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Chronic wounds seriously affect the quality of life of the elderly, obese people, and diabetic patients. The excessive inflammatory response is a key driver of delayed chronic wound healing. Although lavender essential oil (EO [lav]) has been proven to have anti‐inflammatory and accelerate wound curative effects, the specific molecular mechanism involved is still ambiguous. The results showed that the wounds treated with lipopolysaccharide (LPS) not only had delayed healing, but also the expression levels of pro‐inflammatory cytokines, such as tumor necrosis factor‐α (TNF‐α), interleukin‐6 (IL‐6), interleukin‐1β (IL‐1β), and the inflammatory mediator protein, high‐mobility group box 1 protein (HMGB‐1), in the wound tissues were significantly increased. However, treatment of LPS‐induced chronic wounds with EO (lav) accelerated wound healing and decreased IL‐1β and HMGB‐1 expression levels. It was further found that LPS induced macrophage pyroptosis to produce IL‐1β. After treatment with EO (lav), the expression level of macrophage pyroptosis marker Gasdermin D (GSDMD) and pyroptosis‐related cytotoxic effects were significantly reduced. Immunofluorescence results also directly indicate that EO (lav) can protect macrophages from LPS‐induced pyroptosis. Moreover, EO (lav) can down‐regulate expression levels of IL‐1β, GSDMD, and nucleotide‐binding oligomerization domain‐like receptor protein 3 (NLRP3) in the caspase‐11‐related pyroptotic signaling pathway. This study demonstrates that EO (lav) can reduce proinflammatory factor production and ameliorate inflammatory response by inhibiting macrophage pyroptosis, which accelerates LPS‐induced chronic wound healing. [ABSTRACT FROM AUTHOR]

Acute lung injury (ALI) is accompanied by overactivation of multiple pro‐inflammatory factors. Cytochrome P450 1A1 (CYP1A1) has been shown to aggravate lung injury in response to hyperoxia. However, the relationship between CYP1A1 and lipopolysaccharide (LPS)‐induced ALI is unknown. In this study, CYP1A1 was shown to be upregulated in mouse lung in response to LPS. Using CYP1A1‐deficient (CYP1A1−/−) mice, we found that CYP1A1 knockout enhanced LPS‐induced ALI, as evidenced by increased TNF‐α, IL‐1β, IL‐6, and nitric oxide in lung; these effects were mediated by overactivation of NF‐κB and iNOS. Furthermore, we found that aspartate aminotransferase, lactate dehydrogenase, creatine kinase, and creatinine levels were elevated in serum of LPS‐induced CYP1A1−/− mice. Altogether, these data provide novel insights into the involvement of CYP1A1 in LPS‐induced lung injury. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the ability of new injury severity score (NISS), acute physiology and chronic health evaluation II (APACHE II), Glasgow coma scale (GCS), a combination of NISS and GCS, a combination of APACHE II and GCS, a combination of NISS and APACHE II to predict all-cause mortality of patients with severe trauma in mainland China. Methods: This was a multicenter observational cohort study conducted in the ICU of the Chonggang General Hospital, Daping Hospital of the Army Medical University and Affiliated Hospital of Zunyi Medical College from January 2012 to August 2016. The score of NISS, APACHE II, GCS, a combination of NISS and GCS, a combination of APACHE II and GCS, a combination of NISS and APACHE II were calculated based on data from the first 24 hours of ICU admission. Data were processed with Student's t-test, chi-square test, and receiver operating characteristic (ROC) curve of six scoring systems. Calibration was assessed with the Hosmer-Lemeshow test. The primary endpoint was death from any cause during ICU stay. Results: A total of 852 and 238 patients with severe trauma were assigned to the derivation group and validation group, respectively. Area under the ROC curve (AUC) was 0.826 [95% confidence interval (CI)=0.794-0.855)] for NISS, 0.802 (95% CI=0.768-0.832) for APACHE II, 0.808 (95% CI=0.774-0.838) for NGCS, 0.859 (95% CI=0.829 -0.886) for NISS+NGCS, 0.864 (95% CI=0.835-0.890) for APACHE II +NGCS, 0.896 (95% CI=0.869-0.929) for NISS+APACHE II in the derivation cohort. Similarly, the score of NISS+APACHE II was also better than the other five scores in the validation cohort (AUC=0.782; 95% CI=0.725-0.833) and had a good calibration (P=0.41). Conclusions: Taking into account anatomical and physiological parameters completely, the combination of NISS and APACHE II performs better than NISS, APACHE II , NGCS, NISS+NGCS, APACHE II +NGCS for predicting mortality in ICU severe trauma patients. It is needful to develop models that contain various types of accessible predictors (demographic variables, injury cause/mechanism, physiological and anatomical variables, etc.) as comprehensive as possible. [ABSTRACT FROM AUTHOR]

Objective: To estimate the incidence and related risk factors of sepsis between road traffic injuries (RTIs) and non-RTIs. Methods: Clinical data of 339 patients with severe trauma who were admitted into ICU in both Third Affiliated Hospital of Army Military Medical University and ChongGang General Hospital from January 2012 to December 2015 were retrospectively analyzed. Twenty items of potential risk factors affecting sepsis were evaluated by univariate and multivariate Logistic Analysis with the purpose of drawing a comparison between RTI patients and non-RTI patients. Results: There were 154 cases of RTI and 185 cases of non-RTI entering the study period. The significant independent risk factor of sepsis in RTIs was SOFA 11 (OR=4.821; 95% CI=1.901-12.226; P=0.001). The significant independent risk factors of sepsis in non-RTIs were SOFA 11 (OR=12.410; 95% CI=2.559-60.185; P=0.002), tracheal intubation (OR=8.913; 95% CI=2.322-34.206; P=0.001), APACHE II 15 (OR=3.684; 95% CI=1.750-7.753; P=0.001). Conclusions: The clinical medical personnel should not give equal treatment to RTI patients and non-RTI patients admitted in ICU in that factors predicting sepsis within above two groups are different. The sample volume should be increased and validated in further prospective research. [ABSTRACT FROM AUTHOR]

Sepsis, the leading cause of mortality in intensive care unit, is characterized by hyperinflammatory response in the early stage and followed by a period of immunosuppression. This immune disorder is believed to be the potent factor that is tightly associated with high mortality in sepsis. Dendritic cells (DCs) serve as professional antigen-presenting cells that play a vital role in immune response by activating T lymphocytes. During the progression of sepsis, DCs have been reported to take part in the aberrant immune response and be necessary for survival. Therefore, a better understanding of the DCs pathology will be undoubtedly beneficial for resolving the problems occurring in sepsis. This review discusses effects of sepsis on DCs number and function, including surface molecules expression, cytokines secretion, and T cell activation, and the underlying mechanism as well as some potential therapeutic strategies. [ABSTRACT FROM AUTHOR]

Small ubiquitin-like modifier (SUMO) proteins regulate many important eukaryotic cellular processes through reversible covalent conjugation to target proteins. In addition to its many well-known biological consequences, like subcellular translocation of protein, subnuclear structure formation, and modulation of transcriptional activity, we show here that SUMO-2 also plays a role in mRNA translation. SUMO-2 promoted formation of the active eukaryotic initiation factor 4F (eIF4F) complex by enhancing interaction between Eukaryotic Initiation Factor 4E (eIF4E) and Eukaryotic Initiation Factor 4G (eIF4G), and induced translation of a subset of proteins, such as cyclinD1 and c-myc, which essential for cell proliferation and apoptosis. As expected, overexpression of SUMO-2 can partially cancel out the disrupting effect of 4EGI-1, a small molecule inhibitor of eIF4E/eIF4G interaction, on formation of the eIF4F complex, translation of the cap-dependent protein, cell proliferation and apoptosis. On the other hand, SUMO-2 knockdown via shRNA partially impaired cap-dependent translation and cell proliferation and promoted apoptosis. These results collectively suggest that SUMO-2 conjugation plays a crucial regulatory role in protein synthesis. Thus, this report might contribute to the basic understanding of mammalian protein translation and sheds some new light on the role of SUMO in this process. [ABSTRACT FROM AUTHOR]

Objective: Immune cells are key mediators of secondary damage following spinal cord injury (SCI), and dendritic cell (DC)-based vaccines have received considerable interest for treatment of SCI. We previously showed that vaccination with DCs pulsed with homogenate proteins of the spinal cord (hpDCs) promotes functional recovery from SCI in mice. However, the underlying molecular mechanisms remain unclear. Here, changes of neurotrophins, cytokines and T cells at the site of SCI in mice after vaccination with hpDCs were investigated and correlatedwith recovery from SCI. Methods: hpDCs, DCs (control) or PBS (control) were injected intraperitoneally into injured mouse spinal cords. Functional recovery of the spinal cord was measured weekly using the Basso Mouse Scale (BMS) and confirmed by histological and immunohistochemical analysis. Brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), interleukin-4 (IL-4) and interferon-γ(IFN-γ) levels in T cell culture supernatants and spinal cord tissues were determined by ELISA. Results: Eighty-four days after immunization, the BMS score of the hpDCs group (6.92 ± 0.20) was significantly higher than those of the DCs and PBS groups (p < 0.01). Meanwhile, the injury area and number of cysts in the hpDCs group decreased significantly compared with control groups. BDNF, NT-3, IL-4 and IFN-γ levels at the injured site as well as BDNF and NT-3 levels in the supernatant of cultured T cells from the hpDCs group were significantly higher than in control groups (p < 0.05). Conclusion: These results reveal that vaccination with hpDCs can promote SCI repair potentially by upregulat- ing BDNF, NT-3, IL-4 and IFN-γ at the injury site. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular complications, especially myocardial infarctions (MIs), are the leading mortality cause in diabetic patients. The transplantation of stem cells into damaged hearts has had considerable success as a treatment for MI, although whether antidiabetic drugs affect the therapeutic efficacy of stem cell transplantation is still unknown. This study aims to understand whether and how metformin, one of the first-line drugs used to treat type 2 diabetes mellitus (T2DM), induces mesenchymal stromal cell (MSC) apoptosis and dampens their cardioprotective effect after transplantation into infarcted hearts. Methods: A mouse MI model was generated via permanent ligation of the left anterior descending (LAD) coronary artery. MSCs with or without metformin treatment were transplanted after MI in diabetic mice. Echocardiography was used to assess cardiac function and determine cardiac remodeling, and TTC staining was performed to evaluate infarction size. A mouse gavage model was performed to evaluate bone marrow MSCs for flow cytometry assay. Results: Metformin dampened MSC therapeutic efficacy, which increased infarct size and restricted functional cardiac recovery. Specifically, metformin induced the activation of AMP-activated protein kinase (AMPK)-mediated apoptosis through the inhibition of S6K1-Bad-Bcl-xL cell survival signaling, resulting in the upregulated expression of apoptosis-associated proteins and increased MSC apoptosis. Accordingly, counteracting AMPK attenuated metformin-induced apoptosis in MSCs and partially restored their cardioprotective effects in diabetic mice with MI. Furthermore, a decrease in peripheral blood MSCs was found in patients with T2DM who had a metformin medication history. Conclusions: Our results highlight an unexpected adverse effect of metformin-induced MSC apoptosis through AMPK-mediated mTOR suppression, which is attenuated by an AMPK inhibitor. Moreover, AMPK inhibition may be a novel strategy for enhancing the effectiveness of stem cell therapy after MI in diabetes. [ABSTRACT FROM AUTHOR]

Abstract: The present study was performed to clarify the effects of high mobility group box-1 protein (HMGB1), a recently described late-acting pro-inflammatory cytokine, on apoptosis of macrophages. Treatment with HMGB1 (0.01, 0.1, 1, 10μg/ml for 24h, or 10μg/ml for 6, 12, 24, 48h) resulted in a dose- and time-dependent induction of apoptosis in mice macrophages, peaked at 24h after 10μg/ml HMGB1 stimulation. HMGB1 treatment enhanced the receptor for advanced glycation endproducts (RAGE) expression and caspase-3 activation in macrophages. Blockage of RAGE and caspase-3 activation could significantly reduce apoptosis of macrophages induced by HMGB1. The activity of NF-κB/p65 in macrophages was decreased after HMGB1 treatment. These results suggested that HMGB1-induced apoptosis of macrophages in a dose- and time-dependent manner. RAGE, together with caspase-3 activation and inhibition of NF-κB signaling pathways, might be involved in the pathogenesis of macrophage apoptosis induced by HMGB1. [Copyright &y& Elsevier]

The transforming growth factor-β (TGF-β) signaling pathway promotes tissue fibrosis and scarring through SMAD (small mothers against decapentaplegic)-dependent and SMAD-independent mechanisms. However, inhibition of SMAD-mediated signal transduction alone induces an excessive inflammatory response that impairs the antifibrotic effects of TGF-β inhibitors. In this study, we designed and characterized a dual-functional transcription activator protein 1 (AP-1) and SMAD decoy oligodeoxynucleotide, antifibrosis oligodeoxynucleotide 4 (AFODN4) in vitro and in vivo. AFODN4 binds directly to recombinant AP-1 and SMAD with high affinity. AFODN4 significantly inhibited the DNA-binding and transcriptional activities of both AP-1 and SMAD, as well as the production of fibrotic mediators stimulated by TGF-β1 or TGF-β2 in L929 murine fibroblasts. Local administration of AFODN4 significantly inhibited fibrosis associated with acute dermal wounds in mice. Intriguingly, AFODN4 inhibited AP-1-mediated production of proinflammatory mediators, which can be caused by blockage of SMAD alone in vitro and in vivo. Collectively, these findings suggest that dual inhibition of SMAD and AP-1 signaling by AFODN4 is a useful strategy for the development of new antifibrotic agents. [ABSTRACT FROM AUTHOR]

Nuclear factor-κB (NF-κB) is a central regulator of immune response and a potential target for developing anti-inflammatory agents. Mechanistic studies suggest that compounds that directly inhibit NF-κB DNA binding may block inflammation and the associated tissue damage. Thus, we attempted to discover peptides that could interfere with NF-κB signaling based on a highly conserved DNA-binding domain found in all NF-κB members. One such small peptide, designated as anti-inflammatory peptide-6 (AIP6), was characterized in the current study. AIP6 directly interacted with p65 and displayed an intrinsic cell-penetrating property. This peptide demonstrated significant anti-inflammatory effects in vitro and in vivo. In vitro, AIP6 inhibited the DNA-binding and transcriptional activities of the p65 NF-κB subunit as well as the production of inflammatory mediators in macrophages upon stimulation. Local administration of AIP6 significantly inhibited inflammation induced by zymosan in mice. Collectively, our results suggest that AIP6 is a promising lead peptide for the development of specific NF-κB inhibitors as potential anti-inflammatory agents. [ABSTRACT FROM AUTHOR]

• A positive feedback loop existed between NGP and TLR4 in response to multiple bacterial infection or LPS stimulation. • NGP played a critical role in the anti-inflammatory response by targeting the NF-κB signaling pathway and IL-10 secretion. • Endogenous NGP elevated IL-10 expression but exogenous NGP was not elevated. • NGP may be a novel anti-infectious agent by enhancing macrophage phagocytosis. Neutrophilic granule protein (NGP) belongs to the cystatin superfamily. Even though this superfamily is critically involved in cancer biology and adaptive immunity, the relationship of macrophage NGP to inflammation and phagocytosis remains poorly understood. In this study, we observed a significant increase of NGP in peritoneal macrophages (PMs) isolated from mice challenged with E. coli or lipopolysaccharide (LPS), as judged by NGP mRNA microarray. We also found changes in NGP to be mainly Toll-like receptor 4 (TLR4)-dependent. By western blot and electrophoretic mobility shift assay, we demonstrated NGP overexpression to reduce TNF-α and IL-1β production by LPS-induced RAW264.7 cells (RAW) via suppression of the NF-κB (p65 and p50) signalling pathway, rather than the JNK1/AP-1 (fos and jun) signalling pathway. NGP overexpression by LPS-induced RAW also induced IL-10, an anti-inflammatory cytokine, which was partially involved in the anti-inflammatory effect produced by NGP overexpression. Moreover, upregulated NGP enhanced the phagocytosis of E. coli by RAW. Taken together, these results demonstrated NGP to be an important host defense component that regulates inflammatory responses and phagocytosis by activated macrophages. As such, NGP may be useful for the treatment of inflammatory based disease. [ABSTRACT FROM AUTHOR]

• CYP1A1 is a monooxygenase involved in lipid mediators. • IL-4-STAT6-CYP1A1-STAT6 is a novel positive feedback controls M2 polarization. • CYP1A1 has opposing macrophage polarization functions during M1/M2 shift. • Specific regulation of CYP1A1 in inflammation may be a potential treatment. The polarization of macrophages is critical to inflammation and tissue repair, with unbalanced macrophage polarization associated with critical dysfunctions of the immune system. Cytochrome P450 1A1 (CYP1A1) is a hydroxylase mainly controlled by the inflammation-limiting aryl hydrocarbon receptor (AhR), which plays a critical role in mycoplasma infection, oxidative stress injury, and cancer. Arginase-1 (Arg-1) is a surrogate for polarized alternative macrophages and is important to the production of nitric oxide (NO) by the modulation of arginine. In the present study, we found CYP1A1 to be upregulated in IL-4-stimulated mouse peritoneal macrophages (PMs) and human peripheral blood monocytes. Using CYP1A1-overexpressing RAW264.7 cells (CYP1A1/RAW) we found that CYP1A1 augmented Arg-1 expression by strengthening the activation of the JAK1/STAT6 signaling pathway in macrophages treated with IL-4. 15(S)-HETE, a metabolite of CYP1A1 hydroxylase, was elevated in IL-4-induced CYP1A1/RAW cells. Further, in macrophages, the loss-of-CYP1A1-hydroxylase activity was associated with reduced IL-4-induced Arg-1 expression due to impaired 15(S)-HETE generation. Of importance, CYP1A1 overexpressing macrophages reduced the inflammation associated with LPS-induced peritonitis. Taken together, these findings identified a novel signaling axis, CYP1A1-15(S)-HETE-JAK1-STAT6, that may be a promising target for the proper maintenance of macrophage polarization and may also be a means by which to treat immune-related disease due to macrophage dysfunction. [ABSTRACT FROM AUTHOR]