Essential Oils from Zingiber striolatum Diels Attenuate Inflammatory Response and Oxidative Stress through Regulation of MAPK and NF-κB Signaling Pathways

Zingiber striolatum Diels (Z. striolatum), a widely popular vegetable in China, is famous for its medicinal and nutritional values. However, the anti-inflammatory effects of essential oil from Z. striolatum (EOZS) remain unclear. In this study, EOZS from seven regions in China were extracted and analyzed by GC–MS. LPS-induced RAW264.7 cells and 12-O-Tetradecanoylphorbol 13-acetate (TPA)-stimulated mice were used to evaluate the anti-inflammatory effects of EOZS. Results show that 116 compounds were identified in EOZS from seven locations. Samples 2, 4 and 5 showed the best capability on DPPH radical scavenging and NO inhibition. They also significantly reduced the production of ROS, pro-inflammatory cytokines, macrophage morphological changes, migration and phagocytic capability. Transcriptomics revealed MAPK and NF-κB signaling pathways may be involved in the anti-inflammatory mechanism, and the predictions were proven by Western blotting. In TPA-induced mice, EOZS reduced the degree of ear swelling and local immune cell infiltration by blocking the activation of MAPK and NF-κB signaling pathways, which was consistent with the in vitro experimental results. Our research unveils the antioxidant capability and potential molecular mechanism of EOZS in regulating inflammatory response, and suggests the application of EOZS as a natural antioxidant and anti-inflammatory agent in the pharmaceutical and functional food industries.

Combined Blood Indexes of Systemic Inflammation as a Mirror to Admission to Intensive Care Unit in COVID-19 Patients: A Multicentric Study

Background The Coronavirus 2019 is a pandemic that has spread worldwide, threatening human health. The main cause of death in patients with COVID-19 is a systemic pro-inflammatory mechanism that quickly progresses to acute respiratory distress syndrome. Hematological ratios as affordable indicators of inflammatory response were studied in COVID-19 patients. The study aimed to study the importance of the blood cell indexes of the systemic inflammatory response, as the Aggregate Index of Systemic Inflammation (AISI), neutrophils lymphocyte to platelet ratio (NLPR), systemic immune-inflammation index (SII) and, systemic inflammation response index (SIRI) in predicting intensive care unit (ICU) admission of COVID-19 patients. Methods 495 COVID-19 patients managed in four tertiary centers; divided into non-ICU and ICU groups. Results Total leucocyte count (TLC), AISI, NLPR, SII, and SIRI were more elevated in the ICU group (P < 0.001 for all except AMC P = 0.006), while this group had less absolute lymphocyte count (ALC) (P = 0.047). We estimated the optimal cut-off values of the hematological ratio; AISI (729), NLPR (0.0195), SII (1346), and SIRI (2.5). SII had the highest specificity (95.6%), while NLPR had the highest sensitivity (61.3%). Age, AISI, CRP, D-dimer, and oxygen aid were the independent predictors for ICU admission in COVID-19 in multivariate logistic regression. Conclusion AISI is a predictor for severity and ICU admission in COVID-19 patients, SII is a predictor of survival, while NLPR and SIRI have an additive role that needs further evaluation.

Anti-Inflammatory Mechanism of Astragaloside IV in the Recurrence of Asthma: Critical Role of Memory T Cells and OX40/OX40L Signaling Pathway

The recurrence of asthma is partly mediated by central memory CD4(+) T cells(TCM) that promote lung inflammation through the production of effector T cells. Targeting the expansion of pathogenic TCM(central memory CD4(+) T cells) is a promising therapeutic strategy to block production of effector T cells. The study aimed to evaluate the regulatory effects of Astragaloside IV (AS-IV) on TCMs and try to explore the anti-inflammatory mechanism of AS-IV in asthmatic mice. We developed a murine model of asthma by ovalbumin(OVA) challenge. Flow cytometry was used to determine the counts of CD4(+) memory T cells subgroups. Pulmonary tests, inflammatory cytokines in blood and inflammatory cells in bronchoalveolar lavage fluid,were measured to evaluate the inflammatory response level before and after AS-IV treatment. To further determine the role of TCM in the recurrence of inflammation, TCM were isolated by Magnetic-activated cell sorting (MACS) from spleens of asthma, control, AS-IV and dexamethasone treatment mice. The isolated cells were adoptive transferred into nude mice via tail intravenous injection, respectively, and the inflammatory response level of the lung was measured after OVA challenge. The effects of AS-IV on TCM viability, the number of the frequency (in percent) of CD44highCD62Lhigh cells, and the expression of OX40 and OX40L were measured before and after AS-IV treatment. In circulation blood, we demonstrated increased percentages of CCR7highCD62LlowCD4+ effector memory T cells(TEM) and decreased CCR7highCD62LhighCD4(+) TCM in asthma mice. On the contrary, the TEM subgroup percentage were decreased and the TCM phenotypes were increased in asthmatic spleen. AS-IV treatment significantly decreased CD4(+) T effector phenotypes in blood and inhibited the lung inflammatory response. Additionally, the inflammation of nude mice that adoptive transferred TCM from AS-IV treatment asthmatic mice had relieved inflammation compared with asthmatic group. In vitro, we successfully used spleen T lymphoid cells stimulated with IL-7 and OVA to induce a central memory T cell model. TCM co-cultured with DC cells had a significantly increased expression of OX40/OX40L. AS-IV pretreatment partially inhibited the expression of OX40 signal pathway. This study indicates that AS-IV can ameliorate asthma inflammation by inhibiting the production of TEM form TCM. The treatment mechanism maybe involved in the OX40/OX40L pathway.

Short Palate, Lung, and Nasal Epithelial Clone1 (SPLUNC1) level determines steroid-resistant airway inflammation in aging

Asthma and its heterogeneity changes with age. Increased airspace neutrophil numbers contribute to severe steroid-resistant asthma exacerbation in the elderly, which correlates with the changes seen in adult asthmatics. However, whether that resembles the same disease mechanism and pathophysiology in aged and adults is poorly understood. Here, we sought to address the underlying molecular mechanism of steroid-resistant airway inflammation development and response to corticosteroid (Dex) therapy in aged mice. To study the changes in inflammatory mechanism, we employed a clinically relevant treatment model of house-dust mite (HDM)-induced allergic asthma and investigated lung adaptive immune response in adults (20-22 weeks) and aged (80-82 weeks) mice. Our result indicates an age-dependent increase in AHR, mixed granulomatous airway inflammation comprising eosinophils and neutrophils, and Th1/Th17 immune response with progressive decrease in frequencies and numbers of HDM-bearing dendritic cells (DC) accumulation in the draining lymph node (DLn) of aged mice as compared with adult mice. RNAseq experiments of the aged lung revealed SPLUNC1 (Short Palate, Lung, and Nasal Epithelial Clone 1) as one of the steroid-responsive genes, which progressively declined with age and further by HDM-induced inflammation. Moreover, we found increased glycolytic reprogramming, maturation/activation of DCs, the proliferation of OT-II cells, and Th2 cytokine secretion with recombinant SPLUNC1 (rSPLUNC1) treatment. Our results indicate a novel immunomodulatory role of SPLUNC1 regulating metabolic adaptation/maturation of DC. An age-dependent decline in the SPLUNC1 level may be involved in developing steroid-resistant airway inflammation and asthma heterogeneity.

Inonotus obliquus aqueous extract suppresses carbon tetrachloride induced hepatic injury through modulation of antioxidant enzyme system and anti-inflammatory mechanism

Background: Chaga mushroom [Inonotus obliquus] is an edible macrofungus used in traditional and folk medicine for treatment of various gastrointestinal disorders. It has shown potent anti-inflammatory, antioxidant and anticancer effects in several experimental studies including our anti-inflammatory and anticancer effects in colorectal cancer and intestinal inflammation. Whole extract or purified compound ergosterol peroxide from chaga mushroom showed anti-inflammatory mechanism via suppression of NF-κB/iNOS-COX-2 and growth inhibitory mechanism via regulation of apoptosis activation and β-catenin suppression. The emergence of diverse inflammatory and carcinogenic agents like carbon tetrachloride [CCl4] is a potent hepatotoxic chemical that caused liver damage by inducing lipid peroxidation and other oxidative damages. Aims: The study was aimed to analyze the biochemical, cellular and molecular mechanism of CCl4 induced chronic liver inflammation and carcinoma and to analyze the effect of the extract of chaga mushroom on liver inflammation and cancer by virtue of anti-inflammatory mechanisms. Method: Physiological, histological and immunohistochemical the physiological functions and cellular functions. Biochemical assays for assessing enzymatic changes in tissues. Molecular simulation and docking studies were performed for proposing the molecular interaction. Results: CCl4-exposed mice exhibited a significant decrease in the body weight followed by altered histopathological signatures in the liver. Supplementation of IOAE showed that treatment restored towards normal structure of the tissues with large round nuclei in most of the cells. CCl4 caused a steep elevation in the levels of SGOT and SGPT to 2.32- and 1.8-fold as compared to control. The LDH level was increased to 447 IU/L in CCl4 treated mice as compared to control [236 IU/L]. Analysis of the oxidant enzyme pathway showed that CCl4 reduced the GSH level to 16.5 μM as compared to control [52 μM], and induced the catalase enzyme activity to 259 U/mL as compared to control [124 U/L]. These physiological and biochemical alterations were restored towards normal levels by IOAE administration. Immunohistochemical staining for caspase-3 and p53 showed that CCl4 notably increased their expressions which were subsequently suppressed by administration of IOAE. The molecular simulation and docking studies using ergosterol peroxide from chaga mushroom with iNOS, COX-2 and TNF-α showed binding energy of -10.5, -8.9 and -9.1 Kcal/mol, respectively. These proteins interacting with ergosterol peroxide suggests an inhibitory effect on these critical proinflammatory signaling proteins. Conclusions: The results point out that IOAE is able to prevent damage of hepatic cells caused by CCl4 in mouse models through anti-inflammatory and growth inhibitory mechanism which can be utilized in natural prevention of the liver toxicity.

Camel milk ameliorates inflammatory mechanisms in an alcohol-induced liver injury mouse model

Camel milk (CM) is considered to protect the liver in the practice of traditional medicine in nomadic areas. The purpose of the present study was to investigate the effects of CM on the hepatic biochemical and multiple omics alterations induced by chronic alcoholic liver disease (ALD). An intragastric gavage mice Lieber DeCarli + Gao binge model (NIAAA model) was employed to investigate the inflammatory mechanism of camel milk on the liver tissue of mice. A gut microbiota of the feces of mice and transcriptomic and proteomic analyses of the liver of mice were performed. Analysis of serum and liver biochemical indexes revealed that camel milk not only prevents alcohol-induced colonic dysfunction and lipid accumulation, but also regulates oxidative stress and inflammatory cytokine production to protect against chronic ALD in mouse. The gut microbial community of mice treated with camel milk was more similar to the untreated control group than to the model group, indicating that the intake of camel milk pre- and post-alcohol gavage effectively prevents and alleviates the intestinal microbial disorder caused by chronic alcoholism in mice. Furthermore, the results of the transcriptomic and proteomic analyses of the liver tissue showed that camel milk can improve alcoholic liver injury in mice by regulating inflammatory factors and immune system disruptions. This study provides insights into the molecular mechanism by which camel milk can be developed as a potential functional food with no side effects and against liver injury.

Triggering Receptor Expressed on Myeloid Cells 2 Protects Dopaminergic Neurons by Promoting Autophagy in the Inflammatory Pathogenesis of Parkinson’s Disease

Parkinson’s disease is a neurodegenerative disorder with an inflammatory response as the core pathogenic mechanism. Previous human genetics findings support the view that the loss of TREM2 function will aggravate neurodegeneration, and TREM2 is one of the most highly expressed receptors in microglia. However, the role of TREM2 in the inflammatory mechanism of PD is not clear. In our study, it was found both in vivo and in vitro that the activation of microglia not only promoted the secretion of inflammatory factors but also decreased the level of TREM2 and inhibited the occurrence of autophagy. In contrast, an increase in the level of TREM2 decreased the expression of inflammatory factors and enhanced the level of autophagy through the p38 MAPK/mTOR pathway. Moreover, increased TREM2 expression significantly decreased the apoptosis of dopaminergic (DA) neurons and improved the motor ability of PD mice. In summary, TREM2 is an important link between the pathogenesis of PD and inflammation. Our study provides a new view for the mechanism of TREM2 in PD and reveals TREM2 as a potential therapeutic target for PD.

Low Molecular Weight Heparin Improves the Inflammatory State of Acute Sinusitis Rats Through Inhibiting the TLR4-MyD88-NF-κB Signaling Pathway

Introduction: Low molecular weight heparin (LMWH), a natural sulfated glycosaminoglycan with an affinity for proangiogenic factors, is produced by chemical or enzymatic depolymerization of unfractionated heparin (UFH). Known for its anticoagulant effects, LMWH has recently been reported to have a strong anti-inflammatory effect on colitis, myocarditis, and airway inflammation. However, as a newly-developed drug, its anti-inflammatory mechanism in upper respiratory tract inflammation has not been well-studied.Methods: SD rats were randomly divided into control and experimental groups. The experimental group was established by building an acute nasal sinusitis model with expansion sponges mixed with Streptococcus pneumoniae. Then the experimental group rats were subcutaneously injected with different concentrations of LMWH. After seven consecutive days of injection, some rats were sacrificed, and blood and nasal mucosa samples were taken to determine their inflammation status. The remaining acute sinusitis rats were randomly selected for a week of nasal irrigation with normal saline or saline mixed with different concentrations of LMWH. One week later, rats were sacrificed, and samples of blood and nasal mucosa were taken to determine the inflammation status.Results: Rat nasal mucosa in the model group had obvious inflammation. The degree of nasal mucosa inflammation damage in the experimental group was lower than in the experimental control group, proving that LMWH has a protective effect on the nasal mucosa and that the effect correlates with dosage. Irrigation of the nose with saline mixed with LMWH can improve the anti-inflammatory effect. Protein related to the TLR4-MyD88-NF-κB signaling pathway was activated in the acute sinusitis rat model, and LMWH can significantly inhibit its expression.Conclusion: This is the first report of the anti-inflammatory effect of LMWH in acute upper respiratory tract inflammation, together with an explanation of its anti-inflammatory mechanism. The findings contribute a theoretical basis for its potential anti-tumor effect.