay inflammatory cytokine production (r=0.29-0.68; p<0.0001-0.04) and cytokine baseline concentrations (r=0.55; p<0.0001). Upon meeting Sepsis-3 criteria for less than 24h, a mere quarter of patient samples exhibits a strong inflammatory phenotype, as characterized by increased baseline inflammatory cytokine concentrations and a stark TLR-dependent increase upon further ex vivo incubation. Thus, early sepsis patient cohorts as defined by Sepsis-3 criteria are very heterogeneous in regard to inflammation. Accordingly, proper ex vivo assays may be useful in septic individuals before embarking on immunomodulatory treatments.

Partially Hydrolyzed Guar Gum Intake Supports the Gut Microbiota and Attenuates Inflammation during Influenza H1N1 Virus Infection in Mice.

Partially hydrolyzed guar gum (PHGG) is a soluble dietary fiber that is effective for defecation control. It influences the gut microbiota, by which it is metabolized to yield short-chain fatty acids (SCFAs), and it was also recently shown to protect against influenza infection in humans. We here investigated the effects of PHGG in a mouse model of influenza H1N1 virus infection. Eight-week-old C57BL/6 mice were fed normal chow with or without PHGG (500 mg/kg per day) for 4 weeks, infected with H1N1 at 10 weeks of age, and analyzed at 12 weeks of age. Administration of PHGG attenuated the decline in body weight induced by H1N1 infection without affecting food intake. It also ameliorated intestinal atrophy and increased the production of SCFAs including acetic acid, propionic acid, and butyric acid in the cecum, thereby preventing the inhibitory effect of H1N1 infection on SCFA production. The H1N1-induced increases in the serum concentrations of inflammatory cytokines including interferon-γ and interleukin-6 and anti-inflammatory cytokine such as interleukin-10 were all inhibited by PHGG intake. In addition, PHGG administration attenuated inflammatory gene expression in the lung and promoted both natural killer cell activity and regulatory T-cell differentiation in the spleen. Our findings suggest that the consumption of PHGG may improve the gut environment and thereby limit the inflammatory response to H1N1 infection. They may thus provide the basis for novel dietary intervention strategies to suppress the excessive inflammation associated with virus infection.

Cardiopulmonary protective properties of decorated Ag NPs on lignin modified magnetic nanoparticles mediated by Cydonia in CCD-19Lu, WI-38, BEAS-2B, HCASMC, HCAEC, and HPAEC cell lines

Advances in silver nanoparticles and nanotechnology, which can realize sensitive diagnostic modalities, efficient medical treatment, and better prognosis as well as less adverse effects on non-target tissues, provide an amazing window in the field of cardiopulmonary diseases. The present investigation describes a green procedure for the in situ immobilizing silver nanoparticles over calcium lignosulfonate modified Fe3O4 magnetic nanoparticles mediated by Cydonia root extract (Fe3O4@lignosulfonate-Ag NPs) and its catalytic and subsequent biological performances. The characterization of synthesized Fe3O4@lignosulfonate-Ag NPs were analyzed using XRD, VSM, ICP, SEM, EdaX, elemental mapping and TEM. In the medicinal part of the present research, the lung (CCD-19Lu, WI-38, and BEAS-2B) and heart (HCASMC, HCAEC, and HPAEC) cell viability was determined by trypan blue assay. The caspase activity colorimetric assay kit and Rhodamine123 fluorescence dye were used to determine the caspase-3 activity and mitochondrial membrane potential, respectively. Apoptosis and DNA fragmentation were determined by the TUNEL test. In addition, the inflammatory cytokines concentrations were evaluated by the Rat inflammatory cytokine assay kit. Fe3O4@lignosulfonate-Ag NPs-treated cell cutlers decreased significantly (p ≤ 0.01) the caspase-3 activity, inflammatory cytokines concentrations, and DNA fragmentation, and enhanced the mitochondrial membrane potential and cell viability in the high concentration of Methotrexate-treated CCD-19Lu, WI-38, BEAS-2B, HCASMC, HCAEC, and HPAEC cells. In the antioxidant test, the IC50 of Fe3O4@lignosulfonate-Ag NPs and BHT against DPPH free radicals were 168 and 54 µg/mL, respectively. Finally, Fe3O4@lignosulfonate-Ag NPs may be used as a cardiopulmonary protective supplement to treat cardiopulmonary diseases.

Zhenxin Anshen formula ameliorates atopic der-matitis-like skin dysfunction in mice and regulation of transient receptor potential vanilloid 1 and transient receptor potential ankyrin 1 in Neural pathways.

To investigate the efficacy of Zhenxin Anshen formula (, ZXAS) on atopic dermatitis (AD) by transient receptor potential vanilloid 1 (TRPV1) and transient receptor potential ankyrin 1 (TRPA1) signalling pathway in mice and . AD-like lesions were induced by 1-chloro-2,4-dinitrobenzene (DNCB) to the shaved dorsal skin of BALB/c mice. BALB/c mice were divided into five groups: normal control, model control, cetirizine, low-, medium-, and high-dose of ZXAS. After ZXAS in-tervention, the skin lesions and blood samples were collected for hematoxylin and eosin-stained and measuring the concentrations of inflammatory cytokines. Immun-oglobulin E (IgE), interleukin (IL)-4, IL-5, IL-13, and thymic stromal lymphopoietin (TSLP) were de-tected by Enzyme-linked immunosorbent assay (ELISA). The spinal cords were collected for measuring the expression of gastrin-releasing peptide receptor (GRPR), TRPV1, and TRPA1 by using immunohistochemistry, western blotting, and quantitative real-time polymerase chain reaction (qRT-PCR) analyses. In addition, 3-(4,5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide (MTT) assay, flow cytometry, ELISA, and Western blotting were conducted for analysis of primary dorsal root ganglia (DRG) neurons . ZXAS treatment improved DNCB-induced AD-like lesions through reducing dermatitis score, number of scratching and epidermal thickness, accompanied by the de-creased IgE and Th2 inflammatory cytokines. ZXAS also supressed the mRNA and protein expression of GRPR, TRPV1, and TRPA1 in the spinal cord. The medicated sera of ZXAS decreased capsaicin-induced Ca influx and downregulated the expression of TRPV1, TRPA1, and phospholipase C in DRG neurons. The therapeutic effect of ZXAS on AD may be related to the regulation of TRPV1 and TRPA1 and inhibition of Ca2+ signals in neurons.