Secretion Of Pro-inflammatory Cytokines Research Articles

Lactobacillus rhamnosus 1.0320 Postbiotics Ameliorate Dextran Sodium Sulfate-Induced Colonic Inflammation and Oxidative Stress by Regulating the Intestinal Barrier and Gut Microbiota.

Probiotics are increasingly being used as an adjunctive therapy for ulcerative colitis. However, some safety issues have been found in the clinical use of probiotics. Postbiotics have attracted much attention due to their storage stability, safety, and potential functions, but the dose required to exert a significant protective effect is unknown. Therefore, this study evaluated the potential mechanisms of different doses (200, 400, 600 mg/kg) of Lactobacillus rhamnosus 1.0320 postbiotics (1.0320P) in alleviating dextran sodium sulfate (DSS)-induced colitis. The study revealed that 1.0320P could mitigate DSS-induced colitis with signs of reductions in the disease activity index, amelioration of colon tissue damage, decreased secretion of proinflammatory cytokines, reduced oxidative stress levels, and lower bone marrow peroxidase activity. Furthermore, high dose of 1.0320P could upregulated the expression of key proteins in the Nrf2/ARE pathway (NQO1, Nrf2, and HO-1) and downregulated the expression of key proteins in the TLR4/NF-κB signaling pathway (TLR4, MyD88, and NF-κB p65). In addition, high dose of 1.0320P could upregulate the expression of tight junction (TJ) proteins including ZO-1, Occludin, and Claudin-1, contributing to the restoration of the intestinal mucosal barrier function. Additionally, 1.0320P was found to effectively correct imbalances in the intestinal microbiota and enhance the synthesis of short-chain fatty acids (SCFAs), thereby regulating homeostasis in the intestinal internal environment. Overall, our findings suggest that postbiotics could ameliorate colonic inflammation while being somewhat dose-dependent. This study provides new insights into postbiotics as a next-generation biotherapeutic agent for the treatment of ulcerative colitis and even other diseases.

Effects of Phenolic Acids Produced from Food-Derived Flavonoids and Amino Acids by the Gut Microbiota on Health and Disease

The gut microbiota metabolizes flavonoids, amino acids, dietary fiber, and other components of foods to produce a variety of gut microbiota-derived metabolites. Flavonoids are the largest group of polyphenols, and approximately 7000 flavonoids have been identified. A variety of phenolic acids are produced from flavonoids and amino acids through metabolic processes by the gut microbiota. Furthermore, these phenolic acids are easily absorbed. Phenolic acids generally represent phenolic compounds with one carboxylic acid group. Gut microbiota-derived phenolic acids have antiviral effects against several viruses, such as SARS-CoV-2 and influenza. Furthermore, phenolic acids influence the immune system by inhibiting the secretion of proinflammatory cytokines, such as interleukin-1β and tumor necrosis factor-α. In the nervous systems, phenolic acids may have protective effects against neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases. Moreover, phenolic acids can improve levels of blood glucose, cholesterols, and triglycerides. Phenolic acids also improve cardiovascular functions, such as blood pressure and atherosclerotic lesions. This review focuses on the current knowledge of the effects of phenolic acids produced from food-derived flavonoids and amino acids by the gut microbiota on health and disease.

Gingival mesenchymal stem cells derived from patients with rheumatoid arthritis treat experimental arthritis

AbstractA therapeutic strategy using mesenchymal stem cells (MSCs) has been accepted as a novel therapy for treating rheumatoid arthritis (RA). Human gingiva‐derived MSCs (GMSCs) are superior in regulating immune responses. Autologous MSCs are the optimal candidate to avoid the potential risks of allogenic MSCs. However, whether autologous GMSCs from RA patients are therapeutic remains unknown. In this study, we compared the therapeutic efficacy of GMSCs derived from patients with RA (RA‐GMSCs) and that from health donors (H‐GMSCs) in vivo and in vitro. Then, we utilized RNA‐sequencing, the molecular and cellular assays to determine the immunomodulatory molecules that contribute to the therapeutic effect of RA‐GMSCs on both collagen‐induced arthritis (CIA) and humanized synovitis models. We demonstrated that GMSCs derived from patients with RA (RA‐GMSCs) and health donors (H‐GMSCs) shared a similar expression of immunomodulatory molecules. Moreover, RA‐GMSCs were as effective as H‐GMSCs in suppressing T‐cell proliferation, proinflammatory cytokines secretion, as well as osteoclast differentiation in vitro. In addition, RA‐GMSCs had a robust therapeutic effect on the CIA model. Importantly, RA GMSCs can survive for at least 24 days in a CIA mouse model and can be distributed in the spleen, lymph nodes, and joints. Specifically, RA‐GMSCs decreased the frequency of Th1 and Th17 cells whereas enhanced Treg cells, reducing the joint histopathological scores of lymphocytes, osteoclasts, and cartilages. Moreover, RA‐GMSCs were also effective in suppressing inflamed synoviocyte proliferation, migration, and invasion in vitro, and cartilage invasion in a humanized synovitis model in vivo. Our study implies that manipulation of RA‐GMSCs is therapeutic in CIA mice and humanized synovitis models and may have therapeutic potential in RA patients using autologous GMSCs in the future.

Adipose-Derived Stromal Cells and Cancer-Associated Fibroblasts: Interactions and Implications in Tumor Progression

Adipose-derived stromal cells (ASCs) and cancer-associated fibroblasts (CAFs) play pivotal roles in the tumor microenvironment (TME), significantly influencing cancer progression and metastasis. This review explores the plasticity of ASCs, which can transdifferentiate into CAFs under the influence of tumor-derived signals, thus enhancing their secretion of extracellular matrix components and pro-inflammatory cytokines that promote tumorigenesis. We discuss the critical process of the epithelial-to-mesenchymal transition (EMT) facilitated by ASCs and CAFs, highlighting its implications for increased invasiveness and therapeutic resistance in cancer cells. Key signaling pathways, including the transforming growth factor-β (TGF-β), Wnt/β-catenin, and Notch, are examined for their roles in regulating EMT and CAF activation. Furthermore, we address the impact of epigenetic modifications on ASC and CAF functionality, emphasizing recent advances in targeting these modifications to inhibit their pro-tumorigenic effects. This review also considers the metabolic reprogramming of ASCs and CAFs, which supports their tumor-promoting activities through enhanced glycolytic activity and lactate production. Finally, we outline potential therapeutic strategies aimed at disrupting the interactions between ASCs, CAFs, and tumor cells, including targeted inhibitors of key signaling pathways and innovative immunotherapy approaches. By understanding the complex roles of ASCs and CAFs within the TME, this review aims to identify new therapeutic opportunities that could improve patient outcomes in cancer treatment.

Body mass index as a contributor to the accumulation of lipidic plaque materials in statin-treated type 2 diabetic patients with coronary artery disease: sub-analysis from the OPTIMAL randomized study

Abstract Background Patients with type 2 diabetes mellitus more likely exhibit obesity. Pathophysiologically, obesity promotes a range of metabolic disturbances including insulin resistance, dyslipidemia and hypertension, in addition to the secretion of adipokines and pro-inflammatory cytokines from excessive fat accumulation. These atherogenic features may promote instability of atherosclerotic plaques, which ultimately result in elevating a risk of atherosclerotic cardiovascular disease. However, it remains to be fully elucidated how obesity affects atherosclerotic plaque features in type 2 diabetic patients with coronary artery disease (CAD). Near-infrared spectroscopy (NIRS) imaging enables to quantitatively visualize lipidic plaque materials in vivo. This imaging modality provides insights into lipidic plaque features in obese patients with type 2 diabetes mellitus. Purpose To elucidate the association of body mass index (BMI, kg/m2) with lipidic plaque materials in type 2 diabetic patients. Methods The OPTIMAL study was a prospective randomized controlled trial to evaluate the efficacy of continuous glucose monitoring (CGM) guided glycemic control on coronary atherosclerosis in statin-treated type 2 diabetic participants with CAD requiring PCI. 94 patients were randomized into CGM-guided or HbA1c-guided glycemic control. Serial NIRS imaging was conducted to monitor non-culprit lesions at baseline and week 48. The current sub-analysis included 78 patients with both baseline BMI data and evaluable baseline NIRS/IVUS images. Results All of study subjects received a statin (high-intensity statin use=36%), and the averaged LDL-C level was 86.7±26.3 mg/dL. The average BMI and HbA1c level were 24.7±3.1 kg/m2 and 7.5±0.9%, respectively (Table 1). On NIRS imaging analysis, maxLCBI4mm at non-culprit lesions was 286.2±167.0, and 21.8% of study subjects exhibited maxLCBI4mm >400 (Table 2). BMI was associated with maxLCBI4mm (p<0.001). Multivariate analysis adjusting clinical characteristics and LDL-C demonstrated that BMI was an independent contributor to maxLCBI4mm [estimate=17.15 (12.88-21.42), p<0.001] (Table 2). Even in patients receiving high-intensity statin, BMI was still associated with maxLCBI4mm (p<0.001). Conclusions A greater accumulation of lipidic plaque materials was observed in association with BMI in statin-treated type 2 diabetic patients with CAD. This presence of enhanced plaque vulnerability at non-culprit lesions, in the setting of obesity, may contribute to an increased risk of cardiovascular events in type 2 diabetic patients with CAD. The current finding suggests the need to adopt further therapeutic approaches to favourably modify plaque vulnerability in type 2 diabetic patients exhibiting obesity.Table 1:Clinical DemographicsTable 2:Factors Associated with maxLCBI

The epicardial adipose tissue volume is in patients with type 2 diabetes mellitus associated with a lowered myocardial perfusion reserve

Abstract Introduction The epicardial adipose tissue (EAT) has unobstructed vascular connection to the myocardium and has a secretome very different from that of other fat depots. The EAT fat pad and its paracrine and vasocrine secretion of pro-inflammatory and profibrotic cytokines is suggested to contribute to heart failure with preserved ejection fraction (HFpEF) pathogenesis albeit via unknown mechanisms. Animal studies and magnetic resonance imaging studies in patients with type 2 diabetes mellitus (T2DM) have documented that important myocardial changes linking diabetic cardiomyopathy to systolic and diastolic dysfunction are myocardial microvascular dysfunction and myocardial fibrosis. Purpose To investigate whether a high volume of EAT is associated with impaired myocardial perfusion reserve (MPR) or disperse fibrosis in patients with T2DM. Methods 198 patients with T2DM but without ischemic heart disease were identified from a cross-sectional cardiovascular magnetic resonance imaging cohort study. 25 healthy controls were included for characterization of baseline characteristics. With gadolinium for contrast, MPR was determined by perfusion sequences and disperse fibrosis was determined from the myocardial extracellular volume (ECV). Volumes of EAT and pericardial adipose tissue (PAT) were determined from cine images. Results The T2DM patients (69% male) had a median age 59 IQR [50, 67] yrs, BMI 30.7 IQR [27.8, 33.7] kg/m2, and EAT of 17.3 IQR [14.2, 22.4] cm2. All patients had normal left ventricle ejection fraction. Compared to the healthy controls, patients with T2DM had higher BMI, abdominal circumference, ECV, EAT, and PAT volumes, and lower MPR (all p<0.001). In univariable regression analysis, EAT and PAT were both associated with higher BMI, abdominal circumference, and age (all p<0.02). In multivariable regression analysis, however, with adjustments for age, sex, BMI, and T2DM-duration, only EAT and MPR were significantly associated (P<0.01), whereas EAT and ECV were not. The PAT volume was not associated with MPR nor ECV. High-sensitive CRP was associated with the EAT volume (p<0.001), but hs-CRP was not associated with MPR or ECV. Conclusion An increased epicardial adipose tissue volume is in patients with T2DM associated with myocardial microvascular dysfunction. Irrespective of a generally heightened inflammatory level, the mechanism by which EAT contribute to development of HFpEF is therefore possibly via an EAT-induced impairment of the myocardial perfusion reserve. Randomized studies targeting a decreased epicardial adipose tissue volume are needed to demonstrate if this will improve myocardial microvascular dysfunction and hence limit development of HFpEF in patients with T2DM.Univariable analysis of EAT and ECVUnivariable analysis of EAT and MPR

Prognostic value of IL-22 levels and the TH17 pathway in patients with acute myocardial infarction

Abstract Introduction Acute myocardial infarction (AMI) induces a surge in inflammatory cytokines and cells including T helper cells (TH). TH17 cells are activated by pro-inflammatory cytokines such as IL-1, IL-6, and IL-21; they secrete IL-17 and IL-22 to promote neutrophil chemotaxis and to induce pro-inflammatory cytokine secretion from macrophages. Purpose We aimed to explore the prognostic value of the TH17 pathway and its component cytokines in AMI patients. Methods Patients with AMI (STEMI and NSTEMI) were included from the SPUM-ACS cohort (total N=4,787) selecting a time window <24 h from symptom onset to blood sampling before PCI. Patients with malignancies or immunosuppressive therapies were excluded. 160 patients who experienced death (N=85) or recurrent AMI (N=75) within 1-year follow-up (AMI-case) were compared to 152 counterparts with favorable outcome matched for age, sex, AMI subtype, and onset time (AMI-control). 45 healthy blood donors (HD) without cardiovascular disease were added as a reference group. Cytokine levels were reported as median + IQR and were analyzed with multivariate linear regression. Group comparisons were made using the Mann-Whitney U test or Kruskal-Wallis test and multiple comparisons corrected with Dunn’s test. Kaplan-Meier curves were cut off at a median IL-22 level and tested with Log-rank test. Results Our measurement showed correlation among components in TH17 pathway. IL-22 was significantly associated with IL-1β (β=-3.027e-1, p=0.0164), IL-6 (β=5.413e-3, p<0.0001), and IL-21 (β=3.567e-2, p<0.0001), but not with IL-1α or IL-1RA. IL-22 was not correlated with IL-17. Age (median=71.45 vs 71.30 years, p>0.05), percentage of women (23.8% vs 19.7%, p>0.05), and percentage of STEMI (70.6% vs 69.7%, p>0.05) did not differ between AMI-case and AMI-control. AMI-case and AMI-control both showed higher plasma IL-22 levels than HD, whereas there was no difference between AMI groups (Figure 1A). AMI patients who died within 1-year follow-up had higher IL-22 levels than those with recurrent AMI (Figure 1B). Regarding TH17 activation, patients who died had higher IL-17 levels (Figure 1C). Median IL-22 (4.86 pg/mL) levels were tested for predicting outcome: Patients with higher IL-22 levels had more risk for death or recurrent AMI (p=0.0253, Figure 2A). The mortality of patients above median IL-22 levels was higher than those below (p=0.0126); The KM-curves diverged early in less than 1 month after the initial event (Figure 2B). Conclusions Upstream regulators (IL-1β, IL-6) correlated with downstream effectors (IL-22, IL-17) within the pathways involving TH17 cells. Both IL-22 and Il-17 were higher in AMI patients who died within one year than in similar patients who survived. Investigating TH-17- and IL-22-related pathways may be of interest for further investigation in patients with AMI.

Probiotic Characteristics and the Anti-Inflammatory Effects of Lactiplantibacillus plantarum Z22 Isolated from Naturally Fermented Vegetables

Currently, there is increasing interest in the commercial utilization of probiotics isolated from traditional fermented food products. Therefore, this study aimed to investigate the probiotic potential of Lactiplantibacillus plantarum (L. plantarum) Z22 isolated from naturally fermented mustard. The results suggest that L. plantarum Z22 exhibits good adhesion ability, antibacterial activity, safety, and tolerance to acidic conditions and bile salts. We further determined the anti-inflammatory mechanism and properties of L. plantarum Z22 and found that L. plantarum Z22 could significantly reduce the secretion of pro-inflammatory cytokines, including interleukin-6 (IL-6), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and the expression of the pro-inflammatory mediator cyclooxygenase-2 (COX-2) protein in LPS-induced RAW 264.7 cells. In addition, L. plantarum Z22 also effectively inhibited the signaling pathways of nuclear factor κB (NF-κB) and mitogen-activated protein kinases (MAPKs). This effect can be attributed to a decrease in the levels of reactive oxygen species (ROS) and increased heme oxygenase-1 (HO-1) expression. Moreover, whole-genome sequencing revealed that L. plantarum Z22 contains gene-encoding proteins with anti-inflammatory functions, such as beta-glucosidase (BGL) and pyruvate kinase (PK), as well as antioxidant functions, including thioredoxin reductase (TrxR), tyrosine-protein phosphatase, and ATP-dependent intracellular proteases ClpP. In summary, these results indicated that L. plantarum Z22 can serve as a potential candidate probiotic for use in fermented foods such as yogurt (starter cultures), providing a promising strategy for the development of functional foods to prevent chronic diseases.

Tannic Acid-Based Biomimetic Nanomedicine with Pathological Reactive Oxygen Species-Responsive Cargo Release for Relieving Inflammation in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic disease characterized by immune cell infiltration and cartilage damage. The local lesion of RA shows severe oxidative stress and proinflammatory cytokine secretion. For drug therapy, the efficacy of agents, such as methotrexate (MTX), may be greatly limited, resulting from the low bioavailability, immune clearance, and toxic side effects. A nanocarrier (TA-PBA NPs) was developed with anti-inflammatory and antioxidant activities, combined with MTX to prepare nanomedicine (MTX NPs) for synergistic treatment of RA. Moreover, inspired by the biological functions homing to inflammation lesion of macrophages, the biomimetic nanomedicine camouflaged with macrophage membrane (MM@MTX NPs) was constructed. TA-PBA NPs could timely promote MTX release in response to the overaccumulated ROS to exhibit high anti-inflammatory and antioxidant activities for alleviating RA progression. The experimental results confirmed that MM@MTX NPs could significantly reduce the secretion of proinflammatory cytokines (TNF-α) while significantly increasing the typical anti-inflammatory cytokines (IL-10), promote the phenotype transformation of macrophages from M1 to M2, and up-regulate the Nrf2-keap1 pathway-related proteins (HO-1 and NRF2) to positively regulate the local inflammation for effectively inhibiting RA development. Thus, MM@MTX NPs represent a possible candidate as a safe and efficient nanotherapy platform for RA management.

A Multiple Targeting Genome Editing System for Remodulation of Circulating Malignant Cells to Eliminate Cancer Immunosuppression and Restore Immune Responses.

Cancer immunotherapy, which aims to eliminate cancer immunosuppression and reactivate anticancer immunity, holds great promise in oncology treatments. However, it is challenging to accurately study the efficacy of immunotherapy based on human-derived cells through animal experiments due to xenogeneic immune rejection. Herein, a personalized and precise strategy to evaluate the effectiveness of immunotherapy using the blood samples of cancer patients is presented. Through the utilization of multiple cancer-targeting delivery system decorated with the epidermal growth factor receptor (EGFR)-specific aptamer CL4 and the AXL-specific aptamer GL21.T to achieve superior efficiency in delivering the genome editing plasmid for MUC1 knockout, effective modulation on the behavior of circulating malignant cells (CMCs) is realized. After genome editing, both mucin 1 (MUC1) and programmed death-ligand 1 (PD-L1) are significantly downregulated in CMCs. The elimination of immunosuppression results in markedly enhanced secretion of pro-inflammatory anticancer cytokines encompassing interleukins 2, 12, and 15 and interferon-γ by immune cells. The study not only provides a strategy to overcome immunosuppression but also yields critical insights for personalized immunotherapy approaches.

Soluble CD146 cooperates with VEGF-A to generate an immunosuppressive microenvironment in CD146-positive tumors: interest of a combined antibody-based therapy.

Tumor development necessitates immune escape through different mechanisms. To counteract these effects, the development of therapies targeting Immune Checkpoints (ICP) has generated interest as they have produced lasting objective responses in patients with advanced metastatic tumors. However, many tumors do not respond to inhibitors of ICP, necessitating to further study the underlying mechanisms of exhaustion. Vascular Endothelial Growth Factor a (VEGFa), a pro-angiogenic molecule secreted by tumors, was described to participate to tumor immune exhaustion by increasing ICP, justifying in part the use of an anti-VEGFa monoclonal antibody (mAb), bevacizumab, in patients. However, recent studies from our group have demonstrated that tumors can escape anti-VEGFa therapy through the secretion of soluble CD146 (sCD146). In this study, we show that both VEGFa and sCD146 cooperate to create an immunosuppressive microenvironment by increasing the expression of ICP. In addition, sCD146 favors pro-tumoral M2-type macrophages and induces the secretion of pro-inflammatory cytokines. An anti-sCD146 mAb reverses these effects and displays additive effects with anti-VEGFa antibody to eliminate tumors in a syngeneic murine model grafted with melanoma cells. Combining bevacizumab with mucizumab could thus be of major therapeutic interest to prevent immune escape in malignant melanoma and other CD146-positive tumors.

From fat storage to immune hubs: the emerging role of adipocytes in coordinating the immune response to infection.

Adipose tissue is a rich source of diverse cell populations, including immune cells, adipocytes and stromal cells. Interactions between these different cell types are now appreciated to be critical for maintaining tissue structure and function, by governing processes such as adipogenesis, lipolysis and differentiation of white to beige adipocytes. Interactions between these cells also drive inflammation in obesity, leading to an expansion of adipose tissue immune cells, and the secretion of proinflammatory cytokines from immune cells and from adipocytes themselves. However, in evolutionary terms, obesity is a recent phenomenon, raising the question of why adipocytes evolved to express factors that influence the immune response. Studies of various pathogens indicate that adipocytes are highly responsive to infection, altering their metabolic profiles in a way that can be used to release nutrients and fuel the immune response. In the case of infection with the extracellular parasite Trypanosoma brucei, attenuating the ability of adipocytes to sense the cytokine IL-17 results in a loss of control of the local immune response and an increased pathogen load. Intriguingly, comparisons of the adipocyte response to infection suggest that the immune responses of these cells occur in a pathogen-dependent manner, further confirming their complexity. Here, with a focus on murine adipose tissue, we discuss the emerging concept that, in addition to their canonical function, adipocytes are immune signalling hubs that integrate and disseminate signals from the immune system to generate a local environment conducive to pathogen clearance.

PMCNA_RS00975 activates NF-κB and ERK1/2 through TLR2 and contributes to the virulence of Pasteurella multocida.

Pasteurella multocida is a pathogenic bacterium known to cause hemorrhagic septicemia and pneumonia in poultry. Reports have indicated that certain proteins, either directly involved in or regulating iron metabolism, are important virulence factors of P. multocida. Therefore, understanding virulent factors and analyzing the role of pro-inflammatory cytokines can help us elucidate the underlying pathogenesis. In this study, the PMCNA_RS00975 protein, a putative encapsuling protein encoded by a gene from a specific prophage island of the pathogenic strain C48-1 of P. multocida, was investigated. To further explore the impact of the PMCNA_RS00975 protein on pathogenicity, a PMCNA_RS00975 gene mutant of P. multocida strain C48-1 was constructed using positive selection technology. Subcellular localization was performed to determine the location of the PMCNA_RS00975 protein within P. multocida. The recombinant protein PMCNA_RS00975 of P. multocida was soluble expressed, purified, and its role in pro-inflammatory cytokines was investigated. The mutant exhibited significantly reduced pathogenicity in the mice model. Furthermore, subcellular localization indicated that the PMCNA_RS00975 protein was located at the outer membrane and expressed during infection of P. multocida. Additionally, our experiments revealed that recombinant PMCNA_RS00975 protein promotes the secretion of the IL-6 pro-inflammatory cytokines triggered by the TLR2 receptor via NF-κB and ERK1/2 signaling pathways in the macrophages. This study identified a novel virulence factor in the C48-1 strain, providing a basis for understanding the pathogenesis and directions for the development of attenuated vaccines against P. multocida.

ZnO Nanoparticles as Potent Inducers of Dermal Immunosuppression in Contact Hypersensitivity in Mice.

Nanosized zinc oxide (nZnO) metal particles are used in skin creams and sunscreens to enhance their texture and optical properties as UV filters. Despite their common use, little is known about the molecular mechanisms of nZnO exposure on damaged skin. We studied the effects of topically applied nZnO particles on allergic skin inflammation in an oxazolone (OXA)-induced contact hypersensitivity (CHS) mouse model. We investigated whether exposure to nZnO during the sensitization or challenge phase would induce immunological changes and modulate transcriptional responses. We followed skin thickness, cellular infiltration, and changes in the local transcriptome up to 28 days after the challenge. The responses peaked at 24 h and were fully resolved by 28 days. Co-exposure to nZnO and hapten did not interfere with the formation of the sensitization process. Conversely, during the hapten challenge, the application of nZnO fully suppressed the development of the CHS response by the inhibition of pro-inflammatory pathways, secretion of pro-inflammatory cytokines, and proliferation of immune cells. In differentiated and stimulated THP-1 cells and the CHS mouse model, we found that nZnO particles and Zn ions contributed to anti-inflammatory responses. The immunosuppressive properties of nZnO in inflamed skin are mediated by impaired IL-1R-, CXCR2-, and LTB4-mediated pathways. nZnO-induced dermal immunosuppression may be beneficial for individuals with contact allergies who use nZnO-containing cosmetic products. Our findings also provide a deeper understanding of the mechanisms of nZnO, which could be considered when developing nanoparticle-containing skin products.

Effects of Diet and Supplements on Parameters of Oxidative Stress, Inflammation, and Antioxidant Mechanisms in Patients with Chronic Renal Failure Undergoing Hemodialysis.

The prevalence of chronic kidney disease (CKD) worldwide increases as the population ages. The progression of the disease increases the risk of complications and death and leads to end-stage renal failure, requiring renal replacement therapy. Despite the positive effect of hemodialysis (HD), patients are at risk of developing malnutrition, inflammation, oxidative stress, or cardiovascular disease, which worsens quality of life and can lead to organ dysfunction. The occurrence of the mentioned disorders depends largely on the diet, so changes in diet composition are an important part of the treatment of kidney disease. This study aimed to evaluate the effects of a balanced diet on some parameters of oxidative stress, immune response, and nutritional status in patients. This study included 57 HD patients (19 women and 38 men). In all of them, nutritional status and diet were initially determined, and then, they were divided into six groups, which received different diets and supplements. Serum levels of albumin, total protein, MDA, and the cytokines Il-1, IL-6, IL-8, TNF-α, and IL-10 were determined, and the activity of the enzymes such as CAT, SOD, and GSH-Px were determined in erythrocytes by spectrophotometry. Based on the results of BMI, albumin, and total protein, it can be concluded that a well-balanced diet can reduce weight loss. This study shows that a well-balanced diet can reduce the secretion of pro-inflammatory cytokines, and ensure the normal activity of antioxidative enzymes in the blood of HD patients.

Sirt4 Overexpression Modulates the JAK2/STAT3 and PI3K/AKT/mTOR Axes to Alleviate Sepsis-Induced Acute Lung Injury.

Sepsis-induced acute lung injury (ALI) is a severe organ dysfunction characterized by lung inflammation and apoptosis. The mechanisms underlying sepsis-induced ALI remain poorly understood. Here, we determined the effects of sirtuin 4 (SIRT4) on sepsis-induced ALI. Lipopolysaccharide (LPS)-induced injury cell and cecal ligation and puncture (CLP) animal models were established. Overexpression vectors and lentiviral transfections were used to upregulate SIRT4 expression. Lung cell apoptosis, inflammation, and the levels of associated factors were evaluated. Changes in the PI3K/AKT/mTOR and JAK2/STAT3 pathways were measured, and their potential involvement was examined using LY294002 (PI3K inhibitor), 740 Y-P (PI3K agonist), AG490 (JAK2 inhibitor), and coumermycin A1 (JAK2 agonist). Lower SIRT4 expression was observed in LPS-exposed A549 cells and CLP rats. In LPS-induced A549 cells, Sirt4 overexpression enhanced cell viability, resisted apoptosis, restored the expression of apoptosis-associated proteins (HMB1, cleaved CASP3, BAX, and BCL), and reduced the secretion of pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α). In CLP rats, Sirt4 overexpression prolonged survival time, alleviated lung histopathological damage, reduced pulmonary edema, mitigated lung infection, decreased lung apoptosis, and lowered serum levels of inflammatory cytokines. Furthermore, Sirt4 overexpression blocked JAK2/STAT3/AKT/mTOR phosphorylation. 740 Y-P and coumermycin A1 reversed the protective effects of Sirt4 overexpression in LPS-treated A549 cells, resulting in decreased cell viability and increased apoptosis. LY294002 and AG490 enhanced the protective effects of Sirt4 overexpression in LPS-treated A549 cells. SIRT4 alleviates sepsis-induced ALI by inhibiting JAK2/STAT3/PI3K/AKT/mTOR signaling. Upregulating SIRT4 expression may serve as an innovative therapeutic approach for lung injury management in sepsis.

Goat Milk Exosomes Ameliorate Ulcerative Colitis in Mice through Modulation of the Intestinal Barrier, Gut Microbiota, and Metabolites.

Goat milk is rich in a variety of nutrients that are important for intestinal health and disease prevention. However, the role of exosomes in goat milk remains to be elucidated. This study investigated for the first time the therapeutic efficacy and molecular underlying mechanisms of mature milk exosomes (M-exo) and goat colostrum exosomes (C-exo) on dextran sodium sulfate-induced ulcerative colitis (UC) in mice. The findings demonstrate that M-exo and C-exo significantly improved physiological indices, suppressed the secretion of proinflammatory cytokines, and diminished oxidative stress and apoptosis in UC mice. Moreover, C-exo and M-exo restored the intestinal barrier function, remodeled the gut microbiota, and improved metabolite composition in the feces of colitis mice. In conclusion, goat milk exosomes ameliorate UC in mice, which provides a basis for the development of functional food applications for the prevention and treatment of inflammatory bowel disease.

Anti-Inflammatory Effect of Deep-Sea Mineral Water on LPS-Induced Inflammation in Raw 264.7 Murine Macrophage Cells and Zebrafish Larvae

Deep-sea mineral water (DSW) consists of different compositions and properties. The composition can be varied in different seas all around the world. However, previous studies have investigated that DSW is a potential candidate that can be used to prevent different inflammatory diseases. Even though inflammation is an important protective mechanism in an animal, excessive inflammation causes organ failure and ultimate death. Therefore, the present study was carried out to investigate the anti-inflammatory effect of DSW extracted from the South Korean Sea to unveil its potential as an anti-inflammatory drug. To perform this, first, we have compared the cytotoxic effect of DSW on RAW 264.7 murine macrophage cells with NaCl and normal-sea water (NSW). Results reveal that DSW enhances cell survival while other treatments negatively affect cell survival. Furthermore, we have investigated that DSW reduces the LPS-induced cell apoptosis compared to the NaCl- and NSW-treated cells. Moreover, DSW has the ability to suppress the pro-inflammatory cytokine transcription (TNF-α, IL-1β, and IL-6) and NO production upon LPS treatment. In-vivo survival assay in zebrafish larvae shows a more than 50% survival rate in 10, 20, 30, 40, or 50% concentrations of DSW-treated larvae compared to NaCl- or NSW-treated larvae. Further investigations unveiled that DSW can negatively regulate the neutrophil and macrophage recruitment to the inflammatory site, which was induced by fin-fold amputation in zebrafish larvae and pro-inflammatory cytokine (tnf-α, il-1β, and il-6) secretion. Taken together, the present study concluded that DSW may have the ability to act as an anti-inflammatory drug to suppress excessive inflammation and subsequent consequences.

Regulation of voltage-gated sodium channels by TNF-α during herpes simplex virus latency establishment.

During lytic or latent infection of sensory neurons with herpes simplex virus type 1 (HSV-1) there are significant changes in the expression of voltage-gated Na+ channels, which may disrupt the transmission of pain information. HSV-1 infection can also evoke the secretion of various pro-inflammatory cytokines, including TNF-α and IL-6. In this work, we hypothesized that TNF-α regulates the expression of Na+ channels during HSV-1 latency establishment in ND7/23 sensory-like neurons. Latency establishment was mimicked by culturing HSV-1 infected ND7/23 cells in the presence of acyclovir (ACV) for 3 days. Changes in the functional expression of voltage-gated Na+ channels were assessed by whole-cell recordings. Our results demonstrate that infection of ND7/23 cells with the HSV-1 strain McKrae with GFP expression (M-GFP) causes a significant decrease in sodium currents during latency establishment. Exposure of ND7/23 cells to TNF-α during latency establishment reverses the effect of HSV-1, resulting in a significant increase in sodium current density. However, Na+ currents were not restored by 3day-treatment with IL-6. There were no changes in the pharmacological and biophysical properties of sodium currents promoted by TNF-α, including sensitivity to tetrodotoxin and the current-voltage relationship. TNF-α stimulation of ND7/23 cells increases p38 signaling. Inhibition of p38 signaling with SB203580 or SB202190 eliminates the stimulatory effect of TNF-α on sodium currents. These results indicate that TNF-α signaling in sensory neurons during latency establishment upregulates the expression of voltage-gated Na+ channels in order to maintain the transmission of pain information.

A new antibacterial with anti-inflammatory properties promotes wound healing through inhibiting cGAS/STING/NF-κB/IRF3 pathway

Benzothiazole-urea hybrid 8l was found to be a potent anti-bacterial agent against methicillin-resistant Staphylococcus aureus (MRSA2858) (MIC = 0.78 μM, Eur J Med Chem. 2022,236:114333). Herein, 8l was further evaluated to remedy the MRSA-infected scald with bacterial infection and severe inflammation. In scalded skin model with MRSA infection, 8l not only effectively reduced bacterial load, but also decreased pro-inflammatory cytokines secretion and promoted collagen deposition to effectively reverse the progression of wound infection and inflammation by blocking cGAS/STING/NF-κB/IRF3 signaling pathway. In vitro model of RAW264.7 cells verified that 8l can inhibit MRSA-induced inflammation via regulating this pathway. All in all, dual anti-bacterial and anti-inflammatory agent 8l could heal MRSA-infected refractory scald by regulating cGAS/STING/NF-κB/IRF3 pathway.