Increased Levels Of IL-6 Research Articles

Amentoflavone Ameliorates Carrageenan-Induced Pleurisy and Lung Injury by Inhibiting the NF-κB/STAT3 Pathways via Nrf2 Activation.

Many natural flavonoids can activate nuclear factor erythroid 2-related factor 2 (Nrf2), which is pivotal for alleviating various diseases related to inflammation and oxidative stress, including pleurisy. Amentoflavone (AMF), a biflavonoid extracted from many plants, has some beneficial bioactivities, especially anti-inflammatory and antioxidative activities. We aimed to investigate whether AMF protects against pleurisy and lung injury induced by carrageenan (Car) by activating Nrf2. Pleurisy was induced in wild-type (WT) and Nrf2-deficient (Nrf2-/-) mice. Then, pleural exudate and lung tissue were collected for biochemical analysis, H&E staining, immunocytochemistry and western blotting. Our results indicated that AMF protected against Car-induced pleurisy and lung injury. The Wright-Giemsa and H&E staining results showed that AMF alleviated inflammatory effusion and pathological injury. In addition, AMF decreased SOD and GSH depletion and MDA and MPO generation in the lung tissue of mice. AMF activated Nrf2 through keap-1 dissociation and subsequently increased heme oxygenase-1 (HO-1), NAD(P)H-quinone oxidoreductase 1 (NQO1), and γ-glutamylcysteine ligase (GCL) levels. Furthermore, AMF suppressed IL-1β and TNF-α levels and increased IL-10 levels in pleural exudate by blocking the proinflammatory NF-κB, signal transducer and activator of transcription 3 (STAT3) and extracellular signal-regulated kinase (ERK) pathways induced by Car. However, these antioxidative and anti-inflammatory effects were weakened in Nrf2-/- mice. Moreover, AMF failed to suppress the NF-κB and STAT3 pathways in Nrf2-/- mice. Our results demonstrated that AMF exerted anti-inflammatory and antioxidative effects in Car-induced lung injury and pleurisy in a Nrf2-dependent manner.

Novel preparation of bilirubin-encapsulated pluronic F-127 nanoparticles as a potential biomaterial for wound healing

Cutaneous wounds deteriorate the health of patients and liable for high economic loss. Previous studies showed promising wound healing potentials of bilirubin, however, this macromolecule constrained with poor water solubility and skin penetration. In this study, Pluronic F-127, a non-ionic copolymer surfactant, was used for the encapsulation of the wound healing agent the bilirubin. With this strategy, spherical shaped bilirubin nanoparticles of ∼100–150 nm with zeta potential ranging from −13.43 ± 0.56 to −17.53 ± 0.43 mV were obtained. Topical applications of bilirubin nanoparticle (0.3%) on cutaneous wounds of rats showed promising wound healing in comparison with other topical treatments. This topical nano-formulation also modulates the cytokine and growth factor responses in the treated group. On day 7 of healing, bilirubin nanoparticles treatment significantly reduced TNF-α and increased IL-10 levels with increased VEGF and TGF-β1 expressions. Simultaneously, prominent pro-healing activities could be observed histopathologically. These include increased blood vessels, reduced inflammatory cells, more myofibroblasts, increased deposition of collagen fibres, and early re-epithelialization. The changes were prominent in bilirubin nanoparticles (0.3%) treated group indicating better granulation tissue, quality of healing and wound maturity. In conclusion, the proposed new encapsulated bilirubin nanoparticles strategy significantly improved wound healing by modulation of cytokines and growth factors response in comparison with native bulk bilirubin. These observations support its potential as a novel biomaterial for wound healing in the future.

Shigella flexneri vaccine development: Oral administration of peptides derived from the 49.8 kDa pili protein subunit activates the intestinal immune response in mice.

Background and Aim:The morbidity and mortality of Shigella infections remain a global challenge. Epitope-based vaccine development is an emerging strategy to prevent bacterial invasion. This study aimed to identify the ability of the 49.8 kDa pili subunit adhesin protein epitope of Shigella flexneri to induce an intestinal immune response in mice.Materials and Methods:Thirty adult male Balb/c mice were divided into a control group, cholera toxin B subunit (CTB) group, CTB+QSSTGTNSQSDLDS (pep_1) group, CTB+DTTITKAETKTVTKNQVVDTPVTTDAAK (pep_2) group, and CTB+ ATLGATLNRLDFNVNNK (pep_3). We performed immunization by orally administering 50 μg of antigen and 50 μl of adjuvant once a week over 4 weeks. We assessed the cellular immune response by quantifying T helper 2 (Th2) and Th17 using flow cytometry. In addition, we assessed the humoral immune response by quantifying interleukin (IL-4), IL-17, secretory immunoglobulin A (sIgA), and β-defensin using enzyme-linked immunoassay. Statistical analysis was performed using one-way analysis of variance and Kruskal–Wallis test.Results:Peptide oral immunization increases the cellular immune response as reflected by the increase of Th2 (p=0.019) and Th17 (p=0.004) cell counts, particularly in the CTB_pep_1 group. Humoral immune response activation was demonstrated by increased IL-4 levels, especially in the CTB+pep_3 group (p=0.000). The IL-17 level was increased significantly in the CTB+pep_1 group (p=0.042). The mucosal immune response was demonstrated by the sIgA levels increase in the CTB+pep_3 group (p=0.042) and the β-defensin protein levels (p=0.000).Conclusion:All selected peptides activated the cellular and humoral immune responses in the intestine of mice. Further studies are necessary to optimize antigen delivery and evaluate whether the neutralizing properties of these peptides allow them to prevent bacterial infection.

Зміни імунологічного статусу у ВІЛ-інфікованих осіб із хронічною токсоплазмозною інвазією та токсоплазмозним енцефалітом

Актуальність. Інвазія Toxoplasma gondii у ВІЛ-інфікованих осіб може призвести до поглибленої імунопатології, що сприяє реактивації брадизоїтів та розвитку тяжких опортуністичних захворювань. Мета дослідження: вивчити особливості імунологічного статусу ВІЛ-інфікованих пацієнтів, які інвазовані токсоплазмами, та визначити предиктори розвитку токсоплазмозу мозку. Матеріали та методи. Обстежено 61 ВІЛ-інфіковану особу (33 особи серопозитивні на токсоплазмоз і 28 — серонегативні). Застосовували імуноферментний метод для визначення титрів специфічних протитоксоплазмозних IgG та IgМ; загальних IgM, IgA, IgG, а також IL-2, -4, -10, INF-γ, TNF-2α. Статистичну обробку здійснювали в статистичному пакеті програми Exсel з використанням t-критерію Стьюдента, а також z-критерію Фішера. Методом Байєса та послідовного статистичного аналізу А. Вальда визначали діагностичну цінність окремих лабораторних показників. Результати. У ВІЛ-інфікованих осіб виявлено дисбаланс цитокінів порівняно зі здоровими особами. У серонегативних на токсоплазмоз пацієнтів були підвищені рівні IL-4 (1,57 ± 0,30 пг/мл проти 0,81 ± 0,09 пг/мл, р < 0,001), IL-10 (9,81 ± 0,17 пг/мл проти 6,70 ± 0,13 пг/мл, р < 0,001), ТNF-2α (2,89 ± 0,08 пг/мл проти 1,90 ± 0,04 пг/мл, р < 0,001), INF-γ (9,30 ± 0,47 пг/мл проти 4,13 ± 0,12 пг/мл, р < 0,001), а також загальний IgG (20,63 ± 0,65 г/л проти 16,30 ± 0,94 г/л, р < 0,001). На відміну від серонегативних осіб у серопозитивних були вищими показники IL-10 (11,88 ± 0,50 пг/мл проти 9,81 ± 0,17 пг/мл, р < 0,05) та INF-γ (10,75 ± 0,44 пг/мл проти 9,30 ± 0,47 пг/мл, р < 0,05). Поєднання 2 ознак — INF-γ < 8,8 пг/мл та IL-4 < 0,77 пг/мл чи INF-γ < 8,8 пг/мл та IL-10 > 11,8 пг/мл або 3 ознак — IL-4 < 0,77 пг/мл, IL-10 > 11,8 пг/мл та IL-2 < 1,5 пг/мл є предиктором розвитку токсоплазмозного енцефаліту. Висновки. Установлено, що у ВІЛ-інфікованих осіб відмічаються підвищені рівні деяких прозапальних (TNF-α, INF-γ) та протизапальних (IL-4, -10) цитокінів, але порівняно із серонегативними в серопозитивних на токсоплазмоз осіб переважають показники INF-γ і IL-10. Проявом поглибленої імунопатології та предиктором розвитку токсоплазмозного енцефаліту є зниження рівня INF-γ, IL-4, -2 із підвищенням рівня IL-10 у контингенті серопозитивних на токсоплазмоз осіб.

Association of level of IL-6, IL-10, IL-18, tumour necrosis factor-α with rheumatic mitral stenosis and subsequent pulmonary hypertension

Background: Objective of the study was to provide insight on the immune response in patients of rheumatic heart disease, mitral stenosis and evaluation of various cytokines in pulmonary hypertension secondary to rheumatic heart disease.Methods: Total 163 subjects, more than 18 year of age, were enrolled in this study. 84 subjects with rheumatic mitral stenosis (group A) diagnosed on two-dimensional echocardiography (2D echo) and 79 normal healthy volunteers (group B). Patients with mitral stenosis were further divided into subgroups based on severity of mitral stenosis [mitral valve area (MVA >1 cm2 and MVA <1 cm2) (subgroup Aa and Ab)] and presence or absence of pulmonary hypertension [pulmonary arterial systolic pressure (PASP >36 mm Hg) (subgroup Ac and Ad)]. Interleukins IL-6, IL-10, IL-18, tumour necrosis factor alpha (TNF-α) and high-sensitivity C-reactive protein (hs-CRP) levels were assessed in both groups.Results: Mean IL-6, IL-10, IL-18, TNF-α and hs-CRP in group A and group B was 6.57±3.53 and 2.73±1 (p≤0.001), 8.185±2.8 and 3.51±0.86 (p≤0.001), 136.31±89.0 and 47.96±9.76 (p≤0.001), 21.26±18.59 and 5.36±3.57 (p≤0.001), 4.69±6.3 and 2.63±2.22 (p≤0.008) respectively. On subgroup analysis mean TNF-α in subgroup Aa was 20.71±16.84, while in subgroup Ab was 7.56±1.93 (p≤0.001). Mean IL-10 in subgroup Ac and Ad was 8.74±3.29 and 7.47±1.82, respectively. Differences in levels of other cytokines in these subgroups were not found statistically significant.Conclusions: This study finds increased IL-6, IL-10, IL-18, TNF-α and hs-CRP levels in subjects with rheumatic mitral stenosis. Subjects with severe mitral stenosis had increased TNF-α levels. Subjects of mitral stenosis having pulmonary hypertension had increased IL-10 levels.

A New Approach to the Management of COVID-19. Antagonists of IL-6: Siltuximab.

Since the beginning of the pandemic, numerous national and international clinical trials have been conducted with a large number of drugs. Many of them are intended for the treatment of other pathologies; however, despite the great effort made, no specific drug is available for the treatment of the symptoms of respiratory disease caused by SARS-CoV-2 infection. The aim of this article is to provide data to justify the use of drugs to tackle the effects produced by IL-6 as the main inflammatory mediator in patients with COVID-19 with severe respiratory complications, considering all clinical evidence linking the poor prognosis of these patients with increased IL-6 levels in the context of cytokine release syndrome. Furthermore, data are provided to justify the proposal of a rational dosing of siltuximab, a monoclonal antibody specifically targeting IL-6, based on RCP levels, considering the limited results published so far on the use of this drug in COVID-19. A literature search was conducted on the clinical trials of siltuximab published to date as well as on the different IL-6 signalling pathways and the effects of its overexpression. Knowledge of the mechanisms of action on these pathways may provide important information for the design of drugs useful in the treatment of these patients. This article describes the characteristics, properties, mechanism of action, therapeutic uses and clinical studies conducted with siltuximab so far. The results confirm that administration of siltuximab downregulates IL-6 levels, thereby reducing the inflammatory process in COVID-19 patients with severe respiratory disease, suggesting that it can be successfully used to prevent cytokine release syndrome and death from this cause.

P064 IMU-838, a Small Molecule DHODH Inhibitor in Phase 2 Clinical Trial for Ulcerative Colitis, Shows Potent Anti-inflammatory Activity in Cell-Culture-Based and In Vivo Systems

Abstract Background IMU-838 (vidofludimus calcium) is a well-tolerated and orally available small molecule inhibitor of dihydroorotate dehydrogenase (DHODH) and is currently in phase 2 clinical development for ulcerative colitis (UC). Here, we investigated the effect of IMU-838 on different immune cell subsets and analysed the mechanism of action in more detail in T cells. Methods The effect of IMU-838 on regulatory macrophages (Mregs) was investigated by adding IMU-838 or anti-TNFα antibodies (infliximab, adalimumab), alone or in combination, in a mixed lymphocyte reaction assay, determining Mregs (CD206+CD14+) by FACS analysis. To investigate the effect of IMU-838 on human T and B cells, PBMC were stimulated with PHA (48h) or Oligonucleotide 2006-PTO (70h), respectively. An affinity-dependent effect of IMU-838 was assessed on CD8 T cells from OT-I and OT-III mice, containing a high and a low affinity T cell receptor (TCR), respectively, for OVA257-264 peptide. These cells were stimulated with ovalbumin (OVA) peptide loaded splenocytes or anti-CD3/anti-CD28 for 3 days. Oxidative phosphorylation (OXPHOS) and glycolysis in murine T cells was investigated by the Seahorse/Agilent technique in murine CD4 and CD8 T cells activated with anti-CD3/anti-CD28 with or without IMU-838. Results IMU-838 slightly induced Mregs, but strongly and dose-dependently decreased TNFα and IL-6 secretion. Anti-TNFα antibodies alone strongly induced Mregs, but also increased IL-6 levels. When IMU-838 was added, Mregs induction was even higher, and IL-6 was reduced. Besides reducing proinflammatory cytokines secreted by macrophages, IMU-838 also inhibits proliferation of activated B and T cells, as well as inflammatory T cell cytokine secretion, IL-17A, IL-17F and IFNγ, and increased apoptosis up to 3-fold compared to vehicle control. By investigating IMU-838’s role on affinity related activity status of T cells, it was shown that IMU-838 strongly inhibited cell proliferation in the peptide stimulated high affinity, but not in the low affinity, CD8 T cells. Peptide stimulated high affinity T cells show an upregulation of OXPHOS and glycolysis pathways, which are involved in the generation of the cell’s energy supply, compared to low affinity cells. IMU-838 strongly inhibited OXPHOS and glycolysis in both CD4 and CD8 T cells. Conclusion IMU-838 reduces the proinflammatory immune cell response by inducing Mregs, reducing pro-inflammatory cytokine secretion and reducing immune cell proliferation. DHODH is only important in cells that received a strong stimulus and are highly metabolically active. Therefore, IMU-838 will only specifically target these cells and will still allow for a normal immune response, representing a huge safety advantage for treatment of IBD patients.

Gastrodin injection alleviates lung injury caused by focal cerebral ischemia in rats through NGF/TrkA pathway-mediated activation of the anti-inflammatory pathway

To investigate the therapeutic mechanism of gastrodin injection for alleviating lung injury caused by focal cerebral ischemia in rats and the role of the NGF-TrkA pathway in mediating this effect. Forty SD rats were equally randomized into normal group, sham-operated group, model group and gastrodin group, and in the latter two groups, rat models of focal cerebral ischemia were established by embolization of the right middle cerebral artery. After successful modeling, the rats were treated with intraperitoneal injection of gastrodin injection at the daily dose of 10 mg/kg for 14 days. After the treatment, the wet/dry weight ratio of the lung tissue was determined, the pathological changes in the lung tissue were observed using HE staining, and the levels of IL-10 and TNF-α in the arterial blood were detected with ELISA. The expressions of NF-κB p65 and TNF-α in the lung tissue were detected with Western blotting, and the expressions of NGF and TrkA were detected using immunohistochemical staining and Western blotting. Compared with the normal control and sham-operated groups, the rats in the model group showed obvious inflammatory lung injury, significantly increased wet/ dry weight ratio of the lungs (P < 0.01), increased TNF-α level in arterial blood (P < 0.01), and significantly up-regulated protein expressions of NF-κB p65 (P < 0.01), TNF-α (P < 0.01), NGF (P < 0.05) and TrkA(P < 0.05) in the lung tissue. Treatment with gastrodin injection obviously alleviated lung inflammation, decreased the wet/dry weight ratio of the lungs (P < 0.05), and significantly lowered TNF-α level (P < 0.01) and increased IL-10 level in the arterial blood in the rat models (P < 0.01); gastrodin injection also significantly decreased the protein expressions of NF-κB p65 and TNF-α (P < 0.05) and up-regulated the expressions of NGF and TrkA in the lung tissue of the rats (P < 0.05). The NGF/TrkA pathway may participate in cerebral ischemia-induced inflammatory lung injury, which can be obviously alleviated by gastrodin through the activation of the anti-inflammatory pathway mediated by the NGF/TrkA pathway.

Chitin derivatives ameliorate DSS-induced ulcerative colitis by changing gut microbiota and restoring intestinal barrier function

Chitin derivatives (CDs), including chitosan (CS), chitooligosaccharides (COS), and glucosamine (GlcN), were administrated in dextran sodium sulfate (DSS)-induced ulcerative colitis (UC) mice. UC symptoms such as body weight loss, reduced food intake, and increased disease activity index were relieved (except GlcNL group). CDs (except GlcNL) exerted a strong protective effect on colon length and colonic structure. Treatment with CDs (except GlcNL) increased IL-10 level, reduced levels of IL-1β, IL-6, TNF-α, myeloperoxidase, and inducible nitric oxide synthase, and enhanced expression of tight junction proteins significantly. CDs (except GlcNL) significantly upregulated IκB-α level, and downregulated p65 and p38 phosphory lation and TLR-4 mRNA transcription level, indicating inhibition of TRL-4/NF-κB/MAPK signaling pathway activity. CD treatments increased relative abundance of gut microbiota, modulated its composition, and increased the concentrations of SCFAs. Our findings indicate that CDs exert an ameliorative effect on UC by change of gut microbiota composition and restoration of intestinal barrier function.

Inflammatory Cytokines and Risk of Ischemic Stroke: A Mendelian Randomization Study.

Background: Observational studies have revealed the association between some inflammatory cytokines and the occurrence of ischemic stroke, but the causal relationships remain unclear. Methods: We conducted a two-sample Mendelian randomization (MR) analysis to assess the causal effects of thirty inflammatory cytokines and the risk of ischemic stroke. For exposure data, we collected genetic variants associated with inflammatory cytokines as instrumental variables (IVs) from a genome-wide association study (GWAS) meta-analysis from Finland (sample size up to 8,293). For the outcome data, we collected summary data of ischemic stroke from a large-scale GWAS meta-analysis involved 17 studies (34,217 cases and 406,111 controls). We further performed a series of sensitivity analyses as validation of primary MR results. Results: According to the primary MR estimations and further sensitivity analyses, we established one robust association after Bonferroni correction: the odds ratio (95% CI) per unit change in genetically increased IL-4 was 0.84 (0.89–0.95) for ischemic stroke. The chemokine MCP3 showed a nominally significant association with ischemic stroke risk (OR: 0.93, 95% CI: 0.88–0.99, unadjusted p < 0.05). There was no evidence of a causal effect of other inflammatory cytokines and the risk of ischemic stroke. Conclusions: Our study suggested that genetically increased IL-4 levels showed a protective effect on the risk of ischemic stroke, which provides important new insights into the potential therapeutic target for preventing ischemic stroke.

Differential Immunomodulatory Potential of Silver Nanoparticles and Effect on the Kynurenine Pathway in Male Wistar Rats

Silver nanoparticles are increasingly being used in a wide variety of ways that may lead to frequency of exposure for humans and the environment. Thus, it is necessary to understand the biological effect(s) of these nanoparticles. Previously, we showed that AgNPs activated the kynurenine pathway in rat brain independently of oxidative stress in rats. This present study is aimed at evaluating the effect of AgNPs on some selected cytokines, redox parameters, and on the kynurenine level in rats. Male Wistar rats (130-150 g) were divided into 4 groups. Rats were grouped into control, AgNPs only (50 mg/kg bw), coadministration of AgNPs (50 mg/kg bw), and dexamethasone (100 mg/kg bw) and dexamethasone only (100 mg/kg bw). Results indicated that AgNPs did not significantly elevate MDA levels in rat plasma and brain relative to the control group. AgNPs caused a significant alteration in the level of rat brain and plasma total protein concentration. Meanwhile, AgNPs led to an elevation in the level of reduced glutathione (GSH) in rat plasma but decreased plasma kynurenine level significantly. Furthermore, IFN-γ level was reduced following AgNPs administration, IL-1β decreased across the treatment groups, while NF-κB was reduced in the dexamethasone only and AgNPs + dexamethasone groups when compared with the control. AgNPs led to increased IL-4 levels, while IL-10 levels decreased across the treatment groups. Taken together, our data showed a differential immunomodulatory potential of AgNPs in rats.

Therapeutic effects of Chinese medicine Di-Long (Pheretima vulgaris) on rheumatoid arthritis through inhibiting NF-κB activation and regulating Th1/Th2 balance

Chinese medicine Di-Long, the dried body of Pheretima vulgaris (Chen) has been used for the treatment of joint inflammation, arthralgia and numbness of limbs for many years. This study was to investigate the anti-rheumatoid arthritis (RA) effects of Di-Long and to explore its possible mechanisms. The identification and quantification of representative components in Di-Long extracts (DL) were carried out by HPLC analysis. The anti-RA effects and mechanisms of DL were studied in CIA mice, RAW 264.7 macrophages and spleen T lymphocytes. The Th1/Th2 cell ratio in CIA mice spleens were determined by Flow cytometry. The cytokine levels were determined by ELISA method. The expressions of p-NF-κB p65 in ankle joints of CIA mice were detected by Immunohistochemistry analysis. The phosphorylation of NF-κB signaling pathway in RAW 264.7 macrophages and expressions of T-bet and GATA-3 in CIA mice spleens were determined by Western blots. The treatment with DL significantly decreased the paw thickness, arthritis scores and inflammatory cells infiltration in CIA mice. The TNF-α, IL-6 concentrations in both mice serum and macrophages secretion were markedly reduced with the treatment of DL, as well as the phosphorylation of NF-κB pathway. DL inhibited the expressions of T-bet and GATA-3 and decreased Th1/Th2 cells ratio in CIA mice spleens. DL reduced IFN-γ, IL-2 levels in mice serum and spleen T lymphocytes, and increased IL-4 levels in CIA mice serum. Chinese medicine Di-Long have significant anti-RA effects. The mechanisms might be inhibiting the activation of NF-κB signaling pathway and regulating the balance of Th1/Th2 cells.

Supplementation With Chinese Medicinal Plant Extracts From Lonicera hypoglauca and Scutellaria baicalensis Mitigates Colonic Inflammation by Regulating Oxidative Stress and Gut Microbiota in a Colitis Mouse Model.

Colitis, a chronic inflammatory bowel disease, is characterized by bloody diarrhea and inflammation in the colon. Lonicera hypoglauca (“Shanyinhua” in Chinese) and Scutellaria baicalensis (“Huangqin” in Chinese) are two traditional Chinese medicinal plants rich in polyphenols, such as chlorogenic acid (CGA) and baicalin (BA), with the effects of anti-inflammation and antioxidation. However, it remains unknown whether extracts from L. hypoglauca and S. baicalensis (LSEs) could mitigate colonic inflammation. In the present study, ICR mice (22.23 ± 1.65 g) were allocated to three groups treated with chow diet without (CON) or with dextran sulfate sodium (DSS) (CON+DSS) in water or LSE supplementation in diet with DSS (LSE+DSS), and then inflammatory and oxidative parameters and colonic microbiota were detected. The results showed that LSE (500 mg/kg) treatment mitigated DSS-induced colitis symptoms and restored the shortened colon length, the increased disease activity index (DAI), and the damaged intestinal barrier. In serum, LSE supplementation significantly decreased levels of pro-inflammatory cytokines including interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and lipopolysaccharide (LPS) and increased IL-10 level. Meanwhile, superoxide dismutase (SOD) and catalase (CAT) were increased, and malondialdehyde (MDA) and reactive oxygen species (ROS) levels were decreased. In the colon tissue, qPCR results showed that LSE supplementation dramatically downregulated the transcriptional expression of IL-1β, IL-6, TNF-α, and MDA and upregulated the expression of SOD1, CAT, and IL-10. Additionally, the damaged gut barriers occludin and zonula occludens-1 (ZO-1) in the CON+DSS group were enhanced with LSE supplementation. Furthermore, LSE treatment regulated the gut microbial communities with higher relative abundance of Dubosiella and Ruminococcus torques group and lower relative abundance of Bacteroides and Turicibacter. Moreover, the contents of short-chain fatty acids (SCFAs) as products of gut microbiota were also increased. Correlation analysis showed that the mRNA expression of SOD1 was negatively correlated with TNF-α (r = -0.900, P < 0.05); the mRNA expression of IL-6 (r = -0.779, P < 0.05) and TNF-α (r = -0.703, P < 0.05) had a dramatically negative correlation with Dubosiella. In conclusion, LSE supplementation could effectively ameliorate inflammation by modulating oxidative stress and gut microbiota in a colitis mouse model.

Differential effects of various dietary proteins on dextran sulfate sodium-induced colitis in mice.

Chronic colitis is a risk factor for colorectal cancer (CRC) development in both animals and humans. Previously, we reported that a diet rich in protein (with casein as the protein source) significantly increased the risk of mouse CRC development in a dose-dependent manner. In this study, we investigated the effects of different protein sources on the risk of colitis development. Balb/c mice were divided into 7 experimental groups: 20% casein (20C), 20C-dextran sulfate sodium (DSS), 40% casein-DSS (40CD), 40% whey protein-DSS (40WD), 40% soy protein-DSS (40SD), 40% white meat-DSS (40WMD), and 40% red meat-DSS (40RMD). Mice were fed an experimental diet for 4 wk and received 3% DSS in their drinking water for 6 days during the 4th wk of the experimental period. Compared to other groups, the 40CD group showed the most aggravated colitis with increased disease activity and inflammatory markers. In the 40RMD group, interleukin (IL)-6 levels were the highest among all the groups. The 40SD group showed conflicting effects, for example, elevated mortality and disease activity but decreased nitric oxide (NO) levels. The 40WD group showed attenuated colitis with increased IL-10 levels and decreased NO levels. The 40WMD group showed conflicting effects, including decreased NO levels and elevated fecal lipocalin-2 and IL-6 levels. These results suggest that, at levels of 40% in the diet, casein and red meat exacerbate colitis, whereas whey protein mitigates it the most effectively.

“Elucidation of the Shared Pathophysiology between Diabetes and COVID-19”

Background: COVID-19 is a rapidly spreading communicable disease worldwide. It varies widely in its spectrum of manifestations, from being mild self-limiting disease, to fulminant disease, often leading to complications and death. Diabetes is an important co-morbidity linked to severity of infection by SARSCoV- 2, which predisposes them to severe pneumonia. Poor glycaemic control is associated with worse outcomes. The disease burden of COVID-19 is continuously increasing, and with a high prevalence of diabetes, it is all the more important to understand the vital aspects of COVID-19 infection in diabetic population. Hence, we try to provide close insights into its pathophysiology, clinical characteristics, recommendations on management and prevention and possible avenues for improving disease outcomes. Methods: PubMed database and Google Scholar were searched using the key terms ‘COVID-19’, ‘SARS CoV- 2’, ‘Corona’ and ‘diabetes’. Full texts of the retrieved articles were accessed and referred. Three main mechanisms which influence COVID-19 disease manifestation in diabetics include: (a) Entry of virus via ACE-2 receptors (b) Action through Dipeptidyl-peptidase-4, and (c) Elevation of glucose concentration in airways by elevated blood glucose.ACE-2 is expressed in alveolar epithelial cells, heart, renal-tubular and intestinal epithelia and pancreas. S-Glycoprotein on the surface of SARS-CoV-2 binds to this ACE-2 and undergoes a conformational change. This allows its’ proteolytic digestion by host cell proteases TMPRSS2 and Furin, leading to internalization of virus. Viral entry into cells triggers an inflammatory response by T-helper-cells and at times, a ‘cytokine storm’, resulting in organ damage. Apart from diminishing neutrophil chemotaxis and reducing phagocytosis, by which diabetes predisposes individuals to infections, there are several specific factors with respect to SARS-CoV2: (i) Increased ACE-2 expression (ii) Raised Furin (iii) Diminished T-cell functioning, and (iv) Increased IL-6 levels. Movement restrictions, increased stress due to social isolation and lack of physical activity further complicates the issue. It is therefore, much essential to raise awareness among front-line workers. Finally, the current situation emphasizes the need for more clinical investigation and define best practices for optimum outcomes. Bangladesh Journal of Medical Science Vol. 21(1) 2022 Page : 19-23

Maoto, a traditional Japanese medicine, controls acute systemic inflammation induced by polyI:C administration through noradrenergic function.

Maoto, a traditional Japanese medicine (Kampo), is widely used to treat upper respiratory tract infections, including influenza virus infection. Although maoto is known to inhibit pro-inflammatory responses in a rodent model of acute inflammation, its underlying mechanism remains to be determined. In this study, we investigated the involvement of immune responses and noradrenergic function in the inhibitory action of maoto. In a mouse model of polyI:C-induced acute inflammation, maoto was administered orally in conjunction with intraperitoneal injection of PolyI:C (6mg/kg), and blood was collected after 2h for measurement of plasma cytokines by ELISA. Maoto significantly decreased PolyI:C-induced TNF-α levels and increased IL-10 production. Neither pretreatment with IL-10 neutralizing antibodies nor T-cell deficiency using nude mice modified the inhibitory effect of maoto, indicating that the anti-inflammatory effects of maoto are independent of IL-10 and T cells. Furthermore, the inhibitory effects of maoto on PolyI:C-induced TNF-α production were not observed in ex vivo splenocytes, suggesting that maoto does not act directly on inflammatory cells. Lastly, pretreatment with a β-adrenergic receptor antagonist partially cancelled the anti-inflammatory effects of maoto. Collectively, these results suggest that maoto mediates its anti-inflammatory effects via β-adrenergic receptors in vivo.

Comparative Evaluation of Salivary Interleukin-18 in Periodontitis Patients with or without Diabetes Mellitus

Aim: The study was conducted to compare the salivary concentrations of interleukin-18 in periodontitis patients with or without diabetes mellitus&#x0D; Materials and Methods: The sample size in the study was 30 and categorized into 3 groups, in each group 10 individuals were included in the respective category. The three groups are as follows: Group a- patients with clinically healthy gingiva, Group b- patients with periodontitis and diabetes mellitus, Group c- patients with periodontitis only.&#x0D; Results: Salivary Interleukin-18 levels were found to be significantly higher (p&lt;0.013) in periodontitis with diabetes mellitus (110±7.0 ng/L) when compared with periodontitis only (70.06±3.5 ng/L) and also when compared with healthy controls (66±5.6 ng/L).&#x0D; Conclusion: From the study, diabetic patients with periodontitis have increased IL-18 levels than non-diabetic counterparts. Thus salivary IL-18 is an effective non-invasive biomarker associating periodontitis and diabetes mellitus.

Clostridioides difficile Toxin CDT Induces Cytotoxic Responses in Human Mucosal-Associated Invariant T (MAIT) Cells.

Clostridioides difficile is the major cause of antibiotic-associated colitis (CDAC) with increasing prevalence in morbidity and mortality. Severity of CDAC has been attributed to hypervirulent C. difficile strains, which in addition to toxin A and B (TcdA, TcdB) produce the binary toxin C. difficile transferase (CDT). However, the link between these toxins and host immune responses as potential drivers of immunopathology are still incompletely understood. Here, we provide first experimental evidence that C. difficile toxins efficiently activate human mucosal-associated invariant T (MAIT) cells. Among the tested toxins, CDT and more specifically, the substrate binding and pore-forming subunit CDTb provoked significant MAIT cell activation resulting in selective MAIT cell degranulation of the lytic granule components perforin and granzyme B. CDT-induced MAIT cell responses required accessory immune cells, and we suggest monocytes as a potential CDT target cell population. Within the peripheral blood mononuclear cell fraction, we found increased IL-18 levels following CDT stimulation and MAIT cell response was indeed partly dependent on this cytokine. Surprisingly, CDT-induced MAIT cell activation was found to be partially MR1-dependent, although bacterial-derived metabolite antigens were absent. However, the role of antigen presentation in this process was not analyzed here and needs to be validated in future studies. Thus, MR1-dependent induction of MAIT cell cytotoxicity might be instrumental for hypervirulent C. difficile to overcome cellular barriers and may contribute to pathophysiology of CDAC.

Interesterified palm oil increases intestinal permeability, promotes bacterial translocation, alters inflammatory parameters and tight-junction protein genic expression in Swiss mice

High-fat diets seem to have a negative influence on the development of obesity and the processes associated with low-grade chronic systemic inflammation. In recent years, partial hydrogenated oil, rich in trans isomers, has been associated with deleterious health effects. It has been replaced by interesterified fat (IF). However, there is no evidence whether IF ingestion can exert adverse effects on the intestinal mucosa. Thus, this study aimed to evaluate the effect of IF on the intestinal mucosa of male Swiss mice fed a normal or high-fat diet, focusing on its effects on intestinal permeability and bacterial translocation and its possible damage to the intestinal epithelium. The animals were divided into 4 groups: Control (C) and Interesterified Control (IC) groups (10 En% lipids from unmodified fat or interesterified fat, respectively) and High Fat (HF) and Interesterified High Fat (IHF) groups (45 En% lipids from unmodified fat or interesterified fat, respectively). Compare to C, the IC, HF, and IHF groups presented flattened epithelium, a shorter villi length and a lower percentage of goblet cells, less mucin 2, an increased oxidative stress and more inflammatory cells, higher IL-1β, IL-17, and IL-23 levels. These groups also presented increased intestinal permeability and gene expression of the protein claudin 2, while JAM-A and claudin 1 gene expression was reduced. IC and IHF increased IL-6 levels while reducing occludin expression. In addition, the IC group also presented a mucosa with lesions of low intensity in the ileum, an increased mucin 5ac, TNF-α levels, and reduced occludin expression in the distal jejunum. Moreover, there was a significant increase in bacterial translocation in the IC group to blood, liver, and lungs, while HF and IHF groups presented bacterial translocation which was restricted to the mesenteric lymph nodes. In summary, our results supported the hypothesis that IF added to a normolipidic diet can be considered harmful or even worse when compared to a HF.

The Heterogeneity of Inflammatory Response and Emphysema in Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease characterized by chronic inflammation, emphysema, airway remodeling, and altered lung function. Despite the canonical classification of COPD as a neutrophilic disease, blood and airway eosinophilia are found in COPD patients. Identifying the tools to assess eosinophilic airway inflammation in COPD models during stable disease and exacerbations will enable the development of novel anti-eosinophilic treatments. We developed different animal models to mimic the pathological features of COPD. Our results show that eosinophils accumulated in the lungs of pancreatic porcine elastase-treated mice, with emphysema arising from the alveolar septa. A lipopolysaccharide challenge significantly increased IL-17 levels and induced a swift change from a type-2 response to an IL-17-driven inflammatory response. However, lipopolysaccharides can exacerbate cigarette smoking-induced airway inflammation dominated by neutrophil infiltration and airway remodeling in COPD models. Our results suggest that eosinophils may be associated with emphysema arising from the alveolar septa, which may be different from the small airway disease-associated emphysema that is dominated by neutrophilic inflammation in cigarette smoke-induced models. The characterization of heterogeneity seen in the COPD-associated inflammatory signature could pave the way for personalized medicine to identify new and effective therapeutic approaches for COPD.