These results indicate that intracellular and extracellular HSP70 have different roles in the regulation of cardiac remodelling and function in response to hypertension. Extracellular HSP70 is a potential therapeutic target against cardiac hypertrophy and fibrosis.

BackgroundImmunotherapy is often recommended as an adjuvant treatment to reduce the chance of cancer recurrence or metastasis. Interestingly, timing is very important for a successful immunotherapy against metastasis, although the precise mechanism is still unknown.Methods and FindingsUsing a mouse model of melanoma metastasis induced by intravenous injection of B16-F10 cells, we investigated the mechanism responsible for the diverse efficacy of the prophylactic or therapeutic TLR4 and TLR9 agonist complex against metastasis. We found that the activation of TLR4 and TLR9 prevented, but did not reverse, metastasis because the potency of this combination was neither sufficient to overcome the tumor cell-educated immune tolerance nor to induce efficacious autophagy in tumor cells. The prophylactic application of the complex promoted antimetastatic immunity, leading to the autophagy-associated death of melanoma cells via IFNγ/STAT1 activation and attenuated tumor metastasis. IFNγ neutralization reversed the prophylactic benefit induced by the complex by suppressing STAT1 activation and attenuating autophagy in mice. However, the therapeutic application of the complex did not suppress metastasis because the complex could not reverse tumor cell-induced STAT3 activation and neither activate IFNγ/STAT1 signaling and autophagy. Suppressing STAT3 activation with the JAK/STAT antagonist AG490 restored the antimetastatic effect of the TLR4/9 agonist complex. Activation of autophagy after tumor inoculation by using rapamycin, with or without the TLR4/9 agonist complex, could suppress metastasis.Conclusion and SignificanceOur studies suggest that activation of IFNγ/STAT1 signaling and induction of autophagy are critical for an efficacious anti-metastatic immunotherapy and that autophagy activators may overcome the timing barrier for immunotherapy against metastasis.

a b s t r a c tTransforming growth factor-b1 (TGF-b1) regulates a wide variety of cellular responses, such as proliferation, differentiation, migration and apoptosis. Here we report that death effector domain-containing DNA-binding protein (DEDD) physically interacts with Smad3. The inhibition of Smad3 by DEDD resulted in a reduction in TGF-b1/Smad3-mediated transcription. DEDD inhibited the functions of Smad3 by preventing Smad3 phosphorylation, which led to the reduced expression of TGF-b1/Smad3-targeted genes. TGF-b1 inhibited DEDD expression, and DEDD inhibited TGF-b1-mediated invasion. Therefore, our findings suggest that through its interaction with Smad3, DEDD is a novel negative regulator of the TGF-b1 signaling pathway. Structured summary:MINT-7895480: DEDD (uniprotkb:O75618) physically interacts (MI:0915) with Smad3 (uniprotkb:P84022) by anti bait co-immunoprecipitation (MI:0006)

In recent years, with the center of the city to promote ecological construction, polluting enterprises have gradually transferred to the county, and serious environmental pollution and environmental conflicts are brought to the county. And because of county governments are in the end of the status of the urban power pyramid system, the regional environmental collaborative development mechanism remains to be further improve, the county government performance evaluation is still mainly in terms of GDP, the tenure system led to the prevalence of short-term behavior, supervision of production safety and technological transformation not in place, as well as lack of environmental accountability and effective environmental compensation mechanism and so on, the county environmental crisis happened frequently, governance falls into trouble. Therefore, in the context of the environmental crisis, effective county governance embodies fair regional collaborative development mechanism, further innovate performance evaluation and reform the existing cadres of the tenure system, strengthen supervision of production safety and technological innovation, improve environmental accountability and environmental compensation system, etc.