SummaryNuclear factor kappa B (NF-B) signalling is activated by cellular stress and inflammation and regulates cytokine expression. We applied single-cell imaging to investigate dynamic responses to different doses of tumour necrosis factor alpha (TNF). Lower doses activated fewer cells and those responding showed an increasingly variable delay in the initial NF-B nuclear translocation and associated IB degradation. Robust 100 minute nuclear:cytoplasmic NF-B oscillations were observed over a wide range of TNF concentrations. The result is supported by computational analyses, which identified a limit cycle in the system with a stable 100 minute period over a range of stimuli, and indicated no co-operativity in the pathway activation. These results suggest that a stochastic threshold controls functional all-or-nothing responses in individual cells. Deterministic and stochastic models simulated the experimentally observed activation threshold and gave rise to new predictions about the structure of the system and open the way for better mechanistic understanding of physiological TNF activation of inflammatory responses in cells and tissues.

Tendon injuries are common musculoskeletal system disorders in clinical, but the regeneration ability of tendon is limited. Tendon stem cells (TSCs) have shown promising effect on tissue engineering and been used for the treatment of tendon injury. Exosomes that serve as genetic information carriers have been implicated in many diseases and physiological processes, but effect of exosomes from TSCs on tendon injury repair is unclear. The aim of this study is to make clear that the effect of exosomes from TSCs on tendon injury healing. Exosomes were harvested from conditioned culture media of TSCs by a sequential centrifugation process. Rat Achilles tendon tendinopathy model was established by collagenase‐I injection. This was followed by intra‐Achilles‐tendon injection with TSCs or exosomes. Tendon healing and matrix degradation were evaluated by histology analysis and biomechanical test at the post‐injury 5 weeks. In vitro, TSCs treated with interleukin 1 beta were added by conditioned medium including exosomes or not, or by exosomes or not. Tendon matrix related markers and tenogenesis related markers were measured by immunostaining and western blot. We found that TSCs injection and exosomes injection significantly decreased matrix metalloproteinases (MMP)‐3 expression, increased expression of tissue inhibitor of metalloproteinase‐3 (TIMP‐3) and Col‐1a1, and increased biomechanical properties of the ultimate stress and maximum loading. In vitro, conditioned medium with exosomes and exosomes also significantly decreased MMP‐3, and increased expression of tenomodulin, Col‐1a1 and TIMP‐3. Exosomes from TSCs could be an ideal therapeutic strategy in tendon injury healing for its balancing tendon extracellular matrix and promoting the tenogenesis of TSCs.

Objectively: Tendinopathy is a common problem in sports medicine which can lead to severe morbidity. Aspirin, as the classical representative of non-steroidal anti-inflammatory drugs (NSAIDs) for its anti-inflammatory and analgesic actions, has been commonly used in treating tendinopathy. While its treatment effects on injury tendon healing are lacking, illuminating the underlying mechanism may provide scientific basis for clinical treatment. Materials and methods:Firstly, we used immunohistochemistry and qRT-PCR to detect changes in CD14, CD206, iNOS, IL-6, IL-10, MMP-3, TIMP-3, Col-1a1, biglycan, Comp, Fibronectin, TGF-β1，ACAN，EGR-1 and FMOD. Next, Western blot was used to measure the protein levels (IL-6, IL-10, TGF-β1, COMP, TIMP-3, STAT-3/P-STAT-3 and JNK/P-JNK) in TSCs. Then, migration and proliferation of TSCs were measured through wound healing test and BrdU staining. Finally, the mechanical properties of injury tendon were detected. Results:After aspirin treatment, the inflammation and scar formation in injury tendon were significantly inhibited by aspirin. Still, tendon's ECM was positively balanced.Increasing migration and proliferation ability of TSCs induced by IL-1β were significantly reversed. JNK/STAT-3 signalling pathway participated in the process above.In addition, biomechanical properties of injury tendon were significantly improved. Conclusions:Taken together, the findings suggested that aspirin inhibited inflammation and scar formation via regulation of JNK/STAT-3 signalling and decreased rerupture risk of injury tendon. Aspirin could be an ideal therapeutic strategy in tendon injury healing.

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BackgroundChronic muscle injury is characteristics of fatty infiltration and fibrosis. Recently, fibro/adipogenic progenitors (FAPs) were found to be indispensable for muscular regeneration while were also responsible for fibrosis and fatty infiltration in muscle injury. Many myokines have been proven to regulate the adipose or cell proliferation. Because the fate of FAPs is largely dependent on microenvironment and the regulation of myokines on FAPs is still unclear. We screened the potential myokines and found Interleukin-15 (IL-15) may regulate the fatty infiltration in muscle injury. In this study, we investigated how IL-15 regulated FAPs in muscle injury and the effect on muscle regeneration.MethodsCell proliferation assay, western blots, qRT-PCR, immunohistochemistry, flow cytometric analysis were performed to investigate the effect of IL-15 on proliferation and adipogensis of FAPs. Acute muscle injury was induced by injection of glycerol or cardiotoxin to analyze how IL-15 effected on FAPs in vivo and its function on fatty infiltration or muscle regeneration.ResultsWe identified that the expression of IL-15 in injured muscle was negatively associated with fatty infiltration. IL-15 can stimulate the proliferation of FAPs and prevent the adipogenesis of FAPs in vitro and in vivo. The growth of FAPs caused by IL-15 was mediated through JAK-STAT pathway. In addition, desert hedgehog pathway may participate in IL-15 inhibiting adipogenesis of FAPs. Our study showed IL-15 can cause the fibrosis after muscle damage and promote the myofiber regeneration. Finally, the expression of IL-15 was positively associated with severity of fibrosis and number of FAPs in patients with chronic rotator cuff tear.ConclusionsThese findings supported the potential role of IL-15 as a modulator on fate of FAPs in injured muscle and as a novel therapy for chronic muscle injury.Electronic supplementary materialThe online version of this article (10.1186/s12964-018-0251-0) contains supplementary material, which is available to authorized users.

We prove the rigid phase conjecture of Stewart and Parker. It then follows from previous results (of Stewart and Parker and our own) that rigid phase-shifts in periodic solutions on a transitive network are produced by a cyclic symmetry on a quotient network. More precisely, let X(t) = (x 1 (t),. .. , x n (t)) be a hyperbolic T-periodic solution of an admissible system on an n-node network. Two nodes c and d are phase-related if there exists a phase-shift θ cd ∈ [0, 1) such that x d (t) = x c (t + θ cd T). The conjecture states that if phase relations persist under all small admissible perturbations (that is, the phase relations are rigid), then for each pair of phase-related cells, their input signals are also phase-related to the same phase-shift. For a transitive network, rigid phase relations can also be described abstractly as a Z m permutation symmetry of a quotient network. We discuss how patterns of phase-shift synchrony lead to rigid synchrony, rigid phase synchrony, and rigid multirhythms, and we show that for each phase pattern there exists an admissible system with a periodic solution with that phase pattern. Finally, we generalize the results to nontransitive networks where we show that the symmetry that generates rigid phase-shifts occurs on an extension of a quotient network.

The present meta-analysis indicated that preoperative NLR had significant association with the prognosis of hepatocellular carcinoma patients and may be an effectively prognostic indicator.

The signal transducer and activator of transcription 3 (STAT3) signaling pathway has been implicated in cell apoptosis and inflammatory processes. Ischemic preconditioning (IPC) and ischemic postconditioning (IPTC) inhibit both of these processes. In the present study, we investigated the role of phosphorylated STAT3 (p-STAT3)-mediated apoptosis and inflammation following non-invasive remote limb IPTC (NRIPoC) using a classic rat model of focal cerebral ischemia. Forty-five adult male Sprague-Dawley rats were divided randomly into 3 groups (n=15 per group): the sham-operated, ischemia/reperfusion (I/R) and NRIPoC groups. NRIPoC was implemented at the beginning of reperfusion. At 24 h after cerebral reperfusion, we evaluated the neurological deficit score (NDS), assessed the cerebral infarct size and tissue morphology, and evaluated neuronal apoptosis. The protein expression levels of Bcl-2, Bax, nuclear factor-κB (NF-κB), tumor necrosis factor-α (TNF-α) and p-STAT3 in the penumbra region were assessed by western blot analysis. The cerebral infarct volume, the number of apoptotic cells and the protein expression levels of Bcl-2, Bax, NF-κB and TNF-α were all found to be increased in the I/R group compared with the sham-operated group. However, these levels were decreased in the NRIPoC group compared with the I/R group. The number of apoptotic cells in the penumbra in the I/R group was increased compared with that in the NRIPoC and sham-operated groups. The protein expression of p-STAT3 was increased in the NRIPoC group compared with the sham-operated and I/R groups. These results indicate that the protective effects of NRIPoC against cerebral I/R injury may be related to the attenuation of neuronal apoptosis and inflammation through the activation of STAT3.