Serum Proinflammatory Cytokines Research Articles

Inhalation of hydrogen gas protects against mitomycin-induced pulmonary veno-occlusive disease

BackgroundAs a subtype of pulmonary hypertension (PH), pulmonary veno-occlusive disease (PVOD) is devastating and life-threatening disease without effective therapy. Hydrogen has been reported to exhibits antioxidant and anti-inflammatory effects in a rat model induced by monocrotaline of PH. In this study, we investigated the effects of inhaled hydrogen gas on the prevention and treatment of PVOD induced by mitomycin C (MMC) in rats.MethodsPVOD was induced in female Sprague-Dawley rats through intraperitoneal injection of MMC at a concentration of 3 mg·kg− 1·wk− 1 for 2 weeks. Inhalation of hydrogen gas (H2) was administered through a designed rat cage concurrently or two weeks after MMC administration. The severity of PVOD was assessed by using hemodynamic measurements and histological analysis. The expression levels of general control nonderepressible 2 (GCN2), nuclear factor erythroid 2-related factor-2 (Nrf2), heme oxygenase-1 (HO-1) and endothelial-to-mesenchymal transition (EndoMT) related proteins in lung tissue were measured. Levels of lipid peroxidation pro-inflammatory cytokines in serum were determined.ResultsInhaled H2 improved hemodynamics and right heart function, reversed right ventricular hypertrophy, and prevented pulmonary vessel reconstitution in both prevention and treatment approaches. It decreased malondialdehyde (MDA) levels in the serum and the expression of NADPH oxidase 1 (NOX-1) in lung tissue. It regulated Nrf2/HO-1 signaling pathway and anti-inflammatory factor GCN2 in lung tissue, accompanied by a decrease in macrophages and pro-inflammatory cytokines. Our data suggested that H2 inhalation effectively countered EndoMT induced by MMC, as evidenced by the detection of endothelial markers (e.g., VE-cadherin and CD31) and mesenchymal markers (e.g., vimentin and fibronectin). Further research revealed that H2 preserved p-Smad3 and induced p-Smad1/5/9.ConclusionInhalation of H2 effectively inhibits the pathogenesis of PVOD induced by MMC in rats. This inhibitory effect may be attributed to the antioxidant and anti-inflammatory properties of H2.

Serum GM-CSF level is a predictor of treatment response to tocilizumab in rheumatoid arthritis patients: a prospective observational cohort study

BackgroundThe aim of this prospective observational cohort study was to unveil the predictors of treatment response to tocilizumab (TCZ) therapy in rheumatoid arthritis (RA) patients, in terms of clinical characteristics and serum proinflammatory cytokines, especially to explore the predictive value of granulocyte macrophage-colony stimulating factor (GM-CSF).MethodsActive adult RA patients with inadequate response to MTX intending to receive TCZ therapy were recruited prospectively in the study. A total of 174 severe RA patients were included for the identification of the associations between treatment response and the following characteristic features: demographics, medications, disease activity, serum proinflammatory cytokines and so on.ResultsDisease duration (OR = 0.996), tender joint count (TJC)/68 (OR = 0.943), neutrophil ratio (W4/baseline) (OR = 0.224), the high level of GM-CSF > 5 ng/ml (OR = 0.414) at baseline were the independent adverse predictors of good response assessed by clinical disease activity index (CDAI) at week 24 (W24) for TCZ therapy in RA patients. Moreover, DAS28-ESR (OR = 2.951, P = 0.002) and the high level of GM-CSF > 10 ng/ml at baseline (OR = 5.419, P = 0.002) were independent predictors of poor response, but not the high level of GM-CSF > 5 ng/ml (OR = 2.713, P = 0.054). The patients in the high GM-CSF group had significantly higher DAS28-ESR and serum levels of cytokines (IL-17A, IL-1β, IL-6, TNF-α) at baseline, as well as significantly higher rate of non-good response (62.8% vs. 39.4%, P = 0.010) and poor response (27.9% vs. 9.1%, P = 0.004) than the low GM-CSF group at W24. In addition, poor responders had significantly higher levels of GM-CSF with concomitant increase in the serum levels of IL-17A and IL-1β at baseline than those in moderate and good response groups, while serum levels of IL-6 and TNF-α at baseline were not significantly different in three response groups.ConclusionThe high levels of GM-CSF (> 5 ng/ml and > 10 ng/ml) at baseline were the independent predictors of non-good response and poor response to TCZ at W24 respectively. The high level of GM-CSF at baseline is a marker of high disease activity and a predictor of poor response to TCZ in severe RA patients, which may facilitate the development of individualized treatment strategies for refractory RA.

Intersecting Blood Cytokines With Cholesterol Parameters to Profile Patients With Advanced Solid Tumors Receiving Immune Checkpoint Inhibitors.

The study investigated the relationship between serum proinflammatory cytokine levels, cholesterol metabolism, and clinical outcome in cancer patients undergoing immune checkpoint inhibitors (ICIs). Peripheral blood was collected before therapy from ICI-treated advanced cancer patients. We retrospectively assessed plasma total cholesterol (TC), ABCA1- and ABCG1-mediated cholesterol efflux (CE), passive diffusion (PD), cholesterol loading capacity (CLC), and serum IL-6, IL-10, and TNF-α. The association between blood cholesterol parameters and inflammatory cytokines and their effect on overall survival (OS), progression-free survival (PFS), and clinical benefit (CB) from ICIs were statistically assessed. Among 70 consecutively enrolled patients (nonsmall cell lung cancer: 94%; renal cell carcinoma: 6%), TC, CLC, and cholesterol PD resulted significantly higher in IL-6low and IL-10low cases (P<0.05), whereas ABCA1-mediated CE was increased in IL-10high patients (P=0.018). Uni- and multivariable analysis revealed meaningfully longer OS and PFS in IL-6low (HR 2.13 and 2.97, respectively) and IL-10low (HR 3.17 and 2.62) groups. At univariate analysis all cholesterol-related indices significantly correlated with OS and PFS, whereas at multivariate only high PD was validated as a protection factor (OS, HR 0.75; PFS, HR 0.84). Finally, uni- and multivariable showed a statistically significant inverse association of CB with ABCG1-CE (OR 0.62), as with IL-6 (OR 0.13) and IL-10 (OR 0.10). In-depth characterization of the interplay between blood cholesterol metabolism and immune-inflammatory cytokines might provide novel insights into the complex relationship among cancer, inflammation, lipids profile, and response to immunotherapy.

Tirzepatide alleviates oxidative stress and inflammation in diabetic nephropathy via IL-17 signaling pathway.

Oxidative stress (OS) and inflammation play essential roles in the development of diabetic nephropathy (DN). Tirzepatide (TZP) has a protective effect in diabetes. However, its underlying mechanism in DN remains unclear. DN model mice were induced by intraperitoneal injection of streptozotocin (STZ; 60mg/kg), followed by administration of different doses of TZP (3 and 10nmol/kg) via intraperitoneal injection for 8weeks. The effects of TZP on DN were evaluated by detecting DN-related biochemical indicators, kidney histopathology, apoptosis, OS, and inflammation levels. Additionally, to further reveal the potential mechanism, we investigated the role of TZP in modulating the IL-17 pathway. TZP reduced serum creatinine (sCR), blood urea nitrogen (BUN), and advanced glycosylation end products (AGEs) levels, while simultaneously promoting insulin secretion in diabetic mice. Additionally, TZP attenuated tubular and glomerular injury and reduced renal apoptosis levels. Further studies found that TZP increased the levels of SOD and CAT, and decreased MDA. Meanwhile, TZP also reduced the expression of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) in both mouse serum and kidney homogenates. TZP effectively inhibited the IL-17 pathway, and subsequent intervention with an IL-17 pathway agonist (IL-17A) reversed the suppressive effects of TZP on OS and inflammation. TZP can improve DN by inhibiting OS and inflammation through the suppression of the IL-17 pathway.

Features of the expression of the transcription factor NF-kB in patients with secondary edematous breast cancer with various pro-inflammatory cytokines

Background. One of the most prominent features of secondary edematous breast cancer (SEBC), which is the most malignant form of this type of cancer, is severity of chronic inflammation that is important for pathogenesis and progression of the disease. As of now, there is evidence of association of carcinogenesis and inflammation. The transcription factor (NF-kB) and pro-inflammatory cytokines play a pivotal role in both inflammation and carcinogenesis. The regulation of NF-kB signal pathways is impaired in a lot of malignant diseases, including breast cancer (BC). Thus, the study of the content of pro-inflammatory cytokines and NF-kB is of high priority, as it can provide valuable information about the course of the tumor process. However, there are few research papers that deal with association of cytokine profile and NF-kB in breast tumors. Purpose – is to study the content of NF-kB-р105 and pro-inflammatory cytokines (IL-6, IL-8, TNFα) in the blood serum of patients with secondary edematous breast cancer. Materials and Methods. 87 patients (42 with SEBC, 45 with BC) were examined prior to treatment. The age of 42 patients with T4bN0-3M0 SEBC ranged from 34 to 71 years (median 53.1). The ductal cancer was found in 30 patients (71.43%), the lobular cancer – in 12 patients (28.57%). The tumor of more than 5 cm was detected in 20 individuals (47.6%), the tumor of less than 5 cm – in 22 individuals (52.4%). The comparison group consisted of 45 patients with BC, with their age ranging from 30 to 67 years (median 52.3). They had T3-4N1-3M0 non-edematous locally advanced BC. The tumor of more than 5 cm was detected in 12 patients (26.7%), the tumor of less than 5 cm – in 33 patients (73.3%). The ductal cancer was diagnosed in 33 patients (73.3%), the lobular cancer – in 12 patients (26.7%). The control group consisted of 10 patients with fibroadenomas. The content of cytokines (IL-1B, IL-2, IL-6, IL-8, TNFα) in the blood serum of patients was measured using the ELISA assay and CJSC «Vektor-Best» standard assay kits. The content of NF-kB1 subunit (р105 → р50) was measured using the ELISA assay and the Human NFkB – p105 (Nuclear factor NF-kappa-B p 105 subunit) ELISA Kit. The measurement was performed using the Immunochem-2100 American semi-automatic immunoassay analyzer. Results. It was found that in SEBC, the levels of pro-inflammatory cytokines IL-6, IL-8, TNFα were increased by 1.4 times, compared to the parameters in BC, and the level of IL-8 was the highest. The total level of NF-kB increased by 14,7 times in patients with SEBC and by 2,4 times in patients with BC, compared to individuals with fibroadenomas. The level of NF-kB in SEBC in groups with IL-6, TNFα was higher than in groups with BC by 3.1 and 1,7 times, respectively. It was found that the highest level of NF-kB was in the group with cytokine IL-8. In SEBC, it was higher by 5.7 times than in BC. In patients with SEBC, correlations between NF-kB and cytokines were established: NF-kB and IL-8 (r = 0.80; p &lt; 0.05); NF-kB and IL-6 (r = 0.60; p &lt; 0.05); NF-kB and TNFα (r = 0.60; p &lt; 0.05). Thus, one feature of SEBC is the increase in the content of NF-kB, IL-6, and TNFα, and also a significant increase in the level of NF-kB and IL-8, compared to the parameters in patients with BC as well as in patients with fibroadenomas. Conclusions. It was found that there was activation of the transcription factor NF-kB-p105 and a significant increase in the levels of pro-inflammatory cytokines (IL-6, IL-8, TNFα) in the blood serum of patients with SEBC, compared to patients with fibroadenomas, which indicates high carcinogenic potential of the tumor and the presence of the inflammatory component. It was demonstrated that the highest level of NF-kB-p105 was detected in the group of patients with SEBC with the highest level of cytokines IL-8. It was also found that in patients with SEBC, the level of the transcription factor and pro-inflammatory cytokines IL-6, IL-8, TNFα in the blood serum was significantly higher than in patients with BC, thereby confirming severe aggressiveness of this form of the disease.

Fermented Lentinus edodes extract containing α-glucan ameliorates concanavalin A-induced autoimmune hepatitis in mice

Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease that threatens human health worldwide. The aim of this study was to detect the protective effect of a fermented Lentinus edodes extract containing α-glucan (FLA), in a concanavalin A (ConA)-induced AIH mouse model and to determine the underlying liver-protective mechanism. The results showed that compared with the model group, the level of proinflammatory cytokines in serum of FLA pretreated mice was significantly decreased, and the degree of inflammatory cell infiltration in liver, thymus and spleen was significantly reduced. Quantitative polymerase chain reaction, immunohistochemistry, and Western blotting showed that FLA pre-treatment inhibited the ConA-induced apoptosis of hepatocytes by down-regulating the expression of BAX and up-regulating the expression of BCL-2. Further research found that FLA may improve liver injury in mice by activating NRF2 signaling pathway and inhibiting TRAF6/NF-κB signaling pathway. Thus, FLA may improve liver injury in mice by shifting gut microbial composition to reduce the release of inflammatory cytokines in the serum and prevent the necrosis of hepatocytes. Up-regulation of NRF2 signaling pathway, down-regulation of TRAF6/NF-κB signaling pathway, and an increase in the relative abundance of Lactobacillus_johnsonii and Ligilactobacillus_murinus play a protective role in liver.

Antitumor, antioxidant, and anti-inflammatory activity of spirulina against 7,12-dimethylbenzanthracene-induced mammary cancer

Background Breast cancer is the most abundant malignancies worldwide; however, its current therapies encounter drug resistance or exhibit numerous side effects. Marine and freshwater algal biomasses, such as spirulina, are rich with many biological active components. Objective The main objective of the current study was to investigate the therapeutic, antioxidant, and immune-modulating efficiency of spirulina on breast tumor modelled female rats, especially through the inhibition of the phosphoinositide 3-kinases/Akt/mammalian target of rapamycin pathway. Materials and methods 7,12-dimethylbenzanthracene (DMBA)-induced mammary cancer rats were ingested with spirulina (500 mg/kg/day) for 6 weeks, then blood and tissue samples of normal and spirulina-treated cancer rats were obtained and tested for biochemical, immunological, and histopathological assessments. Cancer model is used in this experiment. Results The results showed that spirulina is rich in phenolic compounds that have high scavenger activity and reducing power reflecting the antioxidant potential of spirulina. Treatment of DMBA-induced mammary cancer rats with spirulina resulted in improvement in mammary oxidative stress status that was distorted due to DMBA administration; meanwhile, superoxide dismutase, glutathione peroxidase, and reduced glutathione values were elevated significantly coupled with a marked drop in nitric oxide and malondialdehyde levels. In addition, spirulina boosts the immune-modulating response against tumor as the serum proinflammatory cytokines (tumor necrosis factor alpha, interlukin-1 beta, and interlukin-6) were markedly downregulated, and associated with inhibition of Akt and mammalian target of rapamycin pathway; this in turn suppress the tumor proliferation and progression. Furthermore, the prognosis of the treatment was indicated by the clear reduction of serum cancer antigen 15.3 level accompanied by elevation in serum level of the apoptotic biomarkers (caspase-3 and CD4) inferring the upregulation of tumor suppressor genes. Similarly, spirulina ameliorated lipid profile and the biochemical markers of hepatorenal functions (alanine transaminase, aspartate transaminase, urea, and creatinine) that were disturbed by DMBA; therefore, it has a positive impact on the body health. These biochemical improvements were associated with a notable improvement in the histological architecture of the mammary tissue. Conclusion In conclusion, spirulina has proved considerable antitumor, antioxidant, and anti-inflammatory activities against DMBA-induced mammary cancer.

Linalool as a key component in strawberry VOCs modulates gut microbiota, systemic inflammation, and glucolipid metabolism

Strawberries are rich in volatile organic compounds (VOCs), which are increasingly recognized as potential health-promoting factors. This study explored the health effects of intaking strawberry VOC extract and its dominant terpene, linalool. The results indicated that linalool and strawberry VOC extract significantly increased the abundance of beneficial bacteria like Lactobacillus, Bacillus, and Alistipes in mice. Moreover, mice treated with linalool and strawberry VOC extract exhibited notable reductions in serum pro-inflammatory cytokines; interleukin IL-6 decreased by 14.5% and 21.8%, respectively, while IL-1β levels decreased by 9.6% and 13.4%, respectively. Triglyceride levels in the treated groups were reduced by 38.3% and 58.1%, respectively. Spearman's correlation analysis revealed that Bacillus negatively correlated with glucolipid indices, and Bifidobacterium and Dubosiella negatively correlated with inflammatory factors, indicating that alterations in glucolipid metabolism might be associated with the regulation of gut microbiota and systemic inflammation.

Effect of Bile Acids Supplementation in Fatty Liver Hemorrhagic Syndrome, Production Performance, Physiological and Quality Characteristics of Laying Hen Eggs.

This study aimed to investigate the effects of bile acids (BAs) supplementation on fatty liver hemorrhagic syndrome (FLHS), production performance, and physiological and quality characteristics of laying hen eggs. Sixty Sanhuang laying hens, aged 28 weeks, were randomly allocated to six dietary treatments over a 4-week period, including the control (CON) group (feeding basal diet), the high-fat diet (HFD)-treated group (basal diet containing 10% soybean oil), and HFD supplemented with 0.01% and 0.02% of chenodeoxycholic acid (CDCA) or hyodeoxycholic acid (HDCA) groups. Production performance, egg quality, liver morphology, serum biochemical indexes, antioxidant capacity, proinflammatory cytokines, and intestinal microbiota were evaluated. The average body weight in 0.01% CDCA was larger than in the HFD group (p < 0.05). Eggshell Thickness in the CON group was greater than in the HFD, 0.01% CDCA, and HDCA groups (p < 0.05). Albumen height in the 0.02% HDCA group was higher than the HFD group (p < 0.05). Eggshell weight in the HFD group was less than the CON group (p < 0.05). Haugh unit (HU) in the HDCA group was larger than the HFD group (p < 0.05). Albumen weight in the 0.02% HDCA group was greater than the CON and HFD groups (p < 0.05). In the HFD group, the levels of triglyceride (TG), total cholesterol (TC), and low-density lipo-protein cholesterol (LDL-C) were surpassing the other groups (p < 0.05). The levels of catalase (CAT) and total superoxide dismutase (T-SOD) in the HFD group was smaller than the other groups (p < 0.05). The level of malondialdehyde (MDA) in the HFD group was higher than in the other groups (p < 0.05). Tumor necrosis factor-α (TNF-α) levels were larger in the HFD group than in the other groups (p < 0.05). The 16S rRNA sequencing analysis indicated significant variations in the relative abundance of specific bacterial populations among the different treatment groups. The treatment and CON groups exhibited a higher presence of bacteria that inhibit host energy absorption or promote intestinal health such as Firmicutes, Bacteroidetes, and Ruminococcus, whereas the HFD group showed an increased prevalence of potentially pathogenic or deleterious bacteria, such as Desulfovibrio spp. In conclusion, the supplementation of BAs in poultry feed has been demonstrated to effectively mitigate the detrimental effects of FLHS in laying hens. This intervention regulates lipid metabolism, bolsters antioxidant defenses, reduces inflammation, and modulates the gut microbiota, offering a novel perspective on the application of BAs in the poultry industry.

Markers of chronic low-grade inflammation and serum cytokine levels in patients with type 1 diabetes: associations with time in ranges and glucose variability

BACKGROUND: Increased glucose variability is recognized as a risk factor for vascular diabetic complications. It is assumed that deteriorating effect of GV on blood vessels can be realized through the activation of inflammatory signaling pathways.AIM: to determine associations of low-grade inflammation markers and serum cytokines with time in ranges and GV parameters derived from continuous glucose monitoring (CGM) in patients with type 1 diabetes (T1D).MATERIALS AND METHODS: In 470 adult patients with T1D, high-sensitivity C-reactive protein (hsCRP) and fibrinogen was measured, neutrophil-lymphocyte ratio (NLR) and the Systemic Immune-inflammation Index (SII) were calculated. In a sample of 130 patients and 20 healthy individuals (control), serum concentrations of interleukins (IL-1β, IL-4, IL-6, sIL-6Rα, IL-19, IL-20, IL-22, IL-26, IL-27, IL-28A, IL-29, IL-32, IL-34, IL-35) were assessed by multiplex analysis. Time in the ranges and GV parameters: Coefficient of Variability (CV), Mean Amplitude of Glycemic Excursions (MAGE), and Mean Absolute Glucose rate of changes (MAG) were derived from CGM data.RESULTS: Patients with Time In Range (TIR) &lt;70% had higher concentrations of hs-CRP and fibrinogen, higher SII values, and demonstrated a trend toward higher TIR compared with those with TIR ≥70% (p=0.018, p=0.026, p=0.037, p=0.101, respectively). Patients with T1D, when compared to control, demonstrated increased concentrations of IL-1β (p&lt;0.0001), IL-6 (p&lt;0.0001), decreased levels of IL-4 (p=0.002), and a tendency to decrease IL-22 and IL-29 (p=0.1). Patients with TIR&gt;70% had higher levels of IL-4 (p=0.02) as well as lower concentrations of IL-1β (p=0.0003) and IL-6 (p=0.007) than patients with TIR≤70%. In a multivariate stepwise regression analysis including clinical data and CGM parameters as independent variables, body mass index was positive predictor of hsCRP and fibrinogen levels, TIR was negatively associated with IL-20 and IL-34, time above range was associated positively with IL-1β, MAGE showed positive association with SII, IL-26 and IL28A, while MAG was positively associated with IL-29.CONCLUSION: T1D patients with non-target TIR (&lt;70%) have higher levels of low-intensity inflammatory markers and serum pro-inflammatory cytokines than patients with TIR&gt;70%. Both hyperglycemia and increased GV are associated with intensity of low-grade inflammation in T1D.

Prevention of cyclophosphamide-induced immune suppression by polysaccharides from Apocynum venetum flowers via enhancing immune response, reducing oxidative stress, and regulating gut microbiota in mice

IntroductionEmerging proof suggests that Apocynum venetum flowers polysaccharide (AVFP) has immunomodulatory effects in vitro. However, the action mechanism of AVFA is still unclear in vivo. The purpose of this study is to probe into the potential mechanism of AVFA in immunosuppressed mice by investigating organ index, cytokine levels, anti-oxidative stress capacity, transcriptomics, and gut microbiota.MethodsImmunocompromised mice induced by cyclophosphamide (CTX) were divided into six groups. The enzyme-labeled method, hematoxylin and eosin, transcriptomics, and high-throughput sequencing were used to detect the regulatory effects of AVFP on immunocompromised mice and the function of AVFP on the concentration of short-chain fatty acids (SCFAs) by high-performance liquid chromatography (HPLC) analysis. The Spearman correlation analysis was used to analyze the correlation between the intestinal microbiota and biochemical indexes.ResultsThe experimental results illustrated that AVFP has protective effects against CTX-induced immunosuppression in mice by prominently increasing the organ index and levels of anti-inflammatory factors in serum in addition to enhancing the antioxidant capacity of the liver. Meanwhile, it could also signally decrease the level of pro-inflammatory cytokines in serum, the activity of transaminase in serum, and the content of free radicals in the liver, and alleviate the spleen tissue damage induced by CTX. Transcriptomics results discovered that AVFP could play a role in immune regulation by participating in the NF-κB signaling pathway and regulating the immune-related genes Bcl3, Hp, Lbp, Cebpd, Gstp2, and Lcn2. Gut microbiota results illustrated that AVFP could increase the abundance of beneficial bacteria, reduce the abundance of harmful bacteria, and regulate the metabolic function of intestinal microorganisms while dramatically improving the content of SCFAs, modulating immune responses, and improving the host metabolism. The Spearman analysis further evaluated the association between intestinal microbiota and immune-related indicators.ConclusionThese findings demonstrated that AVFP could enhance the immune effects of the immunosuppressed mice and improve the body’s ability to resist oxidative stress.

Mitochondria targeted esculetin administration improves insulin resistance and hyperglycemia-induced atherosclerosis in db/db mice.

The development and progression of hyperglycemia (HG) and HG-associated atherosclerosis are exacerbated by mitochondrial dysfunction due to dysregulated mitochondria-derived ROS generation. We recently synthesized a novel mitochondria-targeted esculetin (Mito-Esc) and tested its dose-response therapeutic efficacy in mitigating HG-induced atherosclerosis in db/db mice. In comparison to simvastatin and pioglitazone, Mito-Esc administration resulted in a considerable reduction in body weights and improved glucose homeostasis, possibly by reducing hepatic gluconeogenesis, as indicated by a reduction in glycogen content, non-esterified free fatty acids (NEFA) levels, and fructose 1,6-bisphosphatase (FBPase) activity. Interestingly, Mito-Esc treatment, by regulating phospho-IRS and phospho-AKT levels, greatly improved palmitate-induced insulin resistance, resulting in enhanced glucose uptake in adipocytes and HepG2 cells. Also, and importantly, Mito-Esc administration prevented HG-induced atheromatous plaque formation and lipid accumulation in the descending aorta. In addition, Mito-Esc administration inhibited the HG-mediated increase in VACM, ICAM, and MAC3 levels in the aortic tissue, as well as reduced the serum pro-inflammatory cytokines and markers of senescence. In line with this, Mito-Esc significantly inhibited monocyte adherence to human aortic endothelial cells (HAECs) treated with high glucose and reduced high glucose-induced premature senescence in HAECs by activating the AMPK-SIRT1 pathway. In contrast, Mito-Esc failed to regulate high glucose-induced endothelial cell senescence under AMPK/SIRT1-depleted conditions. Together, the therapeutic efficacy of Mito-Esc in the mitigation of hyperglycemia-induced insulin resistance and the associated atherosclerosis is in part mediated by potentiating the AMPK-SIRT1 axis. KEY MESSAGES: Mito-Esc administration significantly mitigates diabetes-induced atherosclerosis. Mito-Esc improves hyperglycemia (HG)-associated insulin resistance. Mito-Esc inhibits HG-induced vascular senescence and inflammation in the aorta. Mito-Esc-mediated activation of the AMPK-SIRT1 axis regulates HG-induced endothelial cell senescence.

Autoprobiotics in the Treatment of Patients with Colorectal Cancer in the Early Postoperative Period.

Despite great advances in the treatment of oncological diseases, the development of medical technologies to prevent or reduce complications of therapy, in particular, those associated with surgery and the introduction of antibiotics, remains relevant. The aim of this study is to evaluate the effectiveness of the use of autoprobiotics based on indigenous non-pathogenic strains of Enterococcus faecium and Enterococcus hirae as a personalized functional food product (PFFP) in the complex therapy of colorectal cancer (CRC) in the early postoperative period. A total of 36 patients diagnosed with CRC were enrolled in the study. Study group A comprised 24 CRC patients who received autoprobiotic therapy in the early postoperative period, while the control group C included 12 CRC patients without autoprobiotic therapy. Prior to surgery and between days 14 and 16 post-surgery, comprehensive evaluations were conducted on all patients, encompassing the following: stool and gastroenterological complaints analysis, examination of the gut microbiota (bacteriological study, quantitative polymerase chain reaction, metagenome analysis), and analysis of interleukins in the serum. Results: The use of autoprobiotics led to a decrease in dyspeptic complaints after surgery. It was also associated with the absence of postoperative complications, did not cause any side effects, and led to a decrease in the level of pro-inflammatory cytokines (IL-6 and IL-18) in the blood serum. The use of autoprobiotics led to positive changes in the structure of escherichia and enterococci populations, the elimination of Parvomonas micra and Fusobacterium nucleatum, and a decrease in the quantitative content of Clostridium perfringens and Akkermansia muciniphila. Metagenomic analysis (16S rRNA) revealed an increase in alpha diversity. Conclusion: The introduction of autoprobiotics in the postoperative period is a highly effective and safe approach in the complex treatment of CRC. Future studies will allow the discovery of additional fine mechanisms of autoprobiotic therapy and its impact on the digestive, immune, endocrine, and neural systems.

Modelling lung infection with Klebsiella pneumoniae after murine traumatic brain injury

Pneumonia is a common comorbidity in patients with severe traumatic brain injury (TBI), and is associated with increased morbidity and mortality. In this study, we established a model of intratracheal Klebsiella pneumoniae administration in young adult male and female mice, at 4 days following an experimental TBI, to investigate how K. pneumoniae infection influences acute post-TBI outcomes. A dose-response curve determined the optimal dose of K. pneumoniae for inoculation (1 x 10^6 colony forming units), and administration at 4 days post-TBI resulted in transient body weight loss and sickness behaviors (hypoactivity and acute dyspnea). K. pneumoniae infection led to an increase in pro-inflammatory cytokines in serum and bronchoalveolar lavage fluid at 24 h post-infection, in both TBI and sham (uninjured) mice. By 7 days, when myeloperoxidase + neutrophil numbers had returned to baseline in all groups, lung histopathology was observed with an increase in airspace size in TBI + K. pneumoniae mice compared to TBI + vehicle mice. In the brain, increased neuroinflammatory gene expression was observed acutely in response to TBI, with an exacerbated increase in Ccl2 and Hmox1 in TBI + K. pneumoniae mice compared to either TBI or K. pneumoniae alone. However, the presence of neuroinflammatory immune cells in the injured brain, and the extent of damage to cortical and hippocampal brain tissue, was comparable between K. pneumoniae and vehicle-treated mice by 7 days. Examination of the fecal microbiome across a time course did not reveal any pronounced effects of either injury or K. pneumoniae on bacterial diversity or abundance. Together, these findings demonstrate that K. pneumoniae lung infection after TBI induces an acute and transient inflammatory response, primarily localized to the lungs with some systemic effects. However, this infection had minimal impact on secondary injury processes in the brain following TBI. Future studies are needed to evaluate the potential longer-term consequences of this dual-hit insult.

Effects of Combined Live Bifidobacterium, Lactobacillus, Enterococcus, and Bacillus Cereus Tablets on the Structure and Function of the Intestinal Flora in Rabbits Undergoing Hepatic Artery Infusion Chemotherapy.

Few studies have explored the biological mechanism by which probiotics alleviate adverse reactions to chemotherapy drugs after local hepatic chemotherapy perfusion by regulating the intestinal flora. This study investigates the effects of Combined Live Bifidobacterium, Lactobacillus, Enterococcus, and Bacillus Cereus Tablets on the intestinal microbial structure and intestinal barrier function, as well as the potential mechanism in rabbits after local hepatic chemotherapy infusion. Eighteen New Zealand White rabbits were randomly divided into a control group, a hepatic local chemotherapy perfusion group, and a hepatic local chemotherapy perfusion + Combined Live Bifidobacterium, Lactobacillus, Enterococcus, and Bacillus Cereus Tablets group to assess the effects of Combined Live Bifidobacterium, Lactobacillus, Enterococcus, and Bacillus Cereus Tablets on the adverse reactions. The administration of Combined Live Bifidobacterium, Lactobacillus, Enterococcus, and Bacillus Cereus Tablets alleviated the intestinal flora disorder caused by local hepatic perfusion chemotherapy, promoted the growth of beneficial bacteria, and inhibited the growth of harmful bacteria. The Combined Live Bifidobacterium, Lactobacillus, Enterococcus, and Bacillus Cereus Tablets also reduced the levels of serum pro-inflammatory cytokines and liver injury factors induced by local hepatic perfusion chemotherapy. Our findings indicate that Combined Live Bifidobacterium, Lactobacillus, Enterococcus, and Bacillus Cereus Tablets can ameliorate the toxicity and side effects of chemotherapy by regulating intestinal flora, blocking pro-inflammatory cytokines, reducing liver injury factors, and repairing the intestinal barrier. Probiotics may be used as a potential alternative therapeutic strategy to prevent the adverse reactions caused by chemotherapy with local hepatic perfusion.

Сytokines as promising diagnostic and prognostic biomarkers of microvascular complications of diabetes

Classical knowledge about the pathogenesis of diabetes and its complications in recent years has been supplemented by ideas about the role of chronic inflammation. It has been established that inflammatory reactions play a role in the beta cell dysfunction, the formation of insulin resistance and remodeling of the vascular wall. Cytokines, soluble low molecular weight proteins and peptides that perform informational and regulatory functions, play central role in the development of inflammation. A wide range of biological activity and involvement in many aspects of pathogenesis make it possible to consider cytokines as promising molecules for diagnosing and predicting the complications. In this review, we summarize data from studies that assessed the role of cytokines as diagnostic and prognostic markers for the development of microvascular diabetic complications. Current data indicate that angiogenic and pro-inflammatory cytokines (VEGF, TNF-α, IL-6, IL-8, IL-15, IL-17, MCP-1, IP-10, INF-γ, PEDF, etc.) are promising biomarkers for proliferative diabetic retinopathy, especially when their local production is assessed (in vitreous, aqueous humor and tears). The role of these molecules as biomarkers of non-proliferative diabetic retinopathy and diabetic macular edema needs further research. Serum proinflammatory and fibrogenic cytokines (primarily MCP-1, IL-6, TNF-α, YKL-40, TGF-β and bFGF) and cytokine receptors (sTNFR1, sTNFR2) are considered as promising diagnostic and prognostic markers of diabetic kidney disease. Urinary excretion of IL-6 and MCP-1 turned out to be a predictor of the progression of diabetic nephropathy. Multi-bead assay and mass spectrometry make it possible to study cytokine panels in small samples of biological material. Combined biomarkers, including several cytokines, may increase the reliability of the prognosis of diabetic complications.

Protective Effect of Perilla Seed Meal and Perilla Seed Extract against Dextran Sulfate Sodium-Induced Ulcerative Colitis through Suppressing Inflammatory Cytokines in Mice.

An excessive inflammatory response of the gastrointestinal tract is recognized as one of the major contributors to ulcerative colitis (UC). Despite this, effective preventive approaches for UC remain limited. Rosmarinic acid (RA), an enriched fraction from Perilla frutescens, has been shown to exert beneficial effects on disease-related inflammatory disorders. However, RA-enriched perilla seed meal (RAPSM) and perilla seed (RAPS) extracts have not been investigated in dextran sulfate sodium (DSS)-induced UC in mice. RAPSM and RAPS were extracted using the solvent-partitioning method and analyzed with high-pressure liquid chromatography (HPLC). Mice with UC induced using 2.5% DSS for 7 days were pretreated with RAPSM and RAPS (50, 250, 500 mg/kg). Then, the clinical manifestation, colonic histopathology, and serum proinflammatory cytokines were determined. Indeed, DSS-induced UC mice exhibited colonic pathological defects including an impaired colon structure, colon length shortening, and increased serum proinflammatory cytokines. However, RAPSM and RAPS had a protective effect at all doses by attenuating colonic pathology in DSS-induced UC mice, potentially through the suppression of proinflammatory cytokines. Concentrations of 50 mg/kg of RAPSM and RAPS were sufficient to achieve a beneficial effect in UC mice. This suggests that RAPSM and RAPS have a preventive effect against DSS-induced UC, potentially through alleviating inflammatory responses and relieving severe inflammation in the colon.

Construction of curcumin-loaded macrophage and HUVECs membrane-derived vesicles for drug delivery in cardiovascular inflammatory

In the progression of cardiovascular disease (CVD), myocardial inflammation and vascular endothelial inflammation are prevalent pathological phenomena. However, the development of drug delivery platform with high specificity against these inflammatory injury sites remains a challenge. To overcome this, we fused RAW264.7 macrophage membranes with human umbilical vein endothelial cell (HUVEC) membranes to prepare hybrid extracellular vesicles (RAW-HEVs) consisted of both types of cell membrane proteins. This hybrid EVs exhibited high uptake ratio towards LPS-induced inflammatory HUVECs and H9C2 cells. By leveraging the stealth properties of HUVEC membranes in the bloodstream and the innate inflammation-targeting ability of RAW264.7 macrophage membranes, RAW-HEVs actively accumulated at inflammatory sites of the heart and thoracic aorta in vivo. By loading curcumin (Cur) with anti-inflammatory activity to prepare Cur-loaded hybrid extracellular vesicles (RAW-H/Cur). RAW-H/Cur significantly reduced the expression of pro-inflammatory cytokines in cell supernatants and mice serum as compared to free Cur, as determined by ELISA. In addition, a significant reduction in LPS-induced organ damage in the heart and thoracic aorta was observed with RAW-H/Cur treatment, determined by Hematoxylin-eosin staining and immunohistochemistry. In conclusion, RAW-H/Cur, as a promising bionic delivery system for cardiovascular inflammatory diseases, is expected to help deliver Cur to inflamed regions of the heart and blood vessels and alleviate inflammatory symptoms.

Melatonin-mediated corrective changes in gut microbiota of experimentally chronodisrupted C57BL/6J mice

ABSTRACT Chronic consumption of a high-calorie diet coupled with an altered sleep-wake cycle causes disruption of circadian clock that can impact the gut microbiome leading to metabolic syndrome and associated diseases. Herein, we investigate the effects of a high fat high fructose diet (H) alone or in combination with photoperiodic shifts induced chronodisruption (CD) on gut microbiota of C57BL/6J male mice. Further, the merits of daily evening intraperitoneal administration of melatonin in restoring gut microbiota are studied herein. Experimental groups viz. H, CD and HCD mice recorded higher levels of serum pro-inflammatory cytokines (TNF-α and IL-6) and lower levels of the anti-inflammatory cytokine, IL-10. These findings correlate with a concomitant increase in the transcripts of TLR4, TNF-α, and IL-6 in small intestine of the said groups. A decrement in mRNA levels of Ocln, ZO-1 and Vdr in these groups implied towards an altered gut permeability. These results were in agreement with the observed decrement in percentage abundance of total gut microflora and Firmicutes: Bacteroidetes (F/B) ratio. Melatonin administration accounted for lower-level inflammation (serum and gut) along with an improvement in gut permeability markers. The total abundance of gut microflora and F/B ratio showed an improvement in all the melatonin-treated groups and the same is the highlight of this study. Taken together, our study is the first to report perturbations in gut microbiota resulting due to a combination of photoperiodic shifts induced CD and a high fat high calorie diet-induced lifestyle disorder. Further, melatonin-mediated rejuvenation of gut microbiome provides prima facie evidence of its role in improving gut dysbiosis that needs a detailed scrutiny.

Anti-Inflammatory Effect of Columbianadin against D-Galactose-Induced Liver Injury In Vivo via the JAK2/STAT3 and JAK2/p38/NF-κB Pathways.

Angelicae pubescentis radix (APR) has been traditionally used for thousands of years in China to treat rheumatoid arthritis (RA), an autoimmune disorder. As the main active coumarin of APR, columbianadin (CBN) exhibits a significant anti-inflammatory effect in vitro. However, the anti-inflammatory activity and underlying mechanism of CBN in vivo remain unclear. This work aimed to elucidate the anti-inflammatory activity of CBN in vivo and its related signaling pathways in a D-Gal-induced liver injury mouse model. Analysis of biochemical indices (ALT and AST) and pro-inflammatory cytokines (IL-1β and IL-6) in serum indicated that CBN significantly ameliorated D-Gal-induced liver injury. CBN treatment also significantly increased the activities of antioxidant enzymes (SOD, CAT, GPx), and decreased the levels of pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) in liver tissue. Liver histology revealed that CBN treatment reduced hepatic inflammation. Western blot analysis indicated that CBN down-regulates the expression of phosphorylated JAK2, STAT3, MAPK, and NF-κB in the related signaling pathways. These findings support the traditional use of APR as a remedy for the immune system, and indicate that the JAK2/STAT3 and JAK2/p38/NF-κB signaling pathways may be important mechanisms for the anti-inflammatory activity of CBN in vivo.