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Objectives: Excessive inflammatory responses and apoptosis are critical pathologies that contribute to sepsis-induced acute kidney injury (SI-AKI). Annexin A1 (ANXA1), a member of the calcium-dependent phospholipid-binding protein family, protects against SI-AKI through its anti-inflammatory and antiapoptotic effects, but the underlying mechanisms are still largely unknown. Methods: In vivo, SI-AKI mouse models were established via caecal ligation and puncture (CLP) and were then treated with the Ac2-26 peptide of ANXA1 (ANXA1 (Ac2-26)), WRW4 (Fpr2 antagonist) or both. In vitro, HK-2 cells were induced by lipopolysaccharide (LPS) and then treated with ANXA1 (Ac2-26), Fpr2–siRNA or both. Results: In the present study, we found that the expression levels of ANXA1 were decreased, and the expression levels of TNF-α, IL-1β, IL-6, cleaved caspase-3, cleaved caspase-8 and Bax were significantly increased, accompanied by marked kidney tissue apoptosis in vivo. Moreover, we observed that ANXA1 (Ac2-26) significantly reduced the levels of TNF-α, IL-1β and IL-6 and cleaved caspase-3, cleaved caspase-8, FADD and Bax and inhibited apoptosis in kidney tissue and HK-2 cells, accompanied by pathological damage to kidney tissue. Seven-day survival, kidney function and cell viability were significantly improved in vivo and in vitro, respectively. Furthermore, the administration of ANXA1 (Ac2-26) inhibited the CLP- or LPS-induced phosphorylation of PI3K and AKT and downregulated the level of NF-κB in vivo and in vitro. Moreover, our data demonstrate that blocking the Fpr2 receptor by the administration of WRW4 or Fpr2–siRNA reversed the abovementioned regulatory role of ANXA1, accompanied by enhanced phosphorylation of PI3K and AKT and upregulation of the level of NF-κB in vivo and in vitro. Conclusions: Taken together, this study provides evidence that the protective effect of ANXA1 (Ac2-26) on SI-AKI largely depends on the negative regulation of inflammation and apoptosis via the Fpr2 receptor. [ABSTRACT FROM AUTHOR]

Background: We investigated whether the degree of inflammation and fibrosis in para-carcinoma tissue can predict prognosis of patients with non-cirrhotic hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) after hepatectomy. We also explored the mechanisms through which inflammation and fibrosis might affect prognosis. Methods: Clinicopathological data were retrospectively analyzed from 293 patients with non-cirrhotic HBV-associated HCC who were treated at our institution by curative resection from 2012 to 2017. Based on the Scheuer score system, patients were classified into those showing mild or moderate-to-severe inflammation and fibrosis. Rates of overall and recurrence-free survival were compared between the groups using Kaplan–Meier curves, and survival predictors were identified using Cox regression. Using tumor and para-tumor tissues from independent samples of patients with non-cirrhotic HBV-associated HCC who were treated at our institution by curative resection from 2018 to 2019, we performed next-generation sequencing and time-of-flight cytometry (CyTOF) to examine the influence of inflammation and fibrosis on gene expression and immune cell infiltration. Results: In the analysis of the 293 patients, those with mild inflammation and fibrosis showed significantly better overall and recurrence-free survival than those with moderate-to-severe inflammation and fibrosis. Multivariate Cox regression confirmed that moderate-to-severe inflammation and fibrosis were independent risk factors for worse survival. RNA sequencing and CyTOF showed that more severe inflammation and fibrosis were associated with stronger invasion and migration by hepatocytes. In cancerous tissues, the biological processes of cell proliferation were upregulated, the signaling pathways promoting tumor growth were activated, the proportion of Th17 cells promoting tumor progression was increased, and CD8+ T cells expressed higher levels of PD-L1. In para-cancerous tissues, biological processes of immune response and cell chemotaxis were downregulated, and the proportion of tumor-killing immune cells was decreased. Conclusion: Worse inflammation and fibrosis in non-cirrhotic HBV-associated HCC is associated with worse prognosis, which may reflect more aggressive tumor behavior and an immunosuppressed, pro-metastatic tumor microenvironment. [ABSTRACT FROM AUTHOR]

Ischemic stroke leads to high mortality and disability rates in humans. Cerebral ischemic injury has a severe complex pathophysiological mechanism. The abnormal release of inflammatory cytokines will cause brain tissue damage and destroy the blood-brain barrier integrity, which aggravates the process of brain injury. Therefore, attenuating the level of inflammatory response is critical for the therapy of cerebral ischemia injury. This study examined the rule of SIP treatment to support neuron protective effect after cerebral injury in an animal model of middle cerebral artery occlusion (MCAO). After ischemia/reperfusion, neurological function, neuroglia cells activation, infarction volume, brain water content, brain tissue apoptosis ratio, and inflammatory response were assessed, and quantitative PCR and western blot were also detected, respectively. Treatment of SIP ameliorated neurological dysfunction, brain infarction, brain edema, and brain cell apoptosis after MCAO operation. Overexpression SIP also suppressed pro-inflammatory cytokines release. Furthermore, the protective effect of SIP on brain injury occurs through reduced neuroglia cells activation through downregulation of the NF-κB pathway. In summary, the present work indicated that SIP prevents ischemic cerebral infarction-induced inflammation and apoptosis by blocking inflammasome activation via NF-κB signaling pathway. Those results suggest that SIP treatment is an attractive strategy for prevention of ischemic cerebral infarction. [ABSTRACT FROM AUTHOR]

The objective of this study was to investigate protective effects of tree peony seed protein hydrolysate by Alcalase (AL-TPSPH) on oxidative damage, inflammation and apoptosis using Cd-induced zebrafish embryos. Zebrafish embryos were treated with either Cd (2 μg/L) or AL-TPSPH (25, 50 and 75 μg/mL) alone or in combination of both from 4 to 144 h post fertilization (hpf). The effects of these treatments on developments, antioxidant parameters and mRNA expression of genes related to oxidative damage, inflammation and apoptosis were examined. The results showed that co-treatment with Cd and AL-TPSPH significantly increased hatching and survival rates and decreased malformation rates of zebrafish embryos compared with Cd treatment alone group (P < 0.05). Cd-induced increase of MDA content, decreases of T-AOC content, GSH/GSSG ratio and activities of SOD, CAT and GPx in zebrafish embryos were modified upon treatment with AL-TPSPH. AL-TPSPH treatment significantly suppressed Cd-induced down-regulations of the antioxidant gene expressions (Mn-sod, Cat and GPx1a) in zebrafish embryos (P < 0.05). AL-TPSPH also prevented Cd-induced up-regulations of pro-inflammatory cytokine (TNF-α , IL-1β and IFN-γ) expressions. Moreover, AL-TPSPH inhibited Cd-induced up-regulations of pro-apoptotic genes (C-jun , Caspase-3 and Caspase-9) in zebrafish embryos. Collectively, these results indicated that AL-TPSPH could reduce Cd-induced oxidative damage, inflammation and apoptosis in zebrafish embryos, suggesting its future applications as functional food or pharmaceutical ingredient. • AL-TPSPH ameliorated Cd-induced developmental damage of zebrafish embryos. • AL-TPSPH alleviated Cd-induced oxidative damage by regulating antioxidant system. • AL-TPSPH prevented up-regulations of genes related to inflammation. • AL-TPSPH inhibited up-regulations of genes related to apoptosis. [ABSTRACT FROM AUTHOR]

Donkey milk is gaining interest as a natural nutritional and medicinal product, mainly because its composition is similar to that of human milk, and it has some potential biological properties, such as antioxidant, anti‐inflammatory, antiaging, antimicrobial, and anticancer properties. Considering the increasing prevalence of several chronic diseases related to oxidative stress and inflammation and the multiple beneficial properties and nutritional value of donkey milk, an up‐to‐date review of the current studies related to the antioxidative and anti‐inflammatory abilities of donkey milk is necessary. Therefore, this review aims to discuss the relationship between inflammation and oxidative stress; and to further systematically review the progress of recent research on donkey milk, mainly including its nutritional value and functional properties. Particularly, we highlighted the anti‐inflammatory and antioxidative properties of donkey milk using in vitro model, animal model, and the potential role of donkey milk in alleviating some chronic diseases related to inflammation. Practical applications: This paper was conducted on anti‐inflammation and antioxidant activities of donkey milk and its related products, in addition to a summary of the relationship between oxidative stress and inflammation and the value of donkey milk. Donkey milk and its related products have been shown to scavenge reactive oxygen species, activate the antioxidant system, enhance immune function, and maintain the balance of intestinal flora in in vitro and in vivo models. This paper should provide a better understanding of the influences of oxidative stress and inflammation on host health and the biological functions and application of donkey milk, and will provide a certain basis for the nutritional regulation of several chronic diseases related to oxidative stress and inflammation. However, the underlying mechanism is poorly understood. In addition, few clinical studies have been performed to establish its multiple benefits in humans. Further research is warranted to evaluate its impacts on health at molecular levels. [ABSTRACT FROM AUTHOR]

AIM: To investigate the effect of protopanaxatriol (PPT) on the drug resistance of paclitaxel (PTX)-resistant human breast cancer MDA-MB-231 cells (MB231-PR cells). METHODS: The MB231-PR cells were constructed as cell models. They were treated with PPT, and incubated for a certain period of time according to the experimental settings. CellTiter-Glo was used to determine the viability of MB231-PR cells and MDA-MB-231 parental cells (MB231-PT cells). The change of sub-G1 phase was detected by flow cytometry. Western blot was used to evaluate the apoptosis-related proteins, such as cleaved caspase-3, cleaved poly (ADP-ribose) polymerase (PARP), B-cell lymphoma2 (Bcl-2), Bcl-2-associated X protein (Bax) and survivin. The activity of nuclear factor-κB (NF-κB) was detected by luciferase reporter assay and immunofluorescence assay. The mRNA expression levels of interleukin-6 (IL-6), IL-8, chemokine CXC motif ligand 1 (CXCL1), chemokine CC motif ligand 2 (CCL2), CD44, NANOG, octamer-binding transcription factor 4 (OCT4), sex-determining region Y-box 2 (SOX2) and aldehyde dehydrogenase 1 (ALDH1) were detected by qPCR. The protein levels of IL-6 and IL-8 were measured by ELISA. Tumor sphere formation assay was used to evaluate the characteristics of stem cells. RESULTS: (1) The viability of MB231-PR cells was suppressed by PPT treatment in a dose-dependent manner compared with MB231-PT cells (P<0. 01). Besides, the viability of MB231-PR cells was decreased after combined treatment with PPT and PTX (P<0. 01), the accumulation of sub-G1 phase was induced (P< 0. 01), the ratio of Bax/Bcl-2 was elevated (P<0. 01), and the protein levels of survivin, cleaved PARP and cleaved caspase-3 were increased (P<0. 05). (2) After PPT treatment combined with PTX, the mRNA expression of inflammatory cytokines (IL-6, IL-8, CXCL1 and CCL2) and cancer stem cell-related markers (OCT4, SOX2, NANOG, ALDH1 and CD44) was reduced (P<0. 05), and the protein levels of IL-6 and IL-8 were decreased (P<0. 01). The activity of NF-κB in MB231-PR cells was suppressed (P<0. 05), and the growth of tumor spheres from MB231-PR cells was damaged (P< 0. 05). (3) Immunofluorescence assay showed that PTX induced nuclear p-p65 expression, but this effect was attenuated by PPT. CONCLUSION: Combined treatment with PPT and PTX could attenuate PTX resistance of MB231-PR cells by inhibiting inflammatory cytokines and cancer stem cells. [ABSTRACT FROM AUTHOR]

Myocardial ischemia/reperfusion (MI/R) has high morbidity and mortality worldwide, but the underlying mechanisms have not been entirely understood. TRIM27 is one of the Tri-domain proteins (TRIM) family proteins with crucial roles in numerous life processes. In the study, we attempted to explore the effects of heart-conditional knockout of TRIM27 (TRIM27cKO) on MI/R progression both in vivo and in vitro. Our results showed that TRIM27 was strongly decreased in murine hearts with MI/R injury and in cardiomyocytes with hypoxic reoxygenation (HR) treatment. TRIM27cKO could further accelerate the infarction size and cardiac dysfunction in MI/R mice. Function study demonstrated that heart-selective TRIM27 deletion significantly aggravated apoptosis in hearts of MI/R mice through enhancing Caspase-3 activities. Moreover, inflammatory response due to MI/R injury was remarkably exacerbated in TRIM27cKO mice by strengthening nuclear factor κB (NF-κB) activation. In addition, p53 expression levels were dramatically up-regulated in hearts of MI/R mice and cardiomyocytes with HR treatment, which were further aggravated by TRIM27cKO. Intriguingly, we found that TRIM27 could interact with p53 and promote its ubquitination. Of note, suppressing p53 remarkably ameliorated TRIM27cKO-intensified apoptotic cell death and inflammation in HR-treated cardiomyocytes. Taken together, all these findings revealed that TRIM27/p53 axis may be involved in MI/R progression, and thus could be a therapeutic target for this disease treatment. • Heart-specific TRIM27 knockout aggravates myocardial damage and dysfunction. • TRIM27 down-regulation could accelerate inflammatory response to promote MI/R. • TRIM27 negatively mediates p53 to control apoptosis and inflammation in H/R-treated cardiomyocytes. [ABSTRACT FROM AUTHOR]

Background: Ezrin-radixin-moesin (ERM) have been explored in many cancer processes. Moesin, as its component, has also been found to play an important role in the prognosis of cancer patients, tumor metastasis, drug resistance, and others. Especially in regulating the immunity, but most results came from direct studies on immune cells, there is no clear conclusion on whether moesin has similar effects in tumor cells. And moesin has certain research results in many cancers in other aspects, but there are few about moesin in lung adenocarcinoma (LUAD). Methods: We detect the expression of moesin in 82 LUAD and matched normal tissue samples by immunohistochemistry. Besides, for the pathological feature, we did a detailed statistical analysis. And with the help of various databases, we have done in-depth exploration of moesin's ability to enhance the extent of immune lymphocyte infiltration. Results: Moesin is a poor expression in lung cancer tissues than the corresponding normal samples. And this phenomenon had a strongly associated with the prognosis and TNM stage of these LUAD patients. Moesin can enhance the infiltration of multiple immune lymphocytes in lung cancer. And this may be related to the interaction between moesin and various inflammatory molecules. Conclusions: Moesin is a newly index for the prognosis of LUAD and improves the prognosis of LUAD patients by regulating a variety of inflammation-related molecules to enhance immune lymphocytes infiltration. [ABSTRACT FROM AUTHOR]

Interleukin (IL)-39 is a novel member of IL-12 family and has been reported to play a pro-inflammatory role in lupus-like mice, but its function in concanavalin A (ConA)-induced liver injury is currently unclear. In this study, we investigated the effects of IL-39 expression in a mouse model of ConA induced-hepatitis. We first showed that delivery of plasmid DNA encoding mouse IL-39 using the hydrodynamic tail vein injection method increased IL-39 mRNA and protein levels in the liver. We then administrated mice with IL-39 plasmid before ConA injection and measured serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, inflammatory infiltration, and hepatocyte necrosis in the liver. Additionally, we further explored the potential mechanism of IL-39 in ConA-induced liver injury by measuring several inflammatory mediators. We found that ectopic IL-39 expression promoted the ConA-induced increase in serum ALT and AST levels, inflammatory infiltration, and hepatocyte necrosis in the liver. We also observed that IL-39 plasmid administration significantly increased serum and liver interferon-γ, tumor necrosis factor-α, and IL-17A levels, but did not affect serum and liver IL-10 levels in ConA-induced hepatitis. Our results suggest that IL-39 can exacerbate ConA-induced hepatitis and may be a therapeutic target in inflammatory liver disease. [ABSTRACT FROM AUTHOR]

Ulcerative colitis (UC) is a kind of chronic intestinal inflammation accompanied with abdominal pain, diarrhea and hematochezia. Huanglian Ganjiang decoction (HGD) derived from "Beiji Qianjin Yao Fang" was used for UC patients clinically. However, the specific mechanism of HGD in treating UC remain unclear. Our study devoted to demonstrating the therapeutic effect of HGD for colitis and clarifying the underlying mechanism. UPLC-MS was carried out to identify the ingredients of HGD. UC mice were induced by giving 3% dextran sulfate sodium (DSS) solution for one week and treated by HGD for another week. Body weight fluctuation, disease activity index (DAI), colon length and pathological change of colon tissues were observed to evaluate therapeutical effect of HGD. ELISA and qPCR were carried out to estimate the inflammatory state. Western blot, qPCR and immunofluorescence were used to access the expression of tight junction proteins. Tandem mass tag (TMT)-Based proteomics and network pharmacology was launched to screen and predict the potential targets and pathway regulated by HGD. Based on the UPLC-MS/MS analysis, 100 components were identified in HGD. After 7-day treatment, HGD significantly alleviated colitis-associated symptoms including body weight loss, shorted colon, increase of DAI score, histopathologic lesions. HGD also reduced inflammatory cytokines IL-6 and IL-1β levels, increased the number of goblet cells and restored tight junction proteins Occludin, Claudin-1 in colon. Network pharmacology study predicted that tight junction and MAPK pathway might be affected by HGD in colitis mice. APOC1 was screened out as key target in HGD-treated mice using TMT-based proteomics study. Further Western blot results showed that HGD reduced expressions of APOC1, p-P38 and p-JNK. HGD improves general symptoms of colitis mice at medium and high doses, which may be associated with restoring tight junction and intestinal barrier integrity and function through suppression of APOC1-JNK/P38 MAPK signal pathway. [Display omitted] • Huanglian Ganjiang decoction alleviated DSS-induced colitis-associated symptoms and reduced inflammation. • Huanglian Ganjiang decoction improved colonic histological structure and repaired colonic mucosal tissue in UC mice. • Huanglian Ganjiang decoction raised the level of tight junction proteins in UC mice colon. • Huanglian Ganjiang decoction might enhance gut barrier function through suppressing APOC1-JNK/P38 MAPK signal pathway. [ABSTRACT FROM AUTHOR]

Nine previously undescribed clerodane-type diterpenoids (1–9), named caseabalanspenes A-I , along with six know compounds (10–15), were isolated from the twigs and leaves of Casearia velutina. Spectroscopic data (1D and 2D NMR) analysis permitted the definition of their structures and then determination of the molecular formula of the compound by high resolution mass spectrometry (HR-ESI-MS). It is worth noting that compound 7 contains N- heterocycle. Compounds 1–8 were tested the anti-inflammasome activity, and compound 3 exhibited potent activity and decreased LDH level in a dose-dependent manner, with IC 50 values of 2.90 μM. [Display omitted] • Nine undescribed clerodane diterpenoids were isolated from Casearia velutina. • Their structures were determined by 1D, 2D-NMR and HR-ESI-MS analyses. • The structure of compound 7 contains an N-heterocycle. • Compound 3 exhibited NLRP3-inflammasome inhibitory activity with IC 50 values of 2.90 μM. [ABSTRACT FROM AUTHOR]

Inhibition of immune and inflammatory reaction induced by the expose of nucleus pulposus (NP) could effectively ameliorate neuropathic pain in the lumbar disc herniation. Maresin1 (MaR1), as a macrophage-derived mediator of inflammation resolution, displayed potent anti-inflammatory action. In the present study, we attempted to elucidate the impact of MaR1 on radicular pain and the interaction with NLRP3 inflammasome. We established a rat model of non-compressive lumbar disc herniation and different administration (MaR1 or Caspase-1 inhibitor) was given to them. The paw withdrawal latency (PWL) and paw withdrawal thresholds (PWTs) were observed to assess pain behaviors. The spinal cord horns were collected and the levels of IL-1β and IL-18 were measured by ELISA. The mRNA and protein expression levels of NLRP3 inflammasome components were tested by RT-PCR, western blot and immunohistochemistry. The endogenous MaR1 levels of the spinal cord were analyzed using LC–MS/MS. The application of NP in the models lead to mechanical and thermal hypersensitivity, increased IL-1β and IL-18 levels and expressions of NLRP3 inflammasome components, which were reversed markedly by administration of MaR1. Caspase-1 inhibition also improved mechanical hypersensitivity, decreased the expressions of inflammatory cytokines and restrained the activation of inflammasome. Meanwhile, Caspase-1 inhibitor promoted the endogenous MaR1 synthesis, which was hindered in the pain models. Altogether, our study indicated that the negative interaction between MaR1 and NLRP3 inflammasome mediated the inflammatory response in spinal dorsal horn, which involved in the pathogenesis of radicular pain. [ABSTRACT FROM AUTHOR]

High-fat diet (HFD) is a predisposing factor for metabolic syndrome-related systemic inflammation and non-alcoholic fatty liver disease (NAFLD). However, there is still no effective therapeutic treatment for NAFLD. Here, we showed that remdesivir (RDV, GS-5734), as a broad-spectrum antiviral nucleotide prodrug with anti-inflammatory effects, was effective for attenuating HFD-induced metabolic disorder and insulin resistance. Results revealed that the liver weight, hepatic dysfunction and lipid accumulation were markedly increased compared with that of the Control group, while that of the RDV group exhibited significant reduction, accompanied by the improved signaling pathway regulating fatty acid metabolism. In agreement with reduced lipid deposition, RDV supplementation suppressed the systematic and hepatic inflammation, as evidenced by reduction of inflammatory cytokines and the blockage of nuclear factor κB (NF-κB) signaling. In addition, stimulator of interferon genes (STING) and its down-streaming factor interferon regulatory factor 3 (IRF3) were greatly increased in livers of HFD-fed mice, which were considerably restrained by RDV treatment. The in vitro analysis suggested that RDV functioned as an inhibitor of STING, contributing to the suppression of dyslipidemia and inflammation induced by palmitate (PA). However, PA-triggered lipid deposition and inflammatory response was further accelerated in hepatocytes with STING over-expression. Notably, RDV-attenuated lipid disorder and inflammation were significantly abrogated by the over-expression of STING in PA-stimulated hepatocytes. Taken together, these findings indicated that RDV exhibited protective effects against NAFLD development mainly through repressing STING signaling, and thus could be considered as a potential therapeutic strategy. • Remdesivir attenuates metabolic syndrome in HFD-fed mice. • Remdesivir alleviates hepatic function and lipid accumulation in HFD-induced mice. • Remdesivir inhibits inflammatory response in liver of HFD-fed mice. • Remdesivir-regulated lipid accumulation and inflammation is dependent on STING in PA-incubated hepatocytes. [ABSTRACT FROM AUTHOR]

Low back pain (LBP) is one of the most common complains in orthopedic outpatient department and intervertebral disc degeneration (IDD) is one of the most important reasons of LBP. The mechanisms of IDD contain a complex biochemical cascade which includes inflammation, vascular ingrowth, and results in degradation of matrix. In our study, we used both in vitro and in vivo models to investigate the relation between tissue inhibitor of metalloproteinase‐3 (TIMP3) expression and IDD. Loss of TIMP3 expression was found in degenerative intervertebral disc (IVD), this change of expression was closely related with the dephosphorylation of smad2/3. Overexpression of TIMP3 significantly inhibited the release of TNF‐α and matrix degradation induced by Lipopolysaccharide. Vascular ingrowth was also suppressed by TIMP3 in the in vitro and in vivo models. Further, animal experiments confirmed that the degeneration of IVD was reduced after overexpression of TIMP3 in nucleus pulposus. Taken together, our results indicated TIMP‐3 might play an important role in the pathogenesis of IDD and therefore be a potential therapeutic target in the future. [ABSTRACT FROM AUTHOR]

Background: Fish immunity is not only affected by the innate immune pathways but is also triggered by stress. Transport and loading stress can induce oxidative stress and further activate the immune inflammatory response, which cause tissue damage and sudden death. Multiple genes take part in this process and some of these genes play a vital role in regulation of the immune inflammatory response and sudden death. Currently, the key genes regulating the immune inflammatory response and the sudden death caused by stress in Coilia nasus are unknown. Results: In this study, we studied the effects of the Glo1 gene on stress, antioxidant expression, and immune-mediated apoptosis in C. nasus. The full-length gene is 4356 bp, containing six exons and five introns. Southern blotting indicated that Glo1 is a single-copy gene in the C. nasus genome. We found two single-nucleotide polymorphisms (SNPs) in the Glo1 coding region, which affect the three-dimensional structure of Glo1 protein. An association analysis results revealed that the two SNPs are associated with stress tolerance. Moreover, Glo1 mRNA and protein expression of the heterozygous genotype was significantly higher than that of the homozygous genotype. Na+ and sorbitol also significantly enhanced Glo1 mRNA and protein expression, improved the fish's antioxidant capacity, and reduced the immune inflammatory response, thus sharply reducing the mortality caused by stress. Conclusions: Glo1 plays a potential role in the stress response, antioxidant capacity, and immune-mediated apoptosis in C. nasus. [ABSTRACT FROM AUTHOR]

Macrophage is a critical regulator in wound healing and scar formation, and SIRT1 is related to macrophage activation and polarization, while the specific mechanism is still unclear. To explore the specific effects of SIRT1 in scarring, we established a skin incision mouse model and LPS-induced inflammation cell model. The expression of SIRT1 in tissue and macrophage was detected, and the level of SIRT1 was changed to observe the downstream effects. LPS-induced macrophages with or without SIRT1 deficiency were used for TMT-based quantitative proteomic analysis. SIRT1 was suppressed in scar while increased in macrophages of scar tissue. And macrophages were proven to be necessary for wound healing. In the early stage of wound healing, knockout of SIRT1 in macrophage could greatly strengthen inflammation and finally promote scarring. NADH-related activities and oxidoreductase activities were differentially expressed in TMT-based quantitative proteomic analysis. We confirmed that ROS production and NOX2 level were elevated after LPS stimulation while the Nrf2 pathway and the downstream proteins, such as Nqo-1 and HO-1, were suppressed. In contrast, the suppression of SIRT1 strengthened this trend. The NF-κB pathway was remarkably activated compared with the control group. Insufficient increase of SIRT1 in macrophage leads to over activated oxidative stress and activates NF-κB pathways, which then promotes inflammation in wound healing and scarring. Further increasing SIRT1 in macrophages could be a promising method to alleviate scarring. Key messages: SIRT1 was suppressed in scar while increased in macrophages of scar tissue. Inhibition of SIRT1 in macrophage leads to further activated oxidative stress. SIRT1 is negatively related to oxidative stress in macrophage. The elevation of SIRT1 in macrophage is insufficient during scarring. [ABSTRACT FROM AUTHOR]

Objective. To explore the protective effect of special electromagnetic field treated water (SEW) and far infrared rays (IFR) on endotoxin (lipopolysaccharide, LPS) induced ARDS rats and the effect on inflammatory factors. Methods. 40 healthy male SD rats were randomly divided into 4 groups with 10 in each group. Preventive experiment: Adaptive feeding was carried out for 1 week according to animal feeding standards. Rats in SEW group drank SEW daily. Samely, rats in SEW and FIR group also drank SEW daily. Besides, rats in SEW and FIR group were also given far infrared rays for 20min/d. Rats in model group drank distilled water daily. After 7 days, rats in each group were injected with LPS (2 mg/kg) via the tail vein for making models. Rats in blank control group were given distilled water for 7 days, without modeling. All rats in the 4 groups were put to death under anesthesia 16 hours after modeling. Lung tissue and abdominal aortic blood were taken from these rats. Results. Pathological observation of lung and lung tissue indicated that rats in model group showed great pathological difference from rats in blank group. Rats in intervention group showed more symptomatic improvement in relation to alveolar and pulmonary interstitial congestion, edema, and inflammatory cell infiltration than rats in model group. The level of inflammatory factors like IL-1β and IL-6 in serum of rats in model group increased compared to blank control group (p<0.05). Comparing SEW group and SEW and FIR group with model group, levels of IL-1β and IL-6 in serum of rats both decreased remarkably (IL-Iβ: P < 0.05; IL-6: P < 0.01) while there was no obvious difference between SEW group and SEW and FIR group (p>0.05). The lung coefficient (LI) in SEW and FIR group was significantly lower than that in model group (P<0.01), which was higher than that of blank control group (P < 0.05), while there was no obvious difference between model group and SEW group (P>0.05). Compared with blank control group, lung permeability index (LPI) in model group showed no obvious difference (P>0.05). Conclusion. Special electromagnetic field treated water and far infrared rays can alleviate lung tissue damage of endotoxin-induced ARDS rats, relieving symptoms of alveolar and pulmonary interstitial congestion, edema, and inflammatory cell infiltration. The protective effect of special electromagnetic field treated water and far infrared rays on endotoxin-induced acute respiratory distress syndrome may result from their role in reducing the levels of IL-1β and IL-6 in serum and the expression level of p65 protein in lung tissue, in addition to reliving inflammatory response, lung coefficient, and lungs edema. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Novel salicylamide derivatives were synthesized. • Most compounds showed selective AChE inhibitory and significant antioxidant activities. • Some compounds exhibited good inhibition of self- or Cu2+-induced A β aggregation. • Some compounds exhibited moderate effect on the disaggregation of A β aggregation. • Compound 15b showed good anti-neuroinflammation activity and BBB permeability. Abstract A series of salicylamide derivatives were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease. In vitro assays demonstrated that most of the derivatives were selective AChE inhibitors. They showed good inhibitory activities of self- and Cu2+-induced A β 1–42 aggregation, and significant antioxidant activities. Among them, compound 15b exhibited good inhibitory activity toward Rat AChE and Ee AChE with IC 50 value of 10.4 μM and 15.2 μM, respectively. Moreover, 15b displayed high antioxidant activity (2.46 Trolox equivalents), good self- and Cu2+-induced A β 1–42 aggregation inhibitory potency (42.5% and 31.4% at 25.0 μM, respectively) and moderate disaggregation ability to self- and Cu2+-induced A β 1–42 aggregation fibrils (23.4% and 27.0% at 25 μM, respectively). Furthermore, 15b also showed biometal chelating abilities, anti-neuroinflammatory ability and BBB permeability. These multifunctional properties indicated compound 15b was worthy of being chosen for further pharmacokinetics, toxicity and behavioral researches to test its potential for AD treatment. [ABSTRACT FROM AUTHOR]

Abstract Background Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age and has a prevalence of 1 in 15 women worldwide. This study aims to investigate the role of lncRNA SRA in the pathological processes of polycystic ovary syndrome (PCOS). Methods Twenty five-day old female C57BL/6 mice received subcutaneous injection of 60 mg/kg dehydroepiandrosterone for 20 days to induce PCOS. Lentivirus containing lncRNA SRA-specific shRNA was subcapsularly injected into the ovaries of PCOS mice. Granulosa cell was primary cultured to explore the mechanism of DHEA-induced inflammatory responses. H&E staining was used to examine the histological changes of ovaries. ELISA was used to assess serum insulin level and proinflammatory cytokines and angiogenetic factors contents in ovary tissue. The expression levels of LncRNA SRA and proteins involved in the NF-κB signaling pathway were detected through Quantitative real-time PCR and Western blot. The nuclear translocation of NF-κB was observed by immunofluorescence and the activity of NF-κB-DNA binding was detected using EMSA. Results Silencing of lncRNA SRA changed insulin release, attenuated ovary injury and reduced the production of angiogenetic factors in the PCOS mice. In addition, shRNA targeting lncRNA SRA inhibited DHEA-induced pro-inflammatory cytokines production and NF-κB nuclear translocation in the ovary of PCOS mice and primary granulosa cells. Conclusion Silencing of lncRNA Steroid Receptor RNA Activator (SRA) attenuates polycystic ovary syndrome (PCOS) in mice. LncRNA SRA plays important roles in the development of PCOS. Highlights • Silencing of lncRNA SRA attenuates PCOS in mice. • Silencing of lncRNA SRA reduces pro-inflammatory cytokines and angiogenetic factors production in the ovary of PCOS mice. • Silencing of lncRNA SRA inhibits TNF-α production and NF-κB activation in DHEA-exposed ovarian granulosa cells. [ABSTRACT FROM AUTHOR]

Background: A growing body of evidence shows that indoor concentrations of airborne particles are often higher than is typically encountered outdoors. Since exposure to indoor PM2.5 is thought to be associated with cardiovascular disease, the health impacts of indoor air pollution need to be explored. Based on animal models, ambient particulate matter has been proved to promote coagulation which is very likely involved in the pathogenic development of cardiovascular disease. However, animal models are insufficient to predict what will happen with any certainty in humans. For this reason, the precise pathogenic mechanisms behind the development of cardiovascular disease in humans have not yet been determined. Results: We generated a 3D functional human microvascular network in a microfluidic device. This model enables human vascular endothelial cells to form tissue-like microvessels that behave very similarly to human blood vessels. The perfusable microvasculature allows the delivery of particles introduced into these generated human-like microvessels to follow the fluid flow. This exposure path effectively simulates the dynamic movement of airborne nanoscale particles (ANPs) within human vessels. In this study, we first identified the existence of ANPs in indoor air pollution. We then showed that ANPs could activate endothelial cells via ROS induced inflammation, and further resulted in abnormal expression of the coagulation factors (TF, TM and t-PA) involved in coagulation cascades. In addition, we found that a protein could cover ANPs, and this biointeraction could interfere with heparan sulfate (HS). Human organotypic 3D microvessel models provide a bridge for how research outcomes can translate to humans. Conclusions: The 3D human microvessel model was used to determine the physiological responses of human vessels to ANP stimulation. Based on the obtained data, we concluded that ANPs not only disrupts normal coagulation functions, but also act directly on anticoagulant factors in human vessels. These experimental observations provide a potential biological explanation for the epidemiologically established link between ANPs and coagulation abnormality. This organ-on-chip model may provide a bridge from in vitro results to human responses. [ABSTRACT FROM AUTHOR]

Abstract Ethnopharmacology relevance Rhizome of Ligusticum chuanxiong Hort. (Abbreviated as LC) is a frequently prescribed component in plenty of traditional Chinese medicine (TCM) formulas which are used to treat diabetic nephropathy (DN). The aims of the present study are to investigate the protective effect of the ethanol extract of LC rhizome (EEL) against DN in vivo , evaluate its potential mechanism, and find the evidence supporting its enthopharmacological use as an anti-DN agent. Materials and methods Hepa 1c1c7 murine hepatoma cells, human breast carcinoma MDA-MB-231 cells, human renal glomerular endothelial cells (HRGEC), and RAW 264.7 murine macrophages were adopted to test the effects of EEL and its active constituents on inhibitions of oxidative stress and inflammation in vitro. A streptozotocin (STZ) -induced DN C57BL/6 mice model was established and used to investigate the preventive effect of EEL against DN in vivo. Results EEL demonstrated potential inhibitory effects against oxidative stress and inflammation in vitro. Using a STZ-induced DN mice model, it has been found that EEL treatment significantly prevented STZ-induced increases of urine production, urinary albumin excretion (UAE) and urine albumin-to-creatinine ratio (UACR), and markedly attenuated STZ-induced renal damages (e.g. glomerulosclerosis and fibrosis). The predominant bioactive constituents, Z -ligustilide (LGT), ferulic acid (FA), and tetramethylpyrazine (TMP), were inhibitors of oxidative stress and inflammation through acting with Nrf2 and NF-κB pathways. Conclusions EEL attenuates structural and functional damages of kidney in STZ-induced DN model in vivo , which might be related to the functions of EEL on inhibitions of oxidative stress and inflammation. These finding definitely supports the ethnopharmacological use of LC as an anti-DN agent. Graphical abstract fx1 [ABSTRACT FROM AUTHOR]

Pulmonary fibrosis is a disease with chronic inflammation and excessive collagen deposition for which there is no effective treatments. Interleukin (IL)-37 is a newly identified anti-inflammatory cytokine but its role in pulmonary fibrosis remains unclear. In this study, we investigated the effect of IL-37 on bleomycin-induced pulmonary fibrosis in mice. A lentivirus expressing IL-37 was administered intranasally to bleomycin-induced C57BL/6 mice. We found that IL-37 improved the survival of mice and reduced the body weight loss of mice caused by bleomycin. Furthermore, IL-37 significantly attenuated pulmonary inflammatory infiltration and collagen deposition and decreased the hydroxyproline content in bleomycin-treated mice. Finally, IL-37 treatment inhibited the expression of monocyte chemoattractant protein-1, IL-6, and tumor necrosis factor-α, but increased the expression of interferon-γ in lung tissues from bleomycin-challenged mice. Taken together, these results suggest that in vivo expression of IL-37 is useful in preventing pulmonary fibrosis induced by bleomycin and provides a possible therapeutic approach to pulmonary fibrosis diseases. [ABSTRACT FROM AUTHOR]

Repeated cycles of dextran sulfate sodium (DSS) administration in mice, inducing chronic relapsing colitis, have been used to mimic human ulcerative colitis (UC). However, no systematic characterization of pro-inflammatory cytokines in these DSS mice has been reported. In this study, the development of colitis was examined by assessment of the disease severity and inflammation in the colon of C57BL/6 mice that received DSS. ELISA was used to analyze the levels of pro-inflammatory cytokines in serum, colon, spleen and supernatant of cultured splenocytes. mRNA levels of the above cytokines in colon and mesenteric lymph node (MLN) were measured with RT-PCR. The mice receiving three cycles of 2% DSS over a 43-day period showed a fluctuating appearance of diarrhea and bloody feces, and a significant reduction in body weight and colon length. When compared with normal control mice, an increase in TNF-α level in serum was detected in the DSS mice, along with a decrease in the amounts of TNF-α, IL-17, IL-1β and IL-6 in the colonic tissue. However, mRNA levels of these cytokines were found to be significantly increased in the colon while decreased in the MLN of the colitis mice. Further, the ELISA assay suggested a pronounced increase of TNF-α production by cultured splenocytes with PMA/ionomycin re-stimulation but no increase in its presence in spleen tissue upon DSS challenge. In conclusion, we have systematically demonstrated the dysregulation of pro-inflammatory cytokines in the DSS-induced chronic relapsing colitis model, which will provide markers to test emerging therapeutic strategies by this model. [ABSTRACT FROM AUTHOR]

Background/aims: Elevation of plasma sulfur-containing amino acids (SAAs) is generally associated with higher body mass index (BMI) and unfavorable lipid profiles. It is not known how dietary SAAs relate to these associations in humans. Methods: A convenient tool named internet-based dietary questionnaire for Chinese (IDQC) was used to estimate dietary SAAs intake. A total of 936 participants were randomly recruited and asked to complete the IDQC. Furthermore, 90 subjects were randomly selected to perform a subgroup study. The associations between dietary SAAs and prevalence of obesity, lipid profiles, and status of insulin resistance (IR), inflammation and oxidative stress were assessed. Results: Dietary total SAAs and cysteine of overweight/obese participants were significantly higher. Dietary total SAAs and cysteine were positively associated with BMI and waist circumference. Higher dietary total SAAs were associated with higher prevalence of overweight/obesity. Higher dietary total SAAs and cysteine also associated with higher serum triglyceride (total cholesterol), low density lipoprotein, fasting blood glucose, 2 h-postprandial glucose, and homeostasis model assessment of IR. In the subgroup study, positive associations between dietary SAAs and inflammation biomarkers were also observed. Conclusions: Dietary SAAs are associated with higher prevalence of overweight/obesity, unfavorable lipid profiles and status of IR, and inflammation. [ABSTRACT FROM AUTHOR]

Diabetic retinopathy (DR) is the common cause of diabetic vascular complications. The NOD-like receptor (NLR) family, pyrin domain containing 1 (NLRP1), also known as NALP1, inflammasome is the first member of the NLR family to be discovered, playing an important role in inflammatory response. However, its effect on DR development has not been reported. In the study, the wild type (WT) and NLRP1 −/− mice were injected with streptozotocin (STZ) to induce DR. The results indicated that NLRP1 −/− significantly increased bodyweight reduction and decreased blood glucose levels induced by STZ. WT/DR mice exhibited higher levels of NLRP1 in retinas. NLRP1 −/− ameliorated retinal abnormalities in DR mice using H&E staining. In addition, attenuated avascular areas and neovascular tufts were also observed in NLRP1 −/− /DR mice. The levels of pro-inflammatory cytokines in serum and retinas were highly induced in WT/DR mice, whereas being markedly reduced by NLRP1 −/− . In addition, vascular endothelial growth factor (VEGF) and Iba1 expressions induced by STZ in serum or retinas were significantly down-regulated in NLRP1 −/− /DR mice. Consistently, NLRP1 −/− attenuated ASC and Caspase-1 expressions in retinas of DR mice. Compared to WT/DR group, NLRP1 −/− markedly decreased retina p-nuclear factor-κB (NF-κB), interleukin-1β (IL-1β) and IL-18 levels. And similar results were confirmed in vitro that suppressing NLRP1/ASC inflammasome ameliorated inflammatory response in fructose-treated retinal ganglion cells. The results above indicated that the modulation of NLRP1 inflammasome might be a promising strategy for DR therapy. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Schisandra chinensis (Turcz.) Baill is a frequently used traditional Chinese medicine, and modern pharmacological research has proven that S. chinensis has antioxidant, anti-hepatotoxity, anti-inflammatory, and anti-nephrotoxic effects. Cisplatin is widely used as antineoplastic drug at present, but the clinical application is limited owing to its nephrotoxicity. Aim of the study To demonstrate the renoprotective activity of the extract of the stems of S. chinensis (SCE) in mice established by cisplatin-triggering acute kidney injury (AKI). The possible molecular mechanism of nephroprotection exhibited by SCE was evaluated for the first time. Materials and methods Mice in SCE groups were pre-treated with SCE for 10 consecutive days, and on 7th day 1 h after final administration, following intraperitoneal injection of cisplatin with 20 mg/kg was treated to cisplatin group and SCE groups. On the 10th day, renal function, histopathological change, and oxidative stress markers were investigated. Results Renal oxidative stress level characterized by elevated heme oxygenase 1 (HO-1), cytochrome P450 E1 (CYP2E1) and 4-hydroxynonenal (4-HNE) expression was obviously reduced by SCE pre-treatment. In addition, SCE was found to suppress inflammatory response through the reduction of nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) expression and nuclear factor-kappa B (NF-κB) p65 activation. SCE treatment also inhibited activation of apoptotic pathways through down-regulating Bax, cleaved caspase-3, 8, 9 and up-regulating Bcl-2 expression levels. Conclusion These findings illustrated that SCE possessed powerful protective effect on AKI caused by cisplatin via amelioration of oxidative stress, inflammation and apoptosis. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) continue to be a major public health problem around the world that frequently presents with microvascular and macrovascular complications. Individuals with T2DM are not only suffering from significant emotional and physical misery, but also at increased risk of dying from severe complications. In recent years, evidence from prospective observational studies and clinical trials has shown T2DM risk reduction with vitamin K2 supplementation. We thus did an overview of currently available studies to assess the effect of vitamin K2 supplementation on insulin sensitivity, glycaemic control and reviewed the underlying mechanisms. We proposed that vitamin K2 improved insulin sensitivity through involvement of vitamin K-dependent-protein osteocalcin, anti-inflammatory properties, and lipid-lowering effects. Vitamin K2 had a better effect than vitamin K1 on T2DM. The interpretation of this review will increase comprehension of the development of a therapeutic strategy to prevent and treat T2DM. [ABSTRACT FROM AUTHOR]

Background: To explore the pathogen distribution in Chinese females with vaginitis. Methods: This retrospective study included Chinese females with vaginitis admitted at the outpatient department of the Gynecology Clinic of the Second Affiliated Hospital of Kunming Medical University between January 2013 and June 2013. Data on the vaginal pathogens and inflammation were analyzed. Results: The vaginal secretions from 15,601 gynecologic outpatients were abnormal, including 8547 (54.78%) with vaginal infection and 7054 (45.22%) without. In patients with vaginal infections, a single infection was observed in 69.72% (5959/8547) of them, and mixed infection was observed in 30.28% (2588/8547). The differences in age and inflammation grade between the infection and no-infection groups were statistically significant (all P < 0.001). In addition, multiple types of vaginitis could be diagnosed in patients with mixed infections. Conclusions: About half of the Chinese women with abnormal vaginal secretions are positive for pathogens in the study period. Patients' age and inflammation grade are associated with co-infection. From the public health perspective, this study suggests that the importance of vaginal hygiene should be enforced in Chinese women. [ABSTRACT FROM AUTHOR]

Previous studies have investigated the prognostic value of the advanced lung cancer inflammation index (ALI) in gastrointestinal (GI) cancers; however, the results are controversial. This meta-analysis aimed to evaluate the prognostic and clinicopathological role of ALI in patients with GI cancers. A systematic search of electronic databases was conducted to evaluate the prognostic and clinicopathological value of ALI in GI cancers. Nine studies comprising 3,750 patients were included in this meta-analysis. The pooled results showed that a low ALI was significantly associated with worse overall survival (OS, hazard ratio [HR] = 1.95, 95% confidence interval [CI] = 1.53–2.47, P < 0.001, I2 = 63.9%) and disease-free survival/relapse-free survival (DFS/RFS, HR = 1.49, 95% CI = 1.28–1.73, P < 0.001, I2 = 0%) in patients with GI cancers. In addition, decreased ALI correlated with the depth of tumor invasion and presence of distant metastasis and tended to be associated with male sex, high carcinoembryonic antigen levels, lymph node metastasis, and right-sided colon cancer. Low ALI was associated with adverse OS and DFS/RFS in patients with GI cancer. In addition, decreased ALI also correlated with clinicopathological factors, indicating higher stage of the malignancy. [ABSTRACT FROM AUTHOR]

The antidiabetic properties and anti-inflammatory effects of Danzhi Jiangtang Capsules (DJC) have been demonstrated in clinical and laboratory experiments. In this study, we explored whether DJC can ameliorate advanced glycation end products- (AGEs-) mediated cell injury and the precise mechanisms of DJC in treating diabetic nephropathy (DN). Western blot analysis was employed to assess the expressions of iNOS, COX2, and SOCS and the phosphorylation of JAK2, STAT1, and STAT3 in glomerular mesangial cells (GMCs) after treatment with DJC. TNF-α, IL-6, and MCP-1 were determined using double-antibody sandwich ELISA. ROS and NADPH oxidase activity were measured by DCFH-DA assay and lucigenin-enhanced chemiluminescence, respectively. DJC significantly reversed the AGEs-induced expression of COX2 and iNOS. Moreover, DJC inhibited the AGEs-induced JAK2-STAT1/STAT3 activation, resulting in the inhibition of inflammatory cytokines such as IL-6, MCP-1, and TNF-α in a concentration-dependent manner. The ability of DJC to suppress STAT activation was also verified by the observation that DJC significantly increased the SOCS3 protein level. DJC reversed the AGEs-induced accumulation of ROS and NADPH oxidase activity, thus confirming that DJC possesses antioxidant activity. The results suggest that the anti-inflammatory effects of DJC in GMCs may be due to its ability to suppress the JAK2-STAT1/STAT3 cascades and reduce ROS production. [ABSTRACT FROM AUTHOR]

The costimulatory protein B7-H3 has been shown to play a contributory role in the development and progression of experimental pneumococcal meningitis by augmentation of the innate immunity-associated inflammatory response via a TLR2-dependent manner. This study aimed to clarify the component(s) of TLR2-mediated signal transduction pathways responsible for B7-H3-augmented inflammatory response and subsequent brain damage during experimental pneumococcal meningitis. Administration of B7-H3 did not augment expression of TLR2 and other TLR2 upstream components, but led to an enhanced formation of MyD88-IRAK immunocomplex in the brain of S. pneumoniae-infected mice. Furthermore, B7-H3 substantially augmented S. pneumoniae-induced activation of TLR2 downstream NF-κB p65 and MAPK p38 pathways in the brain of S. pneumoniae-infected mice. Notably, blockage of NF-κB p65 and/or MAPK p38 with their specific inhibitors strongly attenuated B7-H3-amplified inflammatory response with significantly reduced proinflammatory cytokine and chemokine production, and markedly ameliorated B7-H3-exacerbated disruption of blood-brain barrier and severity of disease status in S. pneumoniae-infected mice. These results indicate that targeting NF-κB p65 and/or MAPK p38 may represent a promising therapeutic option for amelioration of overwhelming inflammatory response-associated brain injury frequently observed during pneumococcal meningitis. [ABSTRACT FROM AUTHOR]

Breast cancer is the most common carcinoma in women. Comprehensive therapy on breast cancer including surgical operation, chemotherapy, radiotherapy, endocrinotherapy, etc. could help, but still has serious side effect and resistance against anticancer drugs. Complementary and alternative medicine (CAM) may avoid these problems, in which traditional Chinese medicine (TCM) has been highlighted. In this section, to analyze the mechanism through which TCM act on breast cancer, we have built a virtual model consisting of the construction of database, oral bioavailability prediction, drug-likeness evaluation, target prediction, network construction. The 20 commonly employed herbs for the treatment of breast cancer were used as a database to carry out research. As a result, 150 ingredient compounds were screened out as active molecules for the herbs, with 33 target proteins predicted. Our analysis indicates that these herbs 1) takes a ‘Jun-Chen-Zuo-Shi” as rule of prescription, 2) which function mainly through perturbing three pathways involving the epidermal growth factor receptor, estrogen receptor, and inflammatory pathways, to 3) display the breast cancer-related anti-estrogen, anti-inflammatory, regulation of cell metabolism and proliferation activities. To sum it up, by providing a novel in silico strategy for investigation of the botanical drugs, this work may be of some help for understanding the action mechanisms of herbal medicines and for discovery of new drugs from plants. [ABSTRACT FROM AUTHOR]

Intervertebral disc (IVD) degeneration contributes to most spinal degenerative diseases, while treatment inhibiting IVD degeneration is still in the experimental stage. Sesamin, a bioactive component extracted from sesame, has been reported to exert chondroprotective and anti-inflammatory effects. Here, we analyzed the anti-inflammatory and anti-catabolic effects of sesamin on rat IVD in vitro and ex vivo. Results show that sesamin significantly inhibits the lipopolysaccharide (LPS)-induced expression of catabolic enzymes (MMP-1, MMP-3, MMP-13, ADAMTS-4, ADAMTS-5) and inflammation factors (IL-1β, TNF-α, iNOS, NO, COX-2, PGE2) in a dose-dependent manner in vitro. It is also proven that migration of macrophages induced by LPS can be inhibited by treatment with sesamin. Organ culture experiments demonstrate that sesamin protects the IVD from LPS-induced depletion of the extracellular matrix ex vivo. Moreover, sesamin suppresses LPS-induced activation of the mitogen-activated protein kinase (MAPK) pathway through inhibiting phosphorylation of JNK, the common downstream signaling pathway of LPS and IL-1β, which may be the potential mechanism of the effects of sesamin. In light of our results, sesamin protects the IVD from inflammation and extracellular matrix catabolism, presenting positive prospects in the treatment of IVD degenerative diseases. [ABSTRACT FROM AUTHOR]

Adequate ovarian hormones secretion is essential for pregnancy success. Oxidative damage and following inflammation can destroy the ovarian normal function in mammals. Daidzein (DAI) is a classical isoflavonic phytoestrogen with specific oestrogenic activity. This study aimed to explore the effects of daidzein supplementation on fertility and ovarian characteristics of sows through biochemical analysis and RNA-seq technology. Twelve multiparous Yorkshire × Landrace sows were randomly divided into CON and DAI groups. We found that DAI increased total number of embryos as well as P4 and E2 levels of serum. DAI not only elevated the activities of T-AOC and GSH-Px, but also tended to decrease the content of MDA and IL-6 in the serum. In ovary, RNA-Seq identified 237 differentially expressed genes (DEGs), and GO analysis showed that these DEGs were linked to functions associated with immune dysfunction. Moreover, STRING analysis demonstrated that most interacting nodes were TLR-4, LCP2, and CD86. Furthermore, DAI decreased the content of MDA, IL-1β, IL-6, and TNF-α, and increased the activities of T-AOC and CAT in ovarian tissue. Interestingly, a partial mantel correlation showed that T-AOC was the strongest correlation between the ovarian dataset and selected DEGs. Additionally, DAI supplementation not only increased the protein expressions of Nrf2, HO-1, and NQO1, but also decreased the protein expressions of TLR-4, p-NFκB, p-AKT, and p-IκBα. Altogether, our results indicated that DAI could ameliorate ovarian oxidative stress and inflammation in sows, which might be mediated by suppressing the TLR4/NF-κB signaling pathway and activating the Nrf2/HO-1 signaling pathway. [ABSTRACT FROM AUTHOR]

Exposure to amorphous silica nanoparticles (SiNPs) has increased dramatically, and concerns are growing about their potential health effects. However, their long-term systemic toxicity profile and underlying mechanisms following respiratory exposure still remains unexplored. It is well documented that the inhalation of ultrafine particles is firmly associated with adverse effects in humans. Environmental pollutants may contribute to diverse adverse effect or comorbidity in susceptible individuals. Thereby, we examined the long-term systemic effects of inhaled SiNPs using a sensitive mouse model (ApoE-/-) fed by a western diet. Male ApoE-/- mice were intratracheally instilled with SiNPs suspension at a dose of 1.5, 3.0 and 6.0 mg/kg·bw, respectively, once per week, 12 times in total. The histological analysis was conducted. The serum cytokine levels were quantified by RayBiotech antibody array. As a result, systemic histopathological alterations were noticed, mainly characterized by inflammation and fibrosis. More importantly, cytokine array analysis indicated the key role of mast cells accumulation in systemic inflammation and fibrosis progression induced by inhaled SiNPs. Collectively, our study firstly demonstrated that long-term exposure to inhaled SiNPs promoted the mast cell-dominated activation of inflammatory response, not only in the lung but also in heart, liver and kidney, etc., eventually leading to the progression of tissue fibrosis in ApoE-/- mice. [Display omitted] • Long-term SiNPs inhalation induced systemic toxicity in a susceptible mouse model. • Histopathological analysis revealed systemic inflammation and fibrosis caused by SiNPs. • Cytokine array hinted mast cell as a key player in SiNPs-elicited inflammatory response. • Mast cell accumulation contributed to the progression of fibrosis upon SiNPs stimuli. [ABSTRACT FROM AUTHOR]

Hypothermia treatment is one of the neuroprotective strategies that improve neurological outcomes effectively after brain damage. Minimally invasive surgery (MIS) has been an important treatment of intracerebral hemorrhage (ICH). Herein, we evaluated the neuroprotective effect and mechanism of MIS joint local cooling lavage (LCL) treatment on ICH via detecting the inflammatory responses, oxidative injury, and neuronal apoptosis around the hematoma cavity in rats. ICH model was established by type IV collagenase caudatum infusion. The rats were treated with MIS 6 h after injection, and then were lavaged by normothermic (37 °C) and hypothermic (33 °C) normal saline in brain separately. The results indicated that MIS joint LCL treatment showed enhanced therapeutic effects against ICH-induced inflammation injury and apoptosis in rats, as convinced by the decline of TUNEL-positive cells, followed by the decrease of IL-1β and LDH and increase of IL-10 and SOD. This study demonstrated that the strategy of using MIS joint LCL may achieve enhanced neuroprotection against ICH-induced inflammation injury and apoptosis in rats with potential clinic application. [ABSTRACT FROM AUTHOR]

It has been shown that the expression of ST2, a receptor of interleukin (IL)-33, is elevated in the lungs of idiopathic pulmonary fibrosis patients and bleomycin-induced mouse models, however its contribution to the development of pulmonary fibrosis has yet to be tested. In the present study, we treated mice by intranasal instillation of lentivirus expressing soluble ST2 and evaluated lung inflammation and fibrosis in the bleomycin-induced pulmonary fibrosis mouse model. We found that ST2 lentivirus treatment significantly improved survival rate and reduced weight loss compared with controls treated with empty lentivirus. Furthermore, ST2 treatment profoundly attenuated the pulmonary inflammatory cell infiltration and fibrotic changes. Finally, ST2 treatment markedly lowered the levels of IL-4, IL-6, IL-13, IL-33, monocyte chemoattractant protein-1, and transforming growth factor-β1, whereas it increased the levels of interferon-γ in bronchoalveolar lavage fluid. The results indicate that ST2 might prevent bleomycin-induced pulmonary fibrosis possibly through downregulating proinflammatory and profibrotic mediators. This study suggests that lentivirus expressing soluble ST2 might represent an effective therapeutic approach in the treatment of pulmonary fibrotic diseases. [ABSTRACT FROM AUTHOR]

Complement system is composed of over 30 proteins and it plays important roles in self-defence and inflammation. There are three activation pathways, including classical pathway, alternative pathway and lectin pathway, in complement system, and they are associated with many diseases such as osteoarthritis and age-related macular degeneration. Modulation of the complement system may be a promising strategy in the treatment of related diseases. Glycosaminoglycans are anionic linear polysaccharides without branches. They are one kind of multi-functional macromolecules which have great potential in regulating complement system. This review is organized around two aspects between the introduction of complement system and the interaction of glycosaminoglycans with complement system. Three complement activation pathways and the biological significance were introduced first. Then functional analysis methods were compared to provide a strategy for potential glycosaminoglycans screen. Finally, the roles of glycosaminoglycans played in the complement system were summed up. [ABSTRACT FROM AUTHOR]

Background: B3GNT7, a glycosyltransferase of significant importance that is highly expressed in intestinal epithelial cells, plays a pivotal role in intestinal physiological processes. This study elucidates novel insights into the potential role and underlying mechanisms of B3GNT7 in ulcerative colitis (UC). Methods: An experimental colitis model was induced using DSS in mice to investigate B3GNT7 expression in the colon via transcriptomics and immunohistochemistry. Bioinformatics analysis was employed to delineate the biological functions of B3GNT7. Additionally, the correlation between the transcription levels of B3GNT7 in colonic tissues from patients with UC, sourced from the IBDMDB database, and the severity of colonic inflammation was analyzed to elucidate potential mechanisms. Results: The DSS-induced colitis model was successfully established, and transcriptomic analysis identified a marked downregulation of B3GNT7 expression in the colonic tissues compared to the controls. Functional enrichment analysis indicated B3GNT7's predominant role in mucin O-glycosylation. Protein interaction analysis revealed that B3GNT7 predominantly interacts with members of the mucin MUC family, including MUC2, MUC3, and MUC6. In patients with UC, B3GNT7 transcription levels were significantly reduced, particularly in those with moderate to severe disease activity. The expression level of B3GNT7 exhibited a negative correlation with the endoscopic severity of UC. Gene set enrichment analysis (GSEA) further demonstrated significant enrichment of B3GNT7 in the mucin O-glycosylation synthesis pathway. Conclusion: The downregulation of B3GNT7 expression in the colonic tissues of UC patients may contribute to the compromised mucin barrier function and the exacerbation of colitis. [ABSTRACT FROM AUTHOR]

Background: The role of α-synuclein in dementia has been recognized, yet its exact influence on cognitive decline in non-demented older adults is still not fully understood. Methods: A total of 331 non-demented individuals were included in the study from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Participants were divided into two distinct groups based on their α-synuclein levels: one with lower levels (α-synuclein-L) and another with higher levels (α-synuclein-H). Measurements included neuropsychiatric scales, cerebrospinal fluid (CSF) biomarkers, and blood transcriptomics. The linear mixed-effects model investigated the longitudinal changes in cognition. Kaplan-Meier survival analysis and the Cox proportional hazards model were utilized to evaluate the effects of different levels of α-synuclein on dementia. Gene set enrichment analysis (GSEA) was utilized to investigate the biological pathways related to cognitive impairment. Pearson correlation, multiple linear regression models, and mediation analysis were employed to investigate the relationship between α-synuclein and neurodegenerative biomarkers, and their potential mechanisms affecting cognition. Results: Higher CSF α-synuclein levels were associated with increased risk of cognitive decline and progression to dementia. Enrichment analysis highlighted the activation of tau-associated and immune response pathways in the α-synuclein-H group. Further correlation and regression analysis indicated that the CSF α-synuclein levels were positively correlated with CSF total tau (t-tau), phosphorylated tau (p-tau) 181, tumor necrosis factor receptor 1 (TNFR1) and intercellular cell adhesion molecule-1 (ICAM-1). Mediation analysis further elucidated that the detrimental effects of CSF α-synuclein on cognition were primarily mediated through CSF t-tau and p-tau. Additionally, it was observed that CSF α-synuclein influenced CSF t-tau and p-tau181 levels via inflammatory pathways involving CSF TNFR1 and ICAM-1. Conclusions: These findings elucidate a significant connection between elevated levels of CSF α-synuclein and the progression of cognitive decline, highlighting the critical roles of activated inflammatory pathways and tau pathology in this association. They underscore the importance of monitoring CSF α-synuclein levels as a promising biomarker for identifying individuals at increased risk of cognitive deterioration and developing dementia. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis is a systemic autoimmune disease characterized by chronic inflammation of multiple joints, with disruption of joint cartilage. The proliferation of synovial fibroblasts in response to multiple inflammation factors is central to the pathogenesis of rheumatoid arthritis. Our previous studies showed that 4-HNE may induce synovial intrinsic inflammations by activating NF-κB pathways and lead to cell apoptosis. However, the molecular mechanisms of how synovial NF-κB activation is modulated are not fully understood. Here, the present findings demonstrated that 4-HNE may induce synovial intrinsic inflammations by mTORC1 inactivation. While ectopic activation of mTORC1 pathway by the overexpression of Pim-2 may disrupt the initiation of inflammatory reactions and maintain synovial homeostasis, our findings will help to uncover novel signaling pathways between inflammations and oxidative stress in rheumatoid arthritis development and imply that Pim-2/mTORC1 pathway may be critical for the initiation of inflammatory reactions in human rheumatoid arthritis synovial cells. [ABSTRACT FROM AUTHOR]

Although vitamin D receptor (VDR) is highly expressed in the intestine, the role of VDR signaling in the gut is not fully understood. Our recent studies unveil a regulatory circuit that centers gut epithelial VDR as a key molecule in the control of mucosal inflammation and colitis development. On the one hand, intestinal epithelial VDR signaling protects the integrity of the mucosal barrier by inhibiting inflammation-induced epithelial cell apoptosis. This barrier-protecting, anti-colitic activity is independent of the non-epithelial immune VDR actions. A healthy and intact mucosal barrier prevents bacterial invasion and thus reduces mucosal inflammation. On the other hand, inflammation in turn down-regulates epithelial VDR expression by inducing VDR-targeting microRNA-346, thus compromising mucosal barrier functions. Consistently, colonic epithelial VDR levels are markedly reduced in patients with inflammatory bowel diseases or in experimental colitis models, whereas vitamin D analog therapy that ameliorates colitis up-regulates epithelial VDR. Thus, gut epithelial VDR signaling appears to play an essential role in controlling mucosal inflammation and thus could be a useful therapeutic target in the management of inflammatory bowel diseases. This article is part of a special issue entitled ‘17th Vitamin D Workshop’ . [ABSTRACT FROM AUTHOR]

Objective The study was aimed to study the anti-thrombotic and anti-inflammatory effects of 4-hydroxybenzyl alcohol from Gastrodia elata. Methods Cerebral thrombosis caused by injection of arachidonic acid (AA) via intracarotid artery method was used to evaluate the anti-thrombotic effect of 4-hydroxybenzyl alcohol. Two methods were used to evaluate anti-inflammatory effect of 4-hydroxybenzyl alcohol, including mouse ear edema induced by xylene and rat metatarsal swelling induced by a single subcutaneous injection of AA or carrageenan. Results The results showed that 4-hydroxybenzyl alcohol markedly reduced the ratio of Evans blue and infracted hemisphere weight in 20 mg/kg and 15 mg/kg (P < 0.01). And it showed significantly inhibitory effect on mouse ear edema induced by xylene (P < 0.01), the inhibitory rates were 60.01%, 52.72% and 45% is 30 mg/kg, 20 mg/kg and 15 mg/kg, respectiuely. And it showed inhibitory effect of rat metatarsal swelling reaction induced by carrageenan, the inhibitory rate was 42.56% in 20 mg/kg (P < 0.01), and it had no effect on Toes swelling reaction induced by AA . Conclusion 4-Hydroxybenzyl alcohol, a component of G. elata, had significant inhibition of experimental cerebral thrombosis and anti-inflammatory effect by inhibiting arachidonic acid cyclooxygenase metabolic pathways. [ABSTRACT FROM AUTHOR]

Vascular restenosis after the interventional angioplasty remains the main obstacle to a favorable long-term patency. Many researches suggest cigarette smoking is one of the most important causes of restenosis. This study was designed to investigate whether melatonin could protect against the cigarette smoke-induced restenosis in rat carotid arteries after balloon injury. Three groups of male rats (normal condition, cigarette smoke exposed, cigarette smoke exposed, and melatonin injected) were used in this study. An established balloon-induced carotid artery injury was performed, and the carotid arteries were harvested from these three groups 14 days later. The ratio of intima to media, the infiltration of inflammatory cells, the expression of inflammatory cytokines (NF-κB, IL-1β, IL-6, TNF-α, MCP-1), adhesion molecules (ICAM-1, VCAM-1), and eNOS were measured. The results showed that cigarette smoke exposure aggravated the stenosis of the lumen, promoted the infiltration of inflammatory cells and induced the expression of the inflammatory cytokines and adhesion molecules after the balloon-induced carotid artery injury. Moreover, cigarette smoke exposure can inhibit the expression of eNOS. Particularly, we surprised that melatonin could minimize this effect caused by cigarette smoke. These results suggested that melatonin could prevent the cigarette smoke-induced restenosis in rat carotid arteries after balloon injury and the mechanism of its protective effect may be the inhibition of the inflammatory reaction. This also implies melatonin has the potential therapeutic applicability in prevention of restenosis after the vascular angioplasty in smokers. [ABSTRACT FROM AUTHOR]

Macrophages play a critical role in innate immune response to protect the host from pathogenic microorganisms. Inflammatory response is regulated by negative feedback mechanisms to prevent detrimental effects. The SOCS family of proteins is key component of the negative feedback loop that regulates the intensity, duration and quality of cytokine signaling, whereas miR-155 is a key regulator of Toll-like receptor (TLR) signaling that targets SOCS1 in activated macrophages to block the negative feedback loop. Recently we showed that 1,25-dihydroxyvitamin D (1,25(OH) 2 D 3 ) modulates innate immune response by targeting the miR-155-SOCS1 axis. We found that Vdr deletion leads to hyper inflammatory response in mice and macrophage cultures when challenged with lipopolysaccharide (LPS), due to miR-155 overproduction to excessively suppress SOCS1. Using mice with bic/miR-155 deletion we confirmed that 1,25(OH) 2 D 3 suppresses inflammation and stimulates SOCS1 by down-regulating miR-155. Mechanistically 1,25(OH) 2 D 3 down-regulates bic transcription by blocking NF-κB activation, which is mediated by a κB cis -DNA element identified within the first intron of the bic gene. At the molecular level, we demonstrated that VDR inhibits NF-κB activation by directly interacting with IKKβ protein. Our studies identified a novel mechanism whereby VDR signaling attenuates TLR-mediated inflammation by enhancing the negative feedback regulation. This article is part of a Special Issue entitled ‘16th Vitamin D Workshop’. [ABSTRACT FROM AUTHOR]

Abstract: Background: Asthma is thought to result from the generation of T helper type 2 (Th2) responses, leading to bronchial inflammation. IFN-λ1 (also known as IL-29) is a recently described member of the IFN-λ family and has been shown to decrease production of Th2 cytokines in vitro. However, the role and mechanism of IFN-λ1 in asthma remain unknown. Objectives: The aim of this study was to clarify the importance of IFN-λ1 in allergen-induced airway hyperresponsiveness (AHR) and inflammation. Methods: We used a murine model for ovalbumin (OVA)-induced asthma to examine the effect of intranasal delivery of recombinant adenovirus expressing human IFN-λ1 (Ad-hIFN-λ1) on AHR and allergic airway inflammation. Results: Intranasal instillation of Ad-hIFN-λ1 before airway antigen challenge in OVA-immunized mice significantly decreased the severity of AHR and numbers of eosinophils and levels of IL-4, IL-5, and IL-13, but not IL-10 and IFN-γ; both in vivo, in the bronchoalveolar lavage fluid and in vitro, following stimulation of lymphocytes from spleens with OVA, compared with administration of a control virus (Ad-mock). Furthermore, Ad-hIFN-λ1 treatment inhibited serum IgE secretion and increased numbers of splenic CD4+CD25+FOXP3 + Treg cells. Histological studies showed that Ad-hIFN-λ1 attenuated OVA-induced lung tissue eosinophilia. Conclusions: These results demonstrate that delivery of the Ad-hIFN-λ1 can mitigate allergic airway inflammation in experimental asthma. The potent immunoregulatory action of IFN-λ1 may offer a novel therapeutic approach to treat allergic asthma. [Copyright &y& Elsevier]

Abstract: Objective: Inflammation is now considered a main pathogenic factor in coronary atherosclerotic heart disease (CHD), and it has a positive correlation with plaque vulnerability. A novel anti-inflammatory factor, milk fat globule-epidermal growth factor 8 (MFG-E8), has been reported as having prominent anti-inflammatory effects in sepsis. However, few studies have reported on the association between MFG-E8 and CHD. In the present study, we aimed to investigate the serum MFG-E8 concentrations in patients with different stages of CHD or without CHD. Then, we studied the associations among MFG-E8, Gensini score, and high-sensitivity C-reactive protein (hs-CRP) in Chinese patients with CHD to illustrate the role of MFG-E8 in CHD. Methods: A total of 176 controls and 295 patients with CHD were selected for this study. To evaluate CHD severity, we calculated the Gensini score for all of the subjects. Serum levels of MFG-E8 were determined by an enzyme-linked immunosorbent assay (ELISA) kit; serum total cholesterol (TC), high density lipoprotein-cholesterol (HDL-c), low density lipoprotein-cholesterol (LDL-c), triglyceride (TG), and hs-CRP were detected by an automatic biochemistry analyzer; and fibrinogen (FIB) was analyzed with an automatic coagulation analyzer. Results: Compared with the controls, the CHD group had a lower level of MFG-E8 (673.20 ± 112.34 ng/mL vs. 134.89 ± 4.74 ng/mL, p < 0.001). The level of serum MFG-E8 in the acute myocardial infarction group (118.07 ± 10.10 ng/mL) was significantly less than that in the stable angina group (p = 0.025). Further analysis showed that MFG-E8 had a negative association with the Gensini score and the hs-CRP level (r = −0.590, p < 0.001; r = −0.105, p = 0.022, respectively). In addition, multiple regression analysis of the association between MFG-E8 and the main cardiovascular risk factors in our cases showed that MFG-E8 had a negative association with hs-CRP and a positive association with LDL-c (all p < 0.05). Conclusion: The serum level of MFG-E8 was negatively associated with the severity of coronary artery stenosis and the risk of clinical events. Thus, MFG-E8 has the potential to be a marker of vascular complications. [Copyright &y& Elsevier]

Propofol (Pro) is well known to regulate the asleep-awake-asleep technique. Increasing indication recommends that Pro also has promising properties such as anti-oxidant and anti-inflammation belongings in several disease models. It has been described that Pro has beneficial properties against renal ischemia/reperfusion (rI/R)-mediated acute lung injury (ALI). Nevertheless, pathogenesis underlying the beneficial action of Pro on the remote ALI mediated by rI/R remains unwell unstated. In this research, we displayed that Pro administration remarkably inhibits rI/R-mediated pro-inflammatory cytokines production. Increased levels of oxidative stress were mainly decreased by Pro. Pro administration ameliorated apoptosis-related caspase-3 activation. Furthermore, the levels of crucial necroptosis-associated protein were reduced by Pro. Sirtuin 1 (SIRT1) inhibitor attenuated the aforementioned changes of Pro. In conclusion, these results propose that Pro attenuates rI/R-induced inflammation, oxidative stress, apoptosis, and necroptosis by up-regulation of SIRT1 in rats. Our findings disclose an original pathogenesis underlying the beneficial effect of Pro against rI/R-mediated ALI and reinforce the knowledge that Pro might be a hopeful beneficial agent for the rI/R-mediated ALI. [ABSTRACT FROM AUTHOR]

Ischemia-reperfusion (I/R) injury causes high morbidity, mortality, and healthcare costs. I/R induces acute kidney injury through exacerbating the mitochondrial damage and increasing inflammatory and oxidative responses. Here, we developed the mitochondria-targeted nanocarrier to delivery of Coenzyme Q10 (CoQ10) for renal I/R treatment in animal model. The mitochondria-targeted TPP CoQ10 nanoparticles (T-NP CoQ10) were synthesized through ABC miktoarm polymers method and characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The I/R mouse model and oxygen-glucose deprivation/reperfusion (D/R) model were created to examine the role of T-NP CoQ10 on renal I/R. Mitochondrial DNA damage, apoptosis, and inflammatory cytokines were measured in I/R injury mice. Plasma creatinine, urea nitrogen, tubular injury score was tested to assess the renal function. T-NP CoQ10 nanoparticles could be delivered to renal mitochondria preciously and efficiently. T-NP CoQ10 administration attenuated oxidative injury in both cell and animal models significantly, alleviated mtDNA damage, suppressed inflammatory and apoptotic responses, and improved renal function. The mitochondria specific CoQ10 delivery provided a precious and efficient method for protecting inflammatory and oxidative responses of I/R-induced renal damage. • T-NP CoQ10 could be delivered to renal mitochondria. • T-NP CoQ10 attenuates I/R-induced renal impairments. • T-NP CoQ10 may be strategy for the treatment of I/R-induced renal damage. [ABSTRACT FROM AUTHOR]