The underlying mechanisms of wound healing are complex but inflammation is one of the determining factors. Besides its traditional role in combating against infection upon injury, the characteristics ...and magnitude of inflammation have dramatic impacts on the pathogenesis of scar. Keloids and hypertrophic scars are pathological scars that result from aberrant wound healing. They are characterized by continuous local inflammation and excessive collagen deposition. In this review, we aim at discussing how dysregulated inflammation contributes to the pathogenesis of scar formation. Immune cells, soluble inflammatory mediators, and the related intracellular signal transduction pathways are our three subtopics encompassing the events occurring in inflammation associated with scar formation. In the end, we enumerate the current and potential medicines and therapeutics for suppressing inflammation and limiting progression to scar. Understanding the initiation, progression, and resolution of inflammation will provide insights into the mechanisms of scar formation and is useful for developing effective treatments.
At steady state, the NOD-like receptor (NLR)-containing pyrin domain (PYD) (NLRP)1 inflammasome is maintained in an auto-inhibitory complex by dipeptidyl peptidases 8 and 9 (DPP8 and DPP9) and is ...activated by pathogen-encoded proteases after infection. Here, we showed that the open reading frame (ORF)45 protein of the Kaposi's sarcoma-associated herpesvirus activated the human NLRP1 (hNLRP1) inflammasome in a non-protease-dependent manner, and we additionally showed that the Linker1 region of hNLRP1, situated between the PYD and NACHT domains, was required for the auto-inhibition and non-protease-dependent activation of hNLRP1. At steady state, the interaction between Linker1 and the UPA subdomain silenced the activation of hNLRP1 in auto-inhibitory complexes either containing DPP9 or not in a manner independent of DPP9. ORF45 binding to Linker1 displaced UPA from the Linker1-UPA complex and induced the release of the C-terminal domain of hNLRP1 for inflammasome assembly. The ORF45-dependent activation of the NLRP1 inflammasome was conserved in primates but was not observed for murine NLRP1b inflammasomes.
RSK1, a downstream kinase of the MAPK pathway, has been shown to regulate multiple cellular processes and is essential for lytic replication of a variety of viruses, including Kaposi's ...sarcoma-associated herpesvirus (KSHV). Besides phosphorylation, it is not known whether other post-translational modifications play an important role in regulating RSK1 function. We demonstrate that RSK1 undergoes robust SUMOylation during KSHV lytic replication at lysine residues K110, K335, and K421. SUMO modification does not alter RSK1 activation and kinase activity upon KSHV ORF45 co-expression, but affects RSK1 downstream substrate phosphorylation. Compared to wild-type RSK1, the overall phosphorylation level of RxRxxS*/T* motif is significantly declined in RSK1K110/335/421R expressing cells. Specifically, SUMOylation deficient RSK1 cannot efficiently phosphorylate eIF4B. Sequence analysis showed that eIF4B has one SUMO-interacting motif (SIM) between the amino acid position 166 and 170 (166IRVDV170), which mediates the association between eIF4B and RSK1 through SUMO-SIM interaction. These results indicate that SUMOylation regulates the phosphorylation of RSK1 downstream substrates, which is required for efficient KSHV lytic replication.
Neuroinflammation has been implicated in hypertension, and microglia have been proposed to play an important role in the progression of this disease. Here, we have studied whether microglia are ...activated within cardiovascular regulatory area(s) of the brain during hypertension, especially in high blood pressure that is associated with chronic activation of the renin-angiotensin-system. In addition, we determined whether prorenin, an essential component of the renin-angiotensin-system, exerts direct pro-inflammatory effects on these microglia. Our data indicate that two rodent models which display neurogenic hypertension and over activation of the renin-angiotensin-system in the brain (sRA mice and spontaneously hypertensive rats) exhibit microglial activation, and increased levels of pro-inflammatory cytokines, in the paraventricular nucleus of the hypothalamus, an area crucial for regulation of sympathetic outflow. Further, the renin-angiotensin-system component prorenin elicits direct activation of hypothalamic microglia in culture and induction of pro-inflammatory mechanisms in these cells, effects that involve prorenin receptor-induced NFκB activation. In addition, the prorenin-elicited increases in cytokine expression were fully abolished by microglial inhibitor minocycline, and were potentiated by pre-treatment of cells with angiotensin II. Taken together with our previous data which indicate that pro-inflammatory processes in the paraventricular nucleus are involved in the hypertensive action of renin-angiotensin-system, the novel discovery that prorenin exerts direct stimulatory effects on microglial activation and pro-inflammatory cytokine production provides support for the idea that renin-angiotensin-system -induced neurogenic hypertension is not restricted to actions of angiotensin II alone.
Hypertension ranks the most common risk factor for cardiovascular diseases, and it affects almost one third of adult population globally. Emerging evidence indicates that immune activation is highly ...involved in the entire progress of hypertension and end organ damage. In addition to immunity, autonomic nervous system, particularly sympathetic nervous system, is one of the most conserved systems to maintain body homeostasis. Immune and sympathetic activities are found simultaneously increased in hypertension, suggesting a synergistic action of these two systems in the progression of this disease. Microglia, the primary immune cells in the central nervous system, have been suggested in the regulation of sympathetic outflow; depletion of microglia alters neuroinflammation and pressor responses in hypertensive models. In this review, we firstly updated the current understanding on microglial ontogeny and functions in both steady state and diseases. Then we reviewed on the interaction between autonomic nervous system and peripheral immunity in hypertension. Microglia bridge the central and peripheral inflammation via regulating the sympathetic nerve activity in hypertension. Future exploration of the molecular linkage of this pathway may provide novel therapeutic angel for hypertension and related cardiovascular diseases.
This paper systematically investigates the effect of artificial aging (AA), solution (SHT), and T6-like (solution followed by artificial aging (SHA)) heat treatments on the microstructural evolution ...and mechanical properties of selective laser melted TiN/AlSi10Mg composites. Results show that the microstructure and mechanical properties reveal inconspicuous changes after AA where the eutectic fibrous Si networks remain. However, SHT vanishes the Si networks, precipitates and coarsens Si particles, and eventually softens the Al matrix, leading to a significant decrease in tensile strength and hardness of heat-treated composites and an increase in ductility. The addition of TiN nanoparticles plays a significant role in microstructural evolution during heat treatment. By increasing solution temperature from 460 °C to 540 °C, Mg2Si phase precipitates out of the Al matrix, followed by AlFeSi intermetallic at 500 °C and AlSiTi intermetallic at 540 °C, respectively. Interestingly, unexpected enhancements of hardness (from 91.5 ± 2.3 HV to 105.9 ± 2.1 HV) and tensile strength (from 268.7 ± 2.5 MPa to 336.8 ± 1.5 MPa) are achieved as the solution temperature increases. This abnormal phenomenon is attributed to the precipitation hardening by the Mg2Si precipitate and needle-like intermetallics, which overcomes the effects of microstructural coarsening and matrix softening. This paper sheds light on how the mechanical properties of as-built TiN/AlSi10Mg composites can be tailored using different heat treatment techniques.
•TiN/AlSi10Mg composites are fabricated by SLM and then heat treated.•The AlFeSi and AlSiTi intermetallics are formed at different solution temperatures.•The unexpected increase of hardness and strength is attributed to precipitate hardening.•The mechanical properties are found to be highly microstructural-dependent.
•The proposed method adopts the sparse-decomposition-based polynomial chaos expansion.•The proposed method can improve efficiency for the propagation of parameterized p-box.•The proposed method can ...provide sufficient accuracy for general engineering problems.
Uncertainty propagation (UP) is the process of determining the effect of input uncertainties on a response of interest. These input uncertainties may be characterized as either aleatory uncertainties, which are irreducible variabilities inherent in nature, or epistemic uncertainties, which are reducible uncertainties resulting from a lack of knowledge. In this paper we propose an efficient uncertainty propagation analysis method for problems with parameterized probability-boxes (P-boxes) accounting for aleatory and epistemic uncertainties. Firstly, the sparse-decomposition-based polynomial chaos expansion (PCE) method is presented to tackle the aleatory uncertainty, in which a basis selection strategy based on the sparse decomposition is devised to automatically detect the significant basis set of PCE. Then, to deal with the epistemic uncertainty on the distribution parameters, the coefficients of the sparse-decomposition-based PCE are treated as quadratic polynomial functions of the interval-valued distribution parameters of parameterized p-boxes. Finally, the bounds of the first four moments and the cumulative distribution function (CDF) of the response function can be successfully obtained. Four numerical examples are analyzed to verify the effectiveness of the proposed method.
RSK1, an essential cellular kinase for Kaposi's sarcoma-associated herpesvirus (KSHV) replication, is highly phosphorylated and SUMOylated during KSHV lytic cycle, which determine the substrate ...phosphorylation and specificity of RSK1, respectively. However, the SUMO E3 ligase responsible for attaching SUMO to RSK1 has not yet been identified. By genome-wide screening, we found that KSHV ORF45 is necessary and sufficient to enhance RSK1 SUMOylation. Mechanistically, KSHV ORF45 binds to SUMOs via two classic SUMO-interacting motifs (SIMs) and functions as a SIM-dependent SUMO E3 ligase for RSK1. Mutations on these ORF45 SIMs resulted in much lower lytic gene expressions, viral DNA replication, and mature progeny virus production. Interestingly, KSHV ORF45 controls RSK1 SUMOylation and phosphorylation via two separated functional regions: SIMs and amino acid 17-90, respectively, which do not affect each other. Similar to KSHV ORF45, ORF45 of Rhesus Macaque Rhadinovirus has only one SIM and also increases RSK1 SUMOylation in a SIM-dependent manner, while other ORF45 homologues do not have this function. Our work characterized ORF45 as a novel virus encoded SUMO E3 ligase, which is required for ORF45-RSK1 axis-mediated KSHV lytic gene expression.
The optimal chemotherapy regimen administered currently with radiation in patients with stage III non-small cell lung cancer (NSCLC) remains unclear. A multicenter phase III trial was conducted to ...compare the efficacy of concurrent thoracic radiation therapy with either etoposide/cisplatin (EP) or carboplatin/paclitaxel (PC) in patients with stage III NSCLC.
Patients were randomly received 60–66 Gy of thoracic radiation therapy concurrent with either etoposide 50 mg/m2 on days 1–5 and cisplatin 50 mg/m2 on days 1 and 8 every 4 weeks for two cycles (EP arm), or paclitaxel 45 mg/m2 and carboplatin (AUC 2) on day 1 weekly (PC arm). The primary end point was overall survival (OS). The study was designed with 80% power to detect a 17% superiority in 3-year OS with a type I error rate of 0.05.
A total of 200 patients were randomized and 191 patients were treated (95 in the EP arm and 96 in the PC arm). With a median follow-up time of 73 months, the 3-year OS was significantly higher in the EP arm than that of the PC arm. The estimated difference was 15.0% (95% CI 2.0%–28.0%) andP value of 0.024. Median survival times were 23.3 months in the EP arm and 20.7 months in the PC arm (log-rank testP = 0.095, HR 0.76, 95%CI 0.55–1.05). The incidence of Grade ≥2 radiation pneumonitis was higher in the PC arm (33.3% versus 18.9%,P = 0.036), while the incidence of Grade ≥3 esophagitis was higher in the EP arm (20.0% versus 6.3%,P = 0.009).
EP might be superior to weekly PC in terms of OS in the setting of concurrent chemoradiation for unresectable stage III NSCLC.
NCT01494558.
Angiotensin-converting enzyme (ACE) inhibitors are widely used to reduce blood pressure. Here, we examined if an ACE is important for the antibacterial effectiveness of neutrophils. ACE knockout mice ...or mice treated with an ACE inhibitor were more susceptible to bacterial infection by methicillin-resistant Staphylococcus aureus (MRSA). In contrast, mice overexpressing ACE in neutrophils (NeuACE mice) have increased resistance to MRSA and better in vitro killing of MRSA, Pseudomonas aeruginosa, and Klebsiella pneumoniae. ACE overexpression increased neutrophil production of reactive oxygen species (ROS) following MRSA challenge, an effect independent of the angiotensin II AT1 receptor. Specifically, as compared with wild-type (WT) mice, there was a marked increase of superoxide generation (>twofold, P < .0005) in NeuACE neutrophils following infection, whereas ACE knockout neutrophils decreased superoxide production. Analysis of membrane p47-phox and p67-phox indicates that ACE increases reduced NAD phosphate oxidase activity but does not increase expression of these subunits. Increased ROS generation mediates the enhanced bacterial resistance of NeuACE mice because the enhanced resistance is lost with DPI (an inhibitor of ROS production by flavoenzymes) inhibition. NeuACE granulocytes also have increased neutrophil extracellular trap formation and interleukin-1β release in response to MRSA. In a mouse model of chemotherapy-induced neutrophil depletion, transfusion of ACE-overexpressing neutrophils was superior to WT neutrophils in treating MRSA infection. These data indicate a previously unknown function of ACE in neutrophil antibacterial defenses and suggest caution in the treatment of certain individuals with ACE inhibitors. ACE overexpression in neutrophils may be useful in boosting the immune response to antibiotic-resistant bacterial infection.
•ACE plays an important physiological role in neutrophil antibacterial activity.•ACE upregulation in mice neutrophils strongly enhances bactericidal activity via increased reduced NAD phosphate oxidase production of ROS.
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