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Pain is a common public health problem and remains as an unmet medical need. Currently available analgesics usually have limited efficacy or are accompanied by many adverse side effects. To achieve satisfactory pain relief by multimodal analgesia, new combinations of nefopam and gabapentinoids (pregabalin/gabapentin) were designed and assessed in inflammatory, osteoarthritis and neuropathic pain. Isobolographic analysis was performed to analyze the interactions between nefopam and gabapentinoids in carrageenan-induced inflammatory pain, mono-iodoacetate-induced osteoarthritis pain and paclitaxel-induced peripheral neuropathic pain in mice. The anti-inflammatory effect and motor performance of monotherapy or their combinations were evaluated in the carrageenan-induced inflammatory responses and rotarod test, respectively. Nefopam (1, 3, 5, 10, 30 mg/kg, p.o.), pregabalin (3, 6, 12, 24 mg/kg, p.o.) or gabapentin (25, 50, 75, 100 mg/kg, p.o.) dose-dependently reversed mechanical allodynia in three pain models. Isobolographic analysis indicated that the combinations of nefopam and gabapentinoids exerted synergistic anti-nociceptive effects in inflammatory, osteoarthritis, and neuropathic pain mouse models, as evidenced by the experimental ED 50 (median effective dose) falling below the predicted additive line. Moreover, the combination of nefopam–pregabalin/gabapentin alleviated carrageenan-induced inflammation and edema, and also prevented gabapentinoids-related sedation or ataxia by lowering their effective doses. Collectively, the co-administration of nefopam and gabapentinoids showed synergistic analgesic effects and may result in improved therapeutic benefits for treating pain. [Display omitted] • Our study indicated nefopam exerted significant anti-allodynic effects in osteoarthritis pain model for the first time. • Nefopam and gabapentinoids exerted synergistic anti-nociceptive effects in inflammatory, osteoarthritis and neuropathic pain. • Nefopam–gabapentinoids showed significantly improved anti-inflammatory effects than the equimolar dose of monotherapy. • Nefopam–gabapentinoids can alleviate gabapentinoids-induced sedation or ataxia by lowering their effective doses. [ABSTRACT FROM AUTHOR]

Atrazine is a widely used herbicide in agricultural production. Previous studies have shown that atrazine affects hormone secretion and oocyte maturation in female reproduction. However, the specific mechanism by which atrazine affects ovarian function remains unclear. In this study, using a mouse gastric lavage model, we report that four weeks of atrazine exposure affects body growth, interferes with the estrous cycle, and increases the number of atretic follicles in mice. The expression levels of follicle development related factors StAR, BMP15, and AMH decreased. Metabolomic analysis revealed that atrazine activates an inflammatory response in ovarian tissue. Further studies confirmed that the expression levels of TNF-α, IL-6, and NF-κB increased in the ovaries of mice exposed to atrazine. Additionally, α-smooth muscle actin (α-SMA) accumulated in ovarian tissue, and transforming growth factor-β (TGF-β) signaling was activated, indicating the occurrence of tissue fibrosis. Moreover, mice exposed to atrazine produced fewer oocytes and exhibited reduced embryonic development. Furthermore, mice exposed to atrazine exhibited altered gut microbiota abundance and a disrupted colon barrier. Collectively, these findings suggest that atrazine exposure induces ovarian inflammation and fibrosis, disrupts ovarian homeostasis, and impairs follicle maturation, ultimately reducing oocyte quality. [Display omitted] • Atrazine exposure induces ovary inflammation and fibrosis. • Oocytes and embryo development would be interfered with atrazine exposure. • Loss of intestinal barrier integrity participates in atrazine induced ovary toxicity. [ABSTRACT FROM AUTHOR]

Accumulating evidence suggests that excess fructose uptake induces metabolic syndrome and kidney injury. Here, we primarily investigated the influence of catalpol on fructose-induced renal inflammation in mice and explored its potential mechanism. Treatment with catalpol improved insulin sensitivity and hyperuricemia in fructose-fed mice. Hyperuricemia induced by high-fructose diet was associated with increases in the expressions of urate reabsorptive transporter URAT1 and GLUT9. Treatment with catalpol decreased the expressions of URAT1 and GLUT9. Futhermore, treatment with catalpol ameliorated renal inflammatory cell infiltration and podocyte injury, and these beneficial effects were associated with inhibiting the production of inflammatory cytokines including IL-1β, IL-18, IL-6 and TNF-α. Moreover, fructose-induced uric acid triggers an inflammatory response by activiting NLRP3 inflammasome, which then processes pro-inflammatory cytokines. Treatment with catalpol could inhibit the activation of NLRP3 inflammasome as well. Additionally, TLR4/MyD88 signaling was activated in fructose-fed mice, while treatment with catalpol inhibited this activation along with promoting NF-κB nuclear translocation in fructose-fed mice. Thus, our study demonstrated that catalpol could ameliorate renal inflammation in fructose-fed mice, attributing its beneficial effects to promoting uric acid excretion and inhibit the activation of TLR4/MyD88 signaling. [ABSTRACT FROM AUTHOR]

• A20 expression was decreased in CAD skin tissues and in UVB- irradiated HaCaT cells. • Secretion of cytokines showed similar trends in CAD skin lesions and in UVB irradiated cells. • A20 knock-down or over-expression altered secretion of inflammatory cytokines through the NF-κB pathway. • Since UVB-induced inflammation is associated with A20, which could provide new insight into the discussion of skin inflammation related to CAD. [ABSTRACT FROM AUTHOR]

Safflower is a traditional Chinese medicine used for treating gynaecological diseases. However, its material basis and mechanism of action in the treatment of endometritis induced by incomplete abortion are still unclear. This study aimed to reveal the material basis and mechanism of action of safflower in the treatment of endometritis induced by incomplete abortion through comprehensive methods, including network pharmacology and 16S rDNA sequencing. Network pharmacology and molecular docking methods were used to screen the main active components and potential mechanisms of action of safflower in the treatment of endometritis induced by incomplete abortion in rats. A rat model of endometrial inflammation by incomplete abortion was established. The rats were treated with safflower total flavonoids (STF) based on forecasting results, serum levels of inflammatory cytokines were analysed, and immunohistochemistry, Western blots, and 16S rDNA sequencing were performed to investigate the effects of the active ingredient and the treatment mechanism. The network pharmacology prediction results showed 20 active components with 260 targets in safflower, 1007 targets related to endometritis caused by incomplete abortion, and 114 drug-disease intersecting targets, including TNF, IL6, TP53, AKT1, JUN, VEGFA, CASP3 and other core targets, PI3K/AKT, MAPK and other signalling pathways may be closely related to incomplete abortion leading to endometritis. The animal experiment results showed that STF could significantly repair uterine damage and reduce the amount of bleeding. Compared with the model group, STF significantly down-regulated the levels of pro-inflammatory factors (IL-6, IL-1β, NO, TNF-α) and the expression of JNK, ASK1, Bax, caspase3, and caspase11 proteins. At the same time, the levels of anti-inflammatory factors (TGF-β and PGE2) and the protein expression of ERα, PI3K, AKT, and Bcl2 were up-regulated. Significant differences in the intestinal flora were seen between the normal group and the model group, and the intestinal flora of the rats was closer to the normal group after the administration of STF. The characteristics of STF used in the treatment of endometritis induced by incomplete abortion were multi-targeted and involved multiple pathways. The mechanism may be related to the activation of the ERα/PI3K/AKT signalling pathway by regulating the composition and ratio of the gut microbiota. [Display omitted] [ABSTRACT FROM AUTHOR]

Introduction: microRNAs (miRs) have been shown to play critical roles in the regulation of trophoblast and endothelial cell functions, and one significant finding concerning the miR-15/16 family is that most members of this family are highly expressed in endothelial cells and contribute to functions, such as tube formation. The interaction between trophoblast and endothelial cell play an important role in normal placentation process. Therefore, the aims of this study were to investigate the expression of miR-15b in human placenta and to uncover the potential role of miR-15b as well as its target functional loop in trophoblast and endothelial cells. Whether inflammation could modulate the expression of miR-15b and its down-stream target was further investigated. Additionally, the potential link between miR-15b deregulation and preeclampsia was also explored in the placenta of patients diagnosed with preeclampsia.Methods: The expression of miR-15b was studied in the placental tissue of a normal pregnancy using in situ hybridization, and the effects of miR-15b on proliferation, invasion, and angiogenesis were further explored in vitro using HTR-8/SVneo and HUVEC cell line models. A Lipopolysaccharides (LPS) treatment model in HTR-8/SVneo cell was utilized to explore the mechanism of how LPS treatment could lead to the activation of miR-15b expression. Western blot was used to detect the expression of proteins related to miR-15b mediated pathway in preeclamptic placentas.Results: miR-15b inhibits trophoblast cell invasion and endothelial cell tube formation by suppressing the expression of Argonaute 2 (AGO2), a major miRNA effecter protein. AGO2 is specifically localized to human placenta cytotrophoblast and endothelial cells, and it plays important roles in trophoblast cell invasion and endothelial cell tube formation. LPS treatment may lead to the overexpression of miR-15b and down-regulation of AGO2, which may be involved in shallow trophoblast cell invasion associated with the pathogenesis of preeclampsia. Chromatin immunoprecipitation assay indicates that increased occupancy of AGO2 to miR-15b promoter is responsible for the increased expression of miR-15b under the condition of LPS treatment. Furthermore, preeclamptic placentas have decreased expression of AGO2, but increased expression of miR-15b and TLR-4 compared to normal controls.Discussion: This is the first report about the function of AGO2 in human trophoblast and endothelial cells in the placenta. The data indicates that the aberrant expression of miR-15b contributes to abnormal placentation by targeting AGO2 mRNA. This study provides insight into the potential role of the miR-15b and AGO2 functional loop in the placentation process. [ABSTRACT FROM AUTHOR]

Perivascular adipose tissue (PVAT) has been recognized as an active contributor to vascular function due to its paracrine effects on cells contained within vascular wall. The present study was designed to investigate the effect of diosgenin on adipokine expression in PVAT with emphasis on the regulation of endothelial function. Palmitic acid (PA) stimulation induced inflammation and dysregulation of adipokine expression in PVAT. Diosgenin treatment inhibited IKKβ phosphorylation and downregulated mRNA expressions of proinflammatory cytokines/proteins including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), monocyte chemoattractant protein (MCP-1), and inducible nitric oxide synthase (iNOS), while reduced gene expressions for adiponectin, PPARγ, and arginase 1 (Arg-1) were reversed by diosgenin treatment. Diosgenin enhanced AMPK phosphorylation under basal and inflammatory conditions in PVAT, whereas knockdown of AMPK by SiRNA diminished its modulatory effect, indicating that diosgenin inhibited inflammation in an AMPK-dependent manner. We prepared conditioned medium from PA-stimulated PVAT to induce endothelial dysfunction and found that pre-treatment of PVAT with diosgenin effectively restored the loss of ACh-induced vasodilation and increased eNOS phosphorylation in rat aorta. High-fat diet feeding in rats induced inflammation in PVAT and the impairment of endothelium-dependent vasodilation, whereas these alterations were prevented by oral administration of diosgenin at doses of 20 and 40 mg/kg. In conclusion, the obtained data showed that diosgenin ameliorated inflammation-associated adipokine dysregulation, and thereby prevented endothelial dysfunction. Our findings would shed a novel insight into the potential mechanism by which diosgenin protected endothelial function against inflammatory insult. [ABSTRACT FROM AUTHOR]

Abstract: Background: General population-based investigations have revealed that red blood cell distribution width (RDW) is associated with inflammatory indexes such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Chronic inflammation is one of the major components of many autoimmune diseases and RDW may reflect the severity of these autoimmune diseases as well. Therefore, the objective of this study was to investigate the correlation between RDW and disease activity of systemic lupus erythematosus (SLE). Methods: The medical records of 131 SLE patients were retrospectively analyzed. Correlations between RDW and disease activity or other inflammatory indexes were analyzed. The effect of glucocorticoid treatment for three months on RDW was estimated in 3 newly diagnosed SLE cases. Results: Increased RDW was observed in SLE patients. RDW was positively correlated with serum IgM, CRP, ESR, and SLE Disease Activity Index 2000 (SLEDAI-2K). Glucocorticoid treatment decreased both SLEDAI-2K and RDW. Conclusion: RDW may be a useful index to estimate the disease activity of SLE. [Copyright &y& Elsevier]

Background & Aims: Integrity of the intestinal epithelium is required for nutrition absorption and defense against pathogens. Claudins are cell adhesion molecules that localize at tight junctions (TJs); many are expressed in the intestinal tract, but little is known about their functions. Claudin-7 is unique in that it has a stronger basolateral membrane distribution than other claudins, which localize primarily to apical TJs in the intestinal epithelium. We investigated the basolateral functions of claudin-7 and assessed the effects of disruption of Cldn7 in intestines of mice. Methods: We generated Cldn7 −/− mice and examined their intestines by histology, molecular and cellular biology, and biochemistry approaches. We performed gene silencing experiments in epithelial cell lines using small interfering RNAs (siRNAs). Results: The Cldn7 −/− mice had severe intestinal defects that included mucosal ulcerations, epithelial cell sloughing, and inflammation. Intestines of Cldn7 −/− mice produced significantly higher levels of cytokines, the nuclear factor κB p65 subunit, and cyclooxygenase 2; they also up-regulated expression of matrix metalloproteinases (MMPs)-3 and -7. siRNA in epithelial cell lines showed that the increased expression of MMP-3 resulted directly from claudin-7 depletion, whereas that of MMP-7 resulted from inflammation. Electron microscopy analysis showed that intestines of Cldn7 −/− mice had intercellular gaps below TJs and cell matrix loosening. Deletion of Cldn7 reduced expression and altered localization of the integrin α2 subunit in addition to disrupting formation of complexes of claudin-7, integrin α2, and claudin-1 that normally form in epithelial basolateral compartments of intestines. Conclusions: In mice, claudin-7 has non-TJ functions, including maintenance of epithelial cell–matrix interactions and intestinal homeostasis. [ABSTRACT FROM AUTHOR]

Abstract: Angiogenesis is a pivotal step occurred both in inflammation and cancer development. In the recent years, relationships between inflammation and cancer have received more and more attention. Baicalein, which was isolated from Radix Scutellariae Georgi, has been widely used in inflammation and cancer therapy. Here, we focus on influence of baicalein on angiogenesis induced by inflammatory factor and its mechanism of action. In our present study, we assessed its potential as an anti-angiogenic agent in vivo employing chicken chorioallantoic membrane (CAM) assay and in vitro cell migration assay of human umbilical vein endothelial cells (HUVECs), tube formation assay and rat aortic ring assay which were induced by lipopolysaccharide (LPS). Baicalein inhibited LPS-induced proliferation, migration and tube formation of human umbilical vein endothelial cell (HUVECs) as well as microvessel sprouting from rat aortic rings in vitro and CAM in vivo. Moreover, western blot analysis showed that baicalein affected the level of cell membrane receptor toll-like receptor 4 (TLR4) of HUVECs and resulted in a significant decrease in LPS-triggered TNF receptor associated factor 6 (TRAF6), and phosphorylated forms of extracellular regulated protein kinases (ERK), AKT and p38. These results of our study provide evidences that baicalein possesses anti-angiogenic potential induced by LPS both in vitro and in vivo through TRAF6 mediated TLR4 pathway. [Copyright &y& Elsevier]

Abstract: Objective: Long-term total parenteral nutrition (TPN) in children is often complicated by parental nutrition–associated liver disease and may even lead to liver failure. Recently, the addition of ω-3 fatty acids to TPN has been shown to reduce the risk of parental nutrition–associated liver disease. The purpose of this study was to explore the anti-inflammatory effects of ω-3 fatty acids (eicosapentaenoic acid [EPA]) to demonstrate the protection of the liver against hepatic steatosis and damage. Materials and Methods: Lipopolysaccharide (LPS) and prostaglandin E2 (PGE2) were used to stimulate human macrophages and hepatocytes (THLE-3) to induce in vitro inflammatory condition. The cells were then incubated with either ω-3 (EPA) or ω-6 (arachidonic acid) fatty acids. Supernatants were collected at different time points for the measurement of tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), and interleukin 10 (IL-10) using enzyme-linked immunosorbent assay. Furthermore, pretreated macrophages by LPS stimulation and after incubation with EPA were added to prestimulated hepatocytes for the subsequent measurement of cytokine response. Results: Eicosapentaenoic acid effectively reduced LPS-induced or PGE2-induced TNF-α and IL-6 expression, and increased IL-10 expression significantly when compared with arachidonic acid. Furthermore, supernatant collected after co-culturing EPA with macrophages also suppressed the levels of TNF-α and IL-6 in hepatocytes. This would suggest that EPA not only had an anti-inflammatory effect on macrophages and hepatocytes directly, it could indirectly reduce hepatocyte inflammation through activated macrophages. Conclusions: The addition of ω-3 fatty acids in TPN suppresses the inflammatory response via direct and indirect routes. The findings may help explain the clinical benefits of EPA in pediatric patients receiving long-term TPN. [Copyright &y& Elsevier]

Abstract: Polymorphisms in several genes on the short arm of chromosome 6 (6p), among them, VEGF, FKBP5, HLA-DR and TNF-α, have been associated with inflammation and transplant outcome, such as acute rejection. Independent segregation of these genes is unproven, so we investigated linkage between distant genes on 6p and the putative existence of evolutionarily conserved long-range 6p haplotypes. SNPs studied were VEGF-2578*C/A (rs69947), VEGF-1154*G/A (rs1570360) TNF-α-308*G/A (rs1800629) and FKBP5*C/T (rs1360780) in 206 random and 80 selected HLA-DR52 positive individuals. To simplify the analysis, the HLA-DR genotypes were collapsed to the five human ancestral supertypes, namely: HLA-DR51, DR52, DR53, DR1 and DR8. Gametic phase and linkage between paired genotypes were determined using Arlequin 3.01 software, and significance was determined by Chi-square and Fisher''s exact test analysis. Significant allelic associations were evident across the 6p region examined. Two putative haplotypes were identified, associated with DR52 and DR1. Within the HLA-DR52 supertype, TNF-α −308*A was associated with DR3, while FKBP5*T was associated with DR6. The interval between VEGF and TNF-α is 12.31Mb. Therefore, allelic associations are surprising considering expected recombination and the evolutionary time (c10MY) since divergence of DR supertypes. This suggests that DR1 and DR52 haplotypes may have a survival advantage. Within the DR52 supertype, VEGF*C-DR3-TNF −308*A is a ‘high inflammatory’ haplotype associated with acute and chronic rejection, while the FKBP5*T-DR6 haplotype is associated with resistance to endogenous and exogenous glucocorticoids. Conversely, the DR1 haplotype is a ‘low inflammatory’ haplotype. [Copyright &y& Elsevier]

Objective: To investigate the attenuating effect of curcumin, an anti-inflammatory compound derived from dietary spice turmeric (Curcuma longa) on the pro-inflammatory insulin-resistant state in 3T3-L1 adipocytes. Methods: Glucose uptake rate was determined with the [3H] 2-deoxyglucose uptake method. Expressions of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were measured by quantitative RT-PCR analysis and ELISA. Nuclear transcription factor kappaB p65 (NF-κB p65) and mitogen-activated protein kinase (MAPKs) were detected by Western blot assay. Results: The basal glucose uptake was not altered, and curcumin increased the insulin-stimulated glucose uptake in 3T3-L1 cells. Curcumin suppressed the transcription and secretion of TNF-α and IL-6 induced by palmitate in a concentration-dependent manner. Palmitate induced nuclear translocation of NF-kB. The activities of Jun NH2-terminal kinase (JNK), extracellular signal–regulated kinase1/2 (ERK1/2) and p38MAPK decreased in the presence of curcumin. Moreover, pretreatment with SP600125 (inhibitor of JNK) instead of PD98059 or SB203580 (inhibitor of ERK1/2 or p38MAPK, respectively) decreased the up-regulation of TNF-α induced by palmitate. Conclusion: Curcumin reverses palmitate-induced insulin resistance state in 3T3-L1 adipocytes through the NF-kB and JNK pathway. [Copyright &y& Elsevier]

Macrophages play an important role in maintaining tissue homeostasis, from regulating the inflammatory response to pathogens to resolving inflammation and aiding tissue repair. The surfactant protein A (SP-A) receptor SP-R210 (MYO18A) has been shown to affect basal and inflammatory macrophage states. Specifically, disruption of the longer splice isoform SP-R210 L /MYO18Aα renders macrophages hyper-inflammatory, although the mechanism by which this occurs is not well understood. We asked whether disruption of the L isoform led to the hyper-inflammatory state via alteration of global genomic responses. RNA sequencing analysis of L isoform-deficient macrophages (SP-R210 L (DN)) revealed basal and influenza-induced upregulation of genes associated with inflammatory pathways, such as TLR, RIG-I, NOD, and cytoplasmic DNA signaling, whereas knockout of both SP-R210 isoforms (L and S) only resulted in increased RIG-I and NOD signaling. Chromatin immunoprecipitation sequencing (ChIP-seq) analysis showed increased genome-wide deposition of the pioneer transcription factor PU.1 in SP-R210 L (DN) cells, with increased representation around genes relevant to inflammatory pathways. Additional ChIP-seq analysis of histone H3 methylation marks showed decreases in both repressive H3K9me3 and H3K27me3 marks with a commensurate increase in transcriptionally active (H3K4me3) histone marks in the L isoform deficient macrophages. Influenza A virus (IAV) infection, known to stimulate a wide array of anti-viral responses, caused a differential redistribution of PU.1 binding between proximal promoter and distal sites and decoupling from Toll-like receptor regulated gene promoters in SP-R210 L (DN) cells. These finding suggest that the inflammatory differences seen in SP-R210 L -deficient macrophages are a result of transcriptional differences that are mediated by epigenetic changes brought about by differential expression of the SP-R210 isoforms. This provides an avenue to explore how the signaling pathways downstream of the receptor and the ligands can modulate the macrophage inflammatory response. [ABSTRACT FROM AUTHOR]

[Display omitted] Intervertebral disc degeneration (IVDD) is a common degenerative disease which is closely related to low back pain (LBP) and brings huge economic and social burdens. In this study, we explored the therapeutic effects of Homoplantaginin (Hom) for IVDD due to its convincing anti-inflammatory and antioxidant functions. TNF-α was used to simulate the inflammatory environment for nucleus pulposus (NP) cells in vitro. We verified that Hom could alleviate the TNF-α-induced inflammation and disturbance of ECM homeostasis through blocking the NF-κB/MAPK signaling pathways. Subsequently, we screened the binding targets of Hom and confirmed that Hom could directly bind to TAK1 and inhibit its phosphorylation to down-regulate the inflammation-related pathways. The therapeutic effects of Hom on IVDD were further validated through a needle puncture rat model in vivo. Overall, Hom was a promising small molecule for IVDD early intervention, possessing huge clinical translational value. [ABSTRACT FROM AUTHOR]

WeiChang'An Pill (WCAP) is used in Traditional Chinese Medicine (TCM) to clinically treat diarrhoea-predominant irritable bowel syndrome (IBS-D); however, the underlying pharmacological mechanisms are unclear to date. To explore the mechanism underlying the therapeutic action of WCAP in IBS-D using a network pharmacology approach and in vivo experiments. The active compounds of WCAP were selected from the TCM Systems Pharmacology Database and TCM Integrated Database, and the potential targets were identified using the Swiss Target Prediction and Similarity Ensemble Approach (SEA) databases. The targets related to IBS-D were mined from the Therapeutic Target Database (TTD), National Center for Biotechnology Information Search database (NCBI), DrugBank database, and DisGeNET database. The intersecting protein-protein interactions (PPIs) of the drug-disease crossover genes were analysed, and the central PPI network was constructed using the String database, version 11.0, and Cytoscape version 3.7.2. Following Gene Ontology and Kyoto Encyclopaedia of Genes and Genomes pathway analyses, the gene-pathway network was constructed for identifying the key target genes and pathways. Based on the results and existing evidence, it was selected the cyclic adenosine monophosphate (cAMP) signalling pathway for further validation using in vivo experiments. A total of 872 targets were identified from the 77 active compounds in WCAP, which shared 78 targets that were predicted to be related to IBS-D. Twenty-one core targets were identified from the PPI network, which was constructed from the common targets. The results of enrichment analysis revealed that HRT2B, ADRA1A, ADRA1D, and CHRM2 could be the key targets of WCAP in IBS-D, and 11 signalling pathways, including the neuroactive ligand-receptor interaction, calcium signalling, and cAMP signalling pathways, were identified as crucial for the therapeutic activity of WCAP in IBS-D. We also identified the possibility of several interactions and crosstalk between the different pathways. Subsequent molecular biology experiments revealed that the expression levels of cAMP, phospho-(Ser/Thr) protein kinase A substrates (p -PKA), 5-hydroxytryptamine, and proteins in the cAMP signalling pathway, including G protein-coupled receptor (GPCR), adenylyl cyclase 5 (AC5), and cAMP-response element binding protein (CREB), were significantly upregulated in rat models of IBS-D following treatment with WCAP (P < 0.05). However, a reverse trend was observed in the expression of nuclear factor kappa-B (NF-κB) (P < 0.05), which could be attributed to the low-grade inflammation that occurs in IBS-D. We demonstrated that WCAP may alleviate the symptoms of diarrhoea and visceral sensitivity in IBS-D by regulating the cAMP signalling pathway. [Display omitted] [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) are a distinctive family of ncRNAs, and they function as key regulators in the initiation, development and progression of various diseases. However, the regulatory roles of circRNAs in the tumorigenesis of cervical cancer (CC) have not been fully understood. In this study, we identified a set of circRNAs in CC and paired normal tissues, using RNA sequencing data, and found that the cancer and normal tissues could be told apart by those differentially expressed (DE) circRNAs, indicating that circRNA expression profiles in CC were significantly different from those in the normal tissues. Meanwhile, the upregulated genes in CC were enriched in inflammation-related pathways, and the correlation analysis between the DE circRNAs and genes revealed that the abundance of DE circRNAs was positively related to the expression of their host genes. However, the expression of TGFBR2 and KDM4C were found to exhibit a negative correlation with their corresponding circRNAs. Furthermore, we also predicted the interactions between circRNAs and proteins, and constructed a competing endogenous RNA (ceRNA) network. Specifically, hsa_circ_0001495 was predicted to interact with ESRP2, and acted as a sponge by competing for miRNAs with TBL1XR1. Functionally, hsa_circ_0001495 was predicted to regulate epithelial cell proliferation and NOTCH signaling via ESRP2 and TBL1XR1, respectively. We also evaluated the prognostic values of downstream target genes of selected circRNAs, using clinical records of CC patients. In summary, the present study provided some regulatory circRNAs involved in CC tumorigenesis based on bioinformatics approaches, which brought strong evidences for researchers to further explore their biological and clinical values. • RNA sequencing data are employed to identify the circRNAs in CC and normal tissues. • CCs have significantly different circRNA expression profiles from the normal tissues. • TGFBR2 and KDM4C have negative correlation with their corresponding circRNAs. • Hsa_circ_0001495 is predicted to regulate ESRP2 and TBL1XR1. • Hsa_circ_0080414 may regulate genes involved in the normal function in cervix. [ABSTRACT FROM AUTHOR]

• Chronic airway inflammation induced by cigarette smoke plays an essential role in chronic obstructive pulmonary disease. • MALAT1 plays an essential role in airway inflammation induced by cigarette smoke exposure. • MALAT1 regulates cigarette smoke induced airway inflammation by activating JNK signaling pathway, via sponging miR-30a-5p. Chronic airway inflammation induced by cigarette smoke (CS) plays an essential role in the pathogenesis of chronic obstructive pulmonary disease (COPD). MALAT1 is involved in a variety of inflammatory disorders. However, studies focusing on the interaction between MALAT1 and CS-induced airway inflammation remain unknown. The present study investigated the effects and mechanisms of MALAT1 in CS-induced airway inflammation in the pathogenesis of COPD. RT-qPCR was employed to determine the mRNA levels of MALAT1, miR-30a-5p and inflammatory cytokines. Protein concentrations of IL-1β and IL-6 in cell culture supernatant and mouse bronchoalveolar lavage fluid (BALF) were assessed by ELISA assay kits. Dual-luciferase reporter assay was conducted to verify the interaction between MALAT1 and miR-30a-5p. The protein expression of JNK and p-JNK was determined by western blot (WB). MALAT1 was highly expressed in cigarette smoke extract (CSE)-treated human bronchial epithelial cells (HBECs) and COPD mice lung tissues. Knockdown of MALAT1 significantly alleviate CS-induced inflammatory response. MALAT1 directly interacted with miR-30a-5p and knockdown of miR-30a-5p significantly inhibit the protective effects of MALAT1 silencing after CS exposure. Additionally, our results showed that miR-30a-5p could regulate inflammation via modulating the activation of JNK signaling pathway. Moreover, our results demonstrated MALAT1 could activate JNK signaling pathway by sponging miR-30a-5p. Our results demonstrated MALAT1 promotes CS-induced airway inflammation by inhibiting the activation of JNK signaling pathway via sponging miR-30a-5p. [ABSTRACT FROM AUTHOR]

The schematic summarizes the underlying mechanisms by which ALA-PDT ameliorates acne in mice. ALA-PDT attenuated tissue injury by suppressing ear swelling and chronic inflammation caused by P. acnes infection. ALA-PDT reduced sebocyte proliferation and lipid synthesis by inducing mitochondrial stress and oxidative stress. [Display omitted] • The proliferative activity of Propionibacterium acnes was inhibited by ALA-PDT in vitro. • ALA-PDT significantly ameliorated ear inflammation caused by Propionibacterium acnes in mice. • ALA-PDT inhibited sebocyte proliferation and lipid secretion by inducing oxidative stress in sebocytes. Acne is a chronic inflammatory skin disease with wide-ranging effects, involving factors such as Propionibacterium acnes (P. acnes) infection and sebum hypersecretion. Current acne treatments are challenged by drug resistance. 5-aminolaevulinic acid (ALA) −based photodynamic therapy (PDT) has been widely used in the clinical treatment of acne, however, the mechanism of its action remains to be elucidated. In this study, by constructing a mice ears model of P. acnes infection, we found that ALA-PDT inhibited the proliferation of P. acnes in vivo and in vitro, significantly ameliorated ear swelling, and blocked the chronic inflammatory process. In vitro, ALA-PDT inhibited lipid secretion and regulated the expression of lipid synthesis and metabolism-related genes in SZ95 cells. Further, we found that ALA-PDT led to DNA damage and apoptosis in SZ95 cells by inducing mitochondrial stress and oxidative stress. Altogether, our study demonstrated the great advantages of ALA-PDT for the treatment of acne and revealed that the mechanism may be related to the blockade of chronic inflammation and the suppression of lipid secretion by ALA-PDT. [ABSTRACT FROM AUTHOR]

• C. acnes triggered cell inflammatory cytokines release, reduced antioxidant activity. • C. acnes increased the expression of PPARγ, Nrf2, HO-1, NQO1, NLRP3, and caspase-1. • Syringic acid effectively improved ear inflammation in living C. acnes -induced mice model group. • Syringic acid inhibited C. acnes -induced inflammation through PPARγ/Nrf2-antioxidant pathway. • Syringic acid inhibited C. acnes -induced inflammation via the NLRP3/caspase-1/IL-1β signaling. Our previous studies have demonstrated a strong relationship between Cutibacterium acnes (C. acnes), oxidative stress, and acne inflammation. Syringic acid (SA) is a plant widely used for its antimicrobial, anti-inflammatory, and antioxidant activities, but lacking data on acne. This study aims to investigate the effect and mechanism of SA on acne inflammation induced by C. acnes in vitro and in vivo. After using the SA to expose HaCaT keratinocytes, we reevaluated the effect of the SA on cell viability, cell apoptosis, ROS, CAT, SOD, and other inflammatory variables in the heat-killed C. acnes -treated HaCaT cells. Next, to induce mice with acne inflammation, ICR mice were given an intradermal injection of live C. acnes into their right ears. The effect of SA on this inflammation was then examined. Moreover, we explored the mechanism of SA on PPARγ/Nrf2 and NLRP3/caspase-1/IL-1β pathways by ELISA, immunofluorescence microscopy, and western blot assay. Heat-killed C. acnes triggered remarkable cell apoptosis, ROS production, interleukin (IL)-1β, IL-18, IL-6, and TNF-α release, reduced SOD and CAT activity, and upregulated the expression of proteins in HaCaT cells, including up-regulating IL-1β, PPARγ, Nrf2, HO-1, NQO1, NLRP3, and caspase-1, whereas SA inhibited these effects by partially impairing PPARγ activation. In addition, PPARγ silencing decreased C. acnes -induced IL-1β secretion and the production of intracellular ROS, down-regulating the expression of Nrf2. Nrf2 activator (SFN) enhanced anti-inflammatory activity through antioxidant mechanisms, boosting intracellular ROS production, reducing SOD and CAT activity, and promoting the increase in ROS, HO-1, NQO1, and IL-1β levels, while PPARγ inhibitor (GW662) effectively inhibited this effect in heat-killed C. acnes -treated cells. Finally, SA also exhibited notable improvements in ear redness, swelling, and the expression of PPARγ, NLRP3, and IL-1β in vivo. SA inhibited C. acnes -induced inflammation via regulating the NLRP3/caspase-1/IL-1β signaling axis by activating the PPARγ/Nrf2-antioxidant pathway, suggesting a new treatment possibility for acne vulgaris. [ABSTRACT FROM AUTHOR]

Although endoscopy is the gold standard to assess disease activity and infliximab efficacy in inflammatory bowel disease (IBD), the invasive, costly, and time-consuming procedure limits its routine applications. We aimed to investigate the clinical value of serum oncostatin M (OSM) as a surrogate biomarker. Fifty healthy controls, 34 non-IBD patients, and 189 IBD patients who were pre-infliximab treatment (n = 122) or in infliximab maintenance (n = 67) were enrolled. A chemiluminescence immunoassay (CLIA) was constructed to quantify serum OSM concentrations. Receiver operator characteristic (ROC) curve analysis was used to evaluate the performance of blood biomarkers for IBD management. The methodology of CLIA exhibited great analytical performance with a wide linear range of 31.25–25000 pg/mL, a low detection limit of 23.2 pg/mL, acceptable precision, and applicable accuracy. Patients with IBD (121.5 [43.3–249.4] pg/mL, p < 0.001) and non-IBD (72.4 [51.4–129.6] pg/mL, p = 0.005) had higher serum OSM levels than healthy controls (35.8 [23.2–56.4] pg/mL). In the analysis of clinical and endoscopic activity, serum OSM levels were elevated in moderate and severe patients compared to those in remission. IBD patients without mucosal healing had higher serum OSM levels than those with mucosal healing (AUC = 0.843). Besides, serum OSM levels were increased in clinical non-responders (287.3 [127.9–438] pg/mL) compared to responders (24.1 [23.2–53.4] pg/mL, p < 0.001), and showed great recognition ability with an AUC of 0.898. The newly developed methodology of CLIA had great potential for use in the clinic. Elevated serum OSM expression was a promising biomarker of severe disease and infliximab non-response in IBD patients. [ABSTRACT FROM AUTHOR]

Abstract: Rhizoma Chuanxiong is widely used as folk medicine to treat the diseases caused by oxidative stress and inflammation. To delineate the underlying molecular mechanisms, we recently found that Rhizoma Chuanxiong extract significantly induced heme oxygenase-1 (HO-1), an enzyme that degrades intracellular heme into three bioactive products: biliverdin, carbon monoxide and free iron. The anti-inflammatory, antiapoptotic and antiproliferative actions of these products highlight HO-1 as a key endogenous antioxidant and cytoprotective gene. This study was designed to further characterize HO-1 induction of Rhizoma Chuanxiong through bioactivity-guided fractionation. All isolated fractions were assayed for HO-1 induction in human HepG2 cell line at mRNA and protein levels. Based on chromatographic profiling, nuclear magnetic resonance (NMR) and mass spectrometric analysis, the active compounds were identified as senkyunolide-H and its stereoisomer senkyunolide-I. Both senkyunolide isomers inhibited the formation of reactive oxygen species and lipid peroxidation and enhanced the cellular resistance to hydrogen peroxide-induced oxidative damage. Notably, heme oxygenase inhibitor tin protoporphyrin IX (SnPP) significantly suppressed the antioxidant activity of senkyunolide stereoisomers. Thus, this study demonstrated that senkyunolide-H and -I attenuated oxidative damage via activation of HO-1 pathway. [Copyright &y& Elsevier]

• Dexmedetomidine has a protective effect on AA rat models. • Invasion, migration, and inflammation of RA-FLSs are inhibited by dexmedetomidine. • DEX can reduce the expression of NLRC5 in RA-FLSs and AA rat models. • NLRC5-RNAi inhibits inflammation, invasion and migration of RA-FLSs. Rheumatoid arthritis (RA) is a chronic, autoimmune disease characterized by inflammatory synovitis, but its pathogenesis remains unclear. NLRC5 is a newly discovered member of the NLR family that is effective in regulating autoimmunity, inflammatory responses, and cell death processes. Dexmedetomidine (DEX) has been reported to have a variety of pharmacological effects, including anti-inflammatory and analgesic effects. However, the role of DEX in RA has not been explored. In adjuvant-induced arthritis (AA) rat models, DEX (10 μg/kg and 20 μg/kg) reduced the pathological score, the arthritis score, paw swelling volume, and the serum levels of IL-1β, IL-6, IL-17A, and TNF-α. Moreover, by using Western blot and real-time quantitative PCR (RT-qPCR), it was demonstrated that DEX can inhibit the expression of IL-1β, IL-6, MMP-3, MMP-9 and P-P65 in the synovial tissue of AA rats. In human rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs), DEX (250 nM and 500 nM) was found to inhibit the expression of IL-1β, IL-6, MMP-3, MMP-9, and P-P65 following stimulation with TNF-α. Moreover, DEX can inhibit the invasion and migration of RA-FLSs stimulated by TNF-α. Finally, the expression of NLRC5 in RA-FLSs and AA rat models was also reduced by DEX. After silencing NLRC5 in RA-FLSs, the expression of IL-1β, IL-6, MMP-3, MMP-9, and P-P65, as well as the invasion and migration of cells, were significantly reduced. These results indicate that DEX inhibits the invasion, migration, and inflammation of RA-FLSs by reducing the expression of NLRC5 and inhibiting the NF-κB activation. [ABSTRACT FROM AUTHOR]

Qing Gan Zi Shen Decoction (QGZS) is a traditional Chinese formula. It has been extensively used for decades in the treatment of hypertension combined with metabolic diseases, but its cardioprotective effects and underlying mechanisms are poorly understood. To explore the cardioprotective effects and potential mechanisms of QGZS in an animal model of obese hypertension. In this study, spontaneously hypertensive rats (SHRs) were utilized as an animal model to examine the effects of a high-fat diet and two concentrations of QGZS. Echocardiography, hematoxylin eosin (H&E) staining, and wheat germ agglutinin (WGA) staining were employed to assess the cardiac structure and function of the SHRs throughout a 16-week therapy period. Furthermore, Western blotting (WB) and immunofluorescence (IF) were employed to identify the levels of Nrf2 expression in the mitochondria, cytoplasm, and nucleus of the myocardium. Additionally, transmission electron microscopy and enzyme-linked immunosorbent assay (ELISA) were utilized to measure mitochondrial morphology and pro-inflammatory cytokine levels, respectively. Furthermore, Western blotting (WB), immunohistochemistry (IHC), and immunofluorescence (IF) techniques were employed to quantify the levels of marker proteins associated with myocardial fibrosis, cardiac inflammation, oxidative stress, and mitochondrial dysfunction. QGZS inhibited weight gain and depressed systolic and mean arterial pressures in high-fat-fed SHRs. Echocardiographic results demonstrated that QGZS prevented the increase in left ventricular mass, restricted the growth of left ventricular diameter, and improved ejection fraction (EF), fractional shortening (FS), and the ratio of early diastolic peak velocity of transmitral flow (E) to late diastolic peak velocity (A) in high-fat-fed SHRs. This suggested that QGZS prevented ventricular remodeling and protected cardiac systolic and diastolic functions. H&E and WGA staining showed that QGZS improved cardiomyocyte disorders and restricted cardiomyocyte hypertrophy. The underlying mechanisms, QGZS attenuated the oxidative stress state, including reducing the generation of reactive oxygen species (ROS) in the myocardium, revitalizing the antioxidant enzyme system, and protecting mitochondrial function. Moreover, QGZS alleviated the pro-inflammatory state in high-fat-fed SHRs. What's more, QGZS significantly increased the expression level of Nrf2 in nuclei and mitochondria in rat heart tissues, exerting a proximate Nrf2 agonist effect. QGZS exerted cardioprotective effects, in part due to its increasing expression of Nrf2 protein in the heart, which promoted Nrf2 nuclear expression. [Display omitted] • In high-fat-induced obese SHRs, Qing Gan Zi Shen reversed ventricular remodeling and protected cardiac function. • In high-fat-induced obese SHRs, Qing Gan Zi Shen alleviated ventricular remodeling and myocardial fibrosis. • QGZS actived Nrf2 to play a role in reducing cardiac inflammation, inhibiting cardiac oxidative stress, and protecting mitochondrial function. [ABSTRACT FROM AUTHOR]

Abstract Fine particulate matter (PM 2.5) exposure could cause many acute and chronic respiratory diseases. In this study the protective effects of polysaccharide from Morchella esculenta (FMP-1) and its derivatives against PM 2.5 -induced inflammation were evaluated. By flow cytometry and ELISA analysis, sulfated polysaccharide SFMP-1 showed the best protective effect in reducing PM 2.5 -induced cell death, cell apoptosis and production of tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β), which was accompanied by a diminished level in reactive oxygen species (ROS) formation caused by PM 2.5 in rat alveolar macrophage NR8383 cells. Furthermore, the mechanism was studied by immunofluorescence, qRT-PCR and western blotting. SFMP-1 could down-regulate the expression of inducible NO synthesis (iNOS) and cyclooxygenase-2 (COX-2) at both mRNA and protein levels in PM 2.5 -treated cells. The PM 2.5 -induced phosphorylation of nuclear factor-kappa B (NF-κB) was also reduced through suppressing nuclear translation of the NF-κB and inhibiting the degradation and phosphorylation of IκBα. These results indicated that SFMP-1 could protect NR8383 cells from PM 2.5 -induced inflammation by inhibiting NF-κB activation. Highlights • Polysaccharide from Morchella esculenta (FMP-1) was chemically modified to obtain sulfated and carboxymethylated derivatives. • Protection of FMP-1 and its derivatives against PM 2.5 -induced inflammation were comparatively investigated. • Sulfated polysaccharide SFMP-1 showed the best protective effect in PM 2.5 -treated alveolar macrophage NR8383 cells. • SFMP-1 could protect NR8383 cells from PM 2.5 -induced inflammation by inhibiting NF-κB activation. [ABSTRACT FROM AUTHOR]

[Display omitted] • Cigarette smoke can significantly induced inflammation and apoptosis in vivo and vitro. • Our results proved the protective effects of TAX against cigarette smoke induced inflammation and apoptosis in COPD. Chronic obstructive pulmonary disease (COPD) is a significant cause of morbidity and mortality worldwide and is characterized by chronic airway inflammation and lung parenchymal cell apoptosis. Cigarette smoke is the major risk factor for the occurrence and development of COPD. Taxifolin (TAX) showed promising pharmacological effects in the management of inflammation, oxidative stress, and apoptosis. In the present study, our results demonstrated that TAX significantly alleviated cigarette smoke-induced inflammation and apoptosis both in vivo and in vitro. TAX notably lowered the elevated total cell count in mouse BALF compared with that in the COPD group. The cigarette smoke-induced emphysematous changes were remarkably reversed by TAX. In addition, treatment with TAX suppressed the elevated mRNA and protein levels of IL-1β, IL-6 and TNF-α in COPD mouse lung tissue and cigarette smoke extract (CSE)-treated human bronchial epithelial cells (HBECs). Additionally, TAX significantly decreased the ratios of p-iκB to iκB and p-p65 to p65 compared with the COPD group and CSE-treated HBECs. Moreover, the results of the TUNEL assay and flow cytometry also demonstrated the anti-apoptotic effect of TAX in mouse lung tissue and HBECs. Furthermore, the elevated Bax and CCP3 levels and decreased Bcl-2 levels induced by cigarette smoke were significantly reversed by TAX treatment in vivo and in vitro. Our results highlight the ameliorating effects of TAX against cigarette smoke-induced inflammation and apoptosis in the pathogenesis of COPD. [ABSTRACT FROM AUTHOR]

• Airway inflammation plays an essential role in the occurrence and progress of COPD. • LncRNA colon cancer-associated transcript 1 (CCAT1) plays well-defined roles in the inflammatory progression. • In cigarette smoke induced airway inflammation, CCAT1 functions as a pro-inflammatory factor by activating ERK signal pathway via sponging miR–152–3p. Emerging studies have noted that dysregulated long non-coding RNAs (lncRNAs) are implicated in the pathological processes of chronic obstructive pulmonary disease (COPD). LncRNA colon cancer-associated transcript 1 (CCAT1) plays well-defined roles in the inflammatory progression. The study aims to figure out the effect and regulatory mechanism of CCAT1 in the cigarette smoke induced inflammation in COPD. The results showed that CCAT1 was highly expressed in lung tissues of smokers with COPD compared with never-smokers without COPD. In human bronchial epithelial (HBE) cells, cigarette smoke extract (CSE) treatment led to an increase in CCAT1 expression in a dose- and time- dependent manner. Functional experiments showed that knockdown of CCAT1 ameliorated CSE-induced inflammation. Mechanistically, CCAT1 directly targeted miR-152-3p, and miR-152-3p overexpression reversed the pro-inflammatory effects of CCAT1 on HBE cells. Subsequently, miR-152-3p was found to regulate ERK signaling pathway. PD98059, an ERK specific inhibitor, reversed miR-152-3p knockdown mediated inflammation in HBE cells. In addition, CCAT1 acted as a sponge for miR-152-3p to positively regulate ERK signaling pathway. Overall, current findings suggest that CCAT1 promoted inflammation by activating ERK signal pathway via sponging miR–152–3p in CSE–treated HBE cells. These results may provide a novel therapeutic target for alleviating cigarette smoke mediated airway inflammation. [ABSTRACT FROM AUTHOR]

EBERs (EBER1 and EBER2) are suggested to be involved in cellular transformation and tumor growth. Cytoplasmic pattern recognition receptor-RIG-I, which is characterized by the recognition of viral dsRNAs, could efficiently trigger the downstream pathways of innate immunity. Although some previous reports have shown that EBERs and RIG-I associate with hematological malignancies, the role of EBERs-RIG-I signaling in solid tumors remains to be clarified. Here we demonstrate that EBER mediation of the inflammatory response via RIG-I contributes to NPC development in vitro and in vivo. We first verified that the expression level of RIG-I was associated with EBER transcription in a dose-dependent manner in NPC cells and specimens from NPC patients. Furthermore, pro-inflammatory cytokine transcription and release were sharply reduced after RIG-I knockdown compared with the control shRNA group in the presence of EBERs, accompanied by an attenuation of the NF-κB and MAPK signaling pathways. Consequently, the tumor burden was greatly alleviated in the RIG-I knockdown group in a xenograft model. In addition, macrophage colony-stimulating factor (M-CSF) and monocyte chemoattractant protein (MCP-1), which promote the maturation and attraction of tumor-associated macrophages, were stimulated upon the introduction of EBERs, and this upregulation conceivably led to the tumor-promoting subset transition of the macrophages. Taken together, our results reveal that EBERs could promote NPC progression through RIG-I-mediated cancer-related inflammation. [ABSTRACT FROM AUTHOR]

Abstract: Ethnopharmacological relevance: Ginkgo biloba extract (EGb 761) is widely used to treat cerebral disorders. Clinical trials have demonstrated therapeutic benefits of EGb 761 in various vascular diseases. Because the potential pathophysiological mechanisms appear similar to those involved in aneurysmal degeneration, we postulated that EGb 761 might affect the development and progression of experimental abdominal aortic aneurysm (AAA). This study was aimed to investigate whether EGb 761 influences the development of experimental AAAs, and to explore the underlying mechanisms. Material and methods: C57/BL6 mice underwent abluminal application of CaCl2 to the abdominal aorta followed by gavages with either 200mg/kg EGb 761 per day or vehicle. Six weeks after AAA induction, aortic tissue was excised for further examinations. Results: EGb 761 treatment reduced the aneurysm size compared with vehicle-treated controls. EGb 761 had no effect on hemodynamics or macrophage infiltration in the aortic wall. However, nuclear factor κB protein levels were decreased in the aortas of EGb 761 treated animals. The increased ROS production, SOD and CAT activities, and mRNA expression of p47phox nicotinamide adenine dinucleotide phosphate oxidase were attenuated by EGb 761 treatment. Moreover, administration of EGb 761 preserved the destruction of the wavy morphology of the elastin during AAA formation. Zymographic activity of matrix metalloproteinase (MMP)-9 and MMP-2 was lowered in EGb 761 treated mice. Conclusions: These results suggest that treatment with EGb 761 in mice prevented the development of CaCl2-induced AAA. The possible mechanisms include decreased oxidative damage and inflammation, preservation of aortic wall architecture, and altered MMPs activities. [Copyright &y& Elsevier]

Abstract: Isoforskolin was isolated from Coleus forskohlii native to Yunnan in China. We hypothesize that isoforskolin pretreatment attenuates acute lung injury induced by lipopolysaccharide (endotoxin). Three acute lung injury models were used: situ perfused rat lung, rat and mouse models of endotoxic shock. Additionally, lipopolysaccharide stimulated proinflammatory cytokine production was evaluated in human mononuclear leukocyte. In situ perfused rat lungs, pre-perfusion with isoforskolin (100, and 200μM) and dexamethasone (65μM, positive control) inhibited lipopolysaccharide (10 mg/L) induced increases in lung neutrophil adhesion rate, myeloperoxidase activity, lung weight Wet/Dry ratio, permeability-surface area product value, and tumor necrosis factor (TNF)-α levels. In rats, pretreatments with isoforskolin (5, 10, and 20 mg/kg, i.p.) and dexamethasone (5mg/kg, i.p.) markedly reduced lipopolysaccharide (6mg/kg i.v.) induced increases of karyocyte, neutrophil counts and protein content in bronchoalveolar lavage fluid, and plasma myeloperoxidase activity. Lung histopathology showed that morphologic changes induced by lipopolysaccharide were less pronounced in the isoforskolin and dexamethasone pretreated rats. In mice, 5 mg/kg isoforskolin and dexamethasone caused 100% and 80% survival, respectively, after administration of lipopolysaccharide (62.5mg/kg, i.v., 40% survival if untreated). In human mononuclear leukocyte, isoforskolin (50, 100, and 200μM) and dexamethasone (10μM) pre-incubation lowered lipopolysaccharide (2μg/mL) induced secretion of the cytokine TNF-α, and interleukins (IL)-1β, IL-6, and IL-8. In conclusion, pretreatment with isoforskolin attenuates lipopolysaccharide-induced acute lung injury in several models, and it is involved in down-regulation of inflammatory responses and proinflammatory cytokines TNF-α, IL-1β, IL-6, and IL-8. [Copyright &y& Elsevier]

Nigella glandulifera Freyn et Sint. (N. glandulifera) seeds are widely used in traditional Uyghur medicine for a variety of immuno-inflammatory diseases. The total saponins from N. glandulifera seeds (TSNGS) have been shown to have analgesic, antioxidant, and anti-inflammatory effects that can alleviate joint pain and swelling. Rheumatoid arthritis (RA) is a chronic and progressive, debilitating autoimmune disease for which current treatments are not sufficiently effective and result in unsatisfactory side effects. This study aimed to mechanistically investigate the therapeutic effects of TSNGS on RA. Qualitative analysis of TSNGS was performed using ultra-high-performance liquid chromatography-Q-Orbitrap-high-resolution mass spectrometry. Rats with collagen-induced arthritis (CIA), IL-1β-induced HFLS-RAs, and VEGF-induced HUVECs were analyzed to determine the efficacy and mechanism of TSNGS on RA. Twenty-one compounds were identified in TSNGS. TSNGS (10, 50, or 250 mg/kg) reduced the severity of arthritis, indicated by a lower arthritis score, reduced paw swelling, and body weight in rats with CIA. TSNGS ameliorated histopathological changes involving inflammatory infiltration, bone degeneration, and angiogenesis in knee and ankle joints. TSNGS improved the immuno-inflammatory response by restoring the levels of the cytokines IFN-γ, TNF-α, IL-1β, IL-6, IL-17A, IL-4, and IL-10, and increasing the number of CD4+CD25+ Tregs in the peripheral circulation and Foxp3 levels in knee joints in rats with CIA. Furthermore, TSNGS increased the OPG/RANKL ratio and downregulated p-p65 in serum and joint synovia. Inhibition of angiogenesis by TSNGS was associated with recovery of the angiogenesis-related Ang/Tie-2 signaling pathway. It was established that TSNGS provides a therapeutic effect on RA by alleviating synovitis, bone degeneration, and angiogenesis via the OPG/RANKL/NF-κB and Ang/Tie-2 pathways and may be used for the treatment of RA. [Display omitted] • TSNGS may have potential as a novel treatment for RA. • TSNGS decreased the severity of arthritis in rats with CIA. • TSNGS reduced synovitis associated with RA via OPG/RANKL/NF-κB pathway. • TSNGS alleviated angiogenesis related to RA via Ang/Tie-2 signaling. • TSNGS upregulated the level of CD4+CD25+ Tregs and Foxp3 in rats with CIA. [ABSTRACT FROM AUTHOR]

Peroxisome proliferator-activated receptors (PPAR) decrease the production of cytokine and inducible nitric-oxide synthase (iNOS) expression, which are associated with aging-related inflammation and insulin resistance. Recently, the involvement of the induction of hemeoxygenase-1 (HO-1) in regulating inflammation has been suggested, but the exact mechanisms for reducing inflammation by HO-1 remains unclear, We found that overexpression of HO-1 and [Ru(CO)3Cl2]2, a carbon monoxide (CO)-releasing compound, increased not only ERK5 kinase activity, but also its transcriptional activity measured by luciferase assay with the transfection of the Gal4-ERK5 reporter gene. This transcriptional activity is required for coactivation of PPARδ by ERK5 in C2C12 cells. [Ru(CO)3Cl2]2 activated PPARδ transcriptional activity via the MEK5/ERK5 signaling pathway. The inhibition of NF-κB activity by ERK5 activation was reversed by a dominant negative form of PPARδ suggesting that ERK5/PPAR6 activation is required for the anti-inflammatory effects of CO and HO-1. Based on these data, we propose a new mechanism by which CO and HO-1 mediate anti-inflammatory effects via activating ERK5/PPARδ, and ERK5 mediates CO and HO-1-induced PPARδ activation via its interaction with PPARδ. [ABSTRACT FROM AUTHOR]

• This is the first study to investigate whether pirfenidone could mediate cigarette smoke extract (CSE) induced inflammation and oxidative stress in vitro and in vivo. • Our study reveals the potential role of pirfenidone in regulating inflammatory response and oxidative stress induced by CSE. Antioxidant and anti-inflammatory effects are two main pharmacological mechanisms of pirfenidone (PFD) besides the anti-fibrotic effect. This study aims to investigate whether PFD could mediate cigarette smoke extract (CSE) induced inflammation and oxidative stress in vitro and in vivo. BALB/C mice and alveolar epithelial (A549) cells treated with CSE were established as disease models in vivo and in vitro. Effects of PFD treatment on disease models were further measured. Hematoxylin and eosin (HE) staining was used to evaluate the pathological changes in lung tissues of mice. CCK-8 assay kit was applied to measure the viability of A549 cells treated by different concentrations of PFD. Inflammation cytokine expression in cell supernatants was measured with ELISA kits. The mRNA and protein levels of inflammation and oxidative stress-related factors were determined by real-time quantitative polymerase chain reaction analysis (RT-qPCR) and Western blotting. Furthermore, myeloperoxidase (MPO), malondialdehyde (MDA), and total antioxidant capacity (T-AOC) were measured to detect the antioxidative activity of lung tissues. Moreover, an assay kit with fluorescent probe 2′,7′-dichlorofluorescin diacetate (DCFH-DA) was used to evaluate the intracellular reactive oxygen species (ROS) generation. In vitro and in vivo, PFD significantly reversed TNF-α, IL-6, CCL2, SOD1, and CAT mRNA level changes led by CSE; in addition, PFD significantly decreased the ratios of p-p65 to p65, p-ikBα to ikBα and increased Nrf-2 protein level compared with CSE group. In mice, high-dose (100 mg/kg/d) PFD significantly reversed MPO and MDA increases induced by CSE. However, PFD didn't significantly reverse T-AOC decrease induced by CSE. In A549 cell supernatant, PFD dramatically reversed the elevated levels of TNF-α and IL-1β induced by CSE. Furthermore, PFD could significantly reverse the increased level of ROS induced by CSE in A549 cells. Our study reveals the potential role of PFD in regulating inflammatory response and oxidative stress induced by CSE. [ABSTRACT FROM AUTHOR]

[Display omitted] • DEX promotes inflammation resolving. • DEX increases the protein levels of TGF-β1. • DEX up-regulates the CD11b+F4/80+Ly6G+ population ratio. • DEX enhances resolution of inflammation via TGF-β1. Dexmedetomidine (DEX) is a highly selective α2-adrenoceptor agonist, which can regulate inflammatory responses. However, whether DEX interferes with the inflammation resolving remains unclear. Here, we reported the effects of DEX on zymosan-induced generalized inflammation in mice during resolution. Mice were administered intraperitoneally with DEX after the initiation of sepsis. The resolution interval (Ri), a vital resolution indice, decreased from twelve hours to eight hours after the administration of DEX. The induction of peritoneal pro-inflammatory interleukin [IL] - 1β and tumour necrosis factor-α (TNF-α) appeared to be inhibited. Of interest, the anti-inflammatory transforming growth factor-β1 (TGF-β1) but not IL-10 levels were up-regulated at twenty-four hours in the DEX group along with 1.0 mg/mice zymosan A (ZyA) treatment. The expression levels of multiple genes related to protective immune processes and clearance functions were detected and revealed the same trends. DEX markedly increased the F4/80+Ly6G+ macrophage population. Additionally, the adequate apoptotic neutrophil clearance from injury after DEX installation could be reverse by opsonization or co-instillation of TGF-β1 neutralizing antibody in vivo, promoting the inflammation-resolution programs. In conclusion, DEX post-treatment, via the increase of F4/80+Ly6G+ macrophages, provokes further secretion of TGF-β1, leading to the attenuated cytokine storm and accelerated inflammation resolving. [ABSTRACT FROM AUTHOR]

Recent studies have revealed that calorie restriction is able to modulate immune system and aid in intervention of immune disorders. Inflammatory bowel disease (IBD) is an immune disease in the intestine caused by interplay between genetic susceptibility and environmental factors such as diets. Here we analyzed the therapeutic effect of intermittent calorie restriction with a fasting-mimicking diet (FMD) on dextran sodium sulfate (DSS)-induced chronic IBD model in mice. Two cycles of FMD was administered after IBD symptoms occurred in the mice. FMD administration significantly reduced the score of disease activity index. FMD reversed DSS-mediated shortening of colon length, infiltration of lymphocytes in the crypt of colon, and accumulation of CD4+ cells in the colon and small intestine. The expression of an inflammation marker NLRP3 was also reduced by FMD administration. The percentage of CD4+ T cells in both peripheral blood and spleen was also reduced by FMD. In addition, FMD application reversed DSS-mediated reduction in intestinal stem cell marker Lgr5, while the cell proliferation markers Ki67 and PCNA were increased by FMD. Taken together, these results indicate that in the mouse model of IBD, application of the FMD can effectively ameliorate the symptoms and pathogenesis of IBD through reducing the inflammation of intestine and promoting the regeneration and repair of the damaged intestinal epithelium. [ABSTRACT FROM AUTHOR]

• Use of immunomodulatory drugs may increase risk of SARS-CoV-2 infection • Summary of guidelines for managing chronic inflammatory disease in the pandemic • Despite limited data, tofacitinib use in RA, PsA and UC in the pandemic is assessed • Tofacitinib's benefit:risk profile during the pandemic requires further research • Careful management of patients on immunomodulatory drugs is warranted Concerns have been raised that the risk of severe acute respiratory syndrome coronavirus 2 infection, or more severe or critical coronavirus disease 2019 (COVID-19), may be higher in immunocompromised individuals receiving immunomodulatory therapies compared with immunocompetent individuals. Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, and polyarticular course juvenile idiopathic arthritis. To date, data on tofacitinib treatment during the COVID-19 pandemic are limited. To summarize current understanding of the use of tofacitinib in adults during the COVID-19 pandemic, and discuss research questions that are yet to be addressed, to further inform the safe and effective use of tofacitinib in clinical practice. We conducted a review of the literature (as of February 2021), to summarize the expert recommendations for the management of rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis in the context of COVID-19, and to assess the current data regarding the use of tofacitinib in adult patients during the pandemic. Current recommendations for rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis state that tofacitinib treatment should be continued during the pandemic, except in cases of positive or presumed severe acute respiratory syndrome coronavirus 2 infection. However, limited data are available; analyses of data from international rheumatology and gastroenterology registries have suggested that tofacitinib may not be associated with an increased risk of hospitalization or treatment switching in adults with COVID-19. Further assessment of tofacitinib use in patients with rheumatoid arthritis, psoriatic arthritis, or ulcerative colitis will be required to elucidate and establish the benefit:risk profile of tofacitinib during the current COVID-19 pandemic. [ABSTRACT FROM AUTHOR]

Dietary interventions such as fasting have been proved to be effective in the prevention of metabolic and autoimmune diseases as well as aging-related conditions. The complicated interaction between nutrition and immunity has drawn wide attention in recent years. In this study, we investigated the therapeutic effect of intermittent caloric restriction on autoimmune encephalomyelitis (EAE), a model of multiple sclerosis, in mice. EAE was induced by immunization of C57BL/6 mice with myelin oligodendrocyte glycoprotein 35-55 peptide. After the EAE symptoms became obvious at the 4th week post-immunization, the mice were administered with a modified fasting-mimicking diet (FMD) at 1/3 cal of control for 3 days, followed by ad libitum with normal chow for 4 days. A total of two cycles of FMD was applied. Compared with the mice without receiving caloric restriction, the mice using FMD had significant decreases in EAE severity, immune cell infiltration in spinal cord and CNS demyelination. FMD administration also reversed EAE-mediated CNS accumulation of total CD4+ T cells and in particular, IFN-γ-producing CD4+ T cells. Moreover, FMD application elevated the cell proliferation rate in CNS and enhanced expression of brain-derived neurotrophic factor (BDNF) and remyelination markers. In conclusion, our results indicate that intermittent caloric restriction using the modified FMD was effective in the treatment of EAE through ameliorating inflammatory response and promoting recovery of the damaged tissue. [ABSTRACT FROM AUTHOR]

• Chronic cold stress activated microglia in the hippocampus of mice. • GABA mediated the activation of microglia. • The NLRP3 inflammasome and NF-κB pathways involved the activation of microglia. Chronic cold stress has long-term dramatic effects on the animal immune and neuroendocrine systems. As one of the important regions of the brain, the hippocampus is the main region involved in response to stressors. Nevertheless, the impact to the hippocampus following cold exposure and the underlying mechanism involved are not clear. To evaluate the response of the hippocampus during chronic cold stress, male C57BL/6 mice were exposed to 4 °C, 3 h per day for 1 week, after which neuroinflammation and the molecular and signaling pathways in the hippocampus response to cold stress were investigated. To confirm the potential mechanism, BV2 cells were treated with γ-aminobutyric acid (GABA) and BAY 11-7082 and MCC950, then the activation of microglia and key proteins involved in the regulation of inflammation were measured. We demonstrated that chronic cold stress induced the activation of microglia, the emergence of neuroinflammation, and the impairment of neurons in the hippocampus, which might be the result of GABA-mediated activation of nod-like receptor protein 3 (NLRP3) inflammasome and the nuclear factor kappa B (NF-κB) signaling pathway. [ABSTRACT FROM AUTHOR]

Sjögren's syndrome (SS) is an autoimmune disease and can cause gastrointestinal disorders such as constipation and intestinal inflammation. As a kind of medicinal material, Paeonia lactiflora Pall has a variety of pharmacological effects, and it is also an indispensable component in many pharmaceutical preparations, which has been widely concerned by the medical and pharmaceutical circles. Total glucosides of paeony (TGP) is a mixture of biologically active compounds extracted from the root of Paeonia lactiflora Pall and has therapeutic effects on a variety of autoimmune diseases. To investigate the therapeutic effect of TGP on constipation and intestinal inflammation in mice modeled by SS, and to provide a basis for clinical research. The SS model was set up by submandibular gland (SMG) immune induction method and then treated with TGP for 24 weeks. The fecal characteristics were observed and the fecal number and moisture content were measured. Colonic pathology was observed by H&E staining. The levels of serum P substance (SP), vasoactive intestinal peptide (VIP), interleukin (IL)-1β, tumor necrosis factor (TNF)-α, nuclear factor (NF)-κB, nitric oxide (NO), and nitric oxide synthase (NOS) were determined by enzyme linked immunosorbent assay (ELISA) and microplate method, respectively. Reverse transcription polymerase chain reaction (RT-PCR) was employed to analyze the mRNA expression of c-kit and stem cell factor (SCF) in colon. Compared with the model group, the dry and rough condition of the feces was improved, and the fecal gloss, number and moisture content significantly increased after the administration of TGP capsules. Meanwhile, TGP treatment improved colonic pathological damage, inhibited the serum concentrations of NO, NOS, IL-1β, TNF-α, NF-κB and SP, increased serum VIP concentration, and up-regulated mRNA expression of SCF and c-kit in colon. TGP could obviously attenuate SS-mediated constipation and intestinal inflammation in mice by acting on some intestinal motility related factors and inflammatory factors. Image 1 [ABSTRACT FROM AUTHOR]

• An UHPLC-QTOF MS method was developed for global identification of Callicarpa nudiflora. • 96 compounds were characterized in the C. nudiflora. • 26 compounds were quantified in 34 batches of C. nudiflora. • Compound-target-disease network of C. nudiflora was constructed based on reverse docking. • 16 compounds were found as potential anti-inflammation ingredients of C. nudiflora. Callicarpa nudiflora, belonging to the family Verbenaceae, is widely used to treat inflammation caused by bacterial infection.However, the underlying active substances of C. nudiflora against inflammation remains obscure. In this work, an ultra high-performance liquid chromatography (UHPLC) coupled with quadrupole time-of-flight mass spectrometry method was developed to characterize the ingredients in C. nudiflora , and a validated UHPLC coupled with triple quadrupole tandem mass spectrometry method was applied to quantify major components. As a result, a total of 96 chemical compounds were identified in C. nudiflora , and 26 compounds of them were further quantified in 34 batches of C. nudiflora. Based on the identified components from C. nudiflora , a compound-target network for the anti-inflammation effect was constructed by reverse docking target prediction, disease associated genes screening in DisGeNET and the protein-protein interaction from STRING. The compound-target network showed that C. nudiflora might exert anti-inflammation effect on the target of complement 3 and 5 in the pathway of cells and molecules involved in local acute inflammatory response, and 16 effective candidate compounds were found such as catalpol, acteoside, rutin, etc. This study provided an opportunity to deepen the understanding of the chemical composition and the potential anti-inflammatory mechanism of C. nudiflora. [ABSTRACT FROM AUTHOR]

Previous studies have shown that FXR is involved in glycolipid metabolism, tissue inflammation and regeneration in organs such as the liver, intestines and kidneys. Although FXR has been reported in cardiac tissue, its function in diabetic cardiomyopathy has not been reported. Here, we successfully constructed a diabetic mouse model of FXR-/- and evaluated the effects of FXR knockout on cardiac function in mice by measuring various indicators. We demonstrated that blood glucose levels in diabetic mice are significantly elevated in the case of FXR knockout. Our findings from cardiac ultrasound and tissue HE staining supported that FXR knockout aggravates diabetic cardiomyopathy. Masson staining of myocardial tissue and quantitative detection of α-SMA by qPCR suggest that FXR knockout exacerbates cardiac fibrosis in diabetic cardiomyopathy. Combined with the results of Oil Red staining and quantitative detection of triglycerides in fresh tissue blocks, we hypothesized that FXR knockout aggravates diabetes-induced cardiac lipid accumulation. Altogether our results revealed a role of the FXR in the diabetic cardiomyopathy, suggesting a possible novel target for the treatment of diabetic cardiomyopathy. [ABSTRACT FROM AUTHOR]