Increasing evidence suggests the important role of metabolic reprogramming in the regulation of the innate inflammatory response, but the underlying mechanism remains unclear. Here, we provide evidence to support a novel role for the pyruvate kinase M2 (PKM2)-mediated Warburg effect, namely aerobic glycolysis, in the regulation of high mobility group box 1 (HMGB1) release. PKM2 interacts with hypoxia-inducible factor 1α (HIF1α) and activates the HIF-1α-dependent transcription of enzymes necessary for aerobic glycolysis in macrophages. Knockdown of PKM2, HIF1α, and glycolysis-related genes uniformly decreases lactate production and HMGB1 release. Similarly, a potential PKM2 inhibitor, shikonin, reduces serum lactate and HMGB1 levels and protects mice from lethal endotoxemia and sepsis. Collectively, these findings shed light on a novel mechanism for metabolic control of inflammation by regulating HMGB1 release and highlight the importance of targeting aerobic glycolysis in the treatment of sepsis and other inflammatory diseases.

Totally laparoscopic TME with ASP is feasible, and it is a minimally invasive technique with the benefits of much less blood loss during operation, earlier return of bowel function, and shorter hospitalization.

In this paper, we first extend the celebrated PageRank modification to a higher-order Markov chain. Although this system has attractive theoretical properties, it is computationally intractable for many interesting problems. We next study a computationally tractable approximation to the higher-order PageRank vector that involves a system of polynomial equations called multilinear PageRank, which is a type of tensor PageRank vector. It is motivated by a novel "spacey random surfer" model, where the surfer remembers bits and pieces of history and is influenced by this information. The underlying stochastic process is an instance of a vertex-reinforced random walk. We develop convergence theory for a simple fixed-point method, a shifted fixed-point method, and a Newton iteration in a particular parameter regime. In marked contrast to the case of the PageRank vector of a Markov chain where the solution is always unique and easy to compute, there are parameter regimes of multilinear PageRank where solutions are not unique and simple algorithms do not converge. We provide a repository of these non-convergent cases that we encountered through exhaustive enumeration and randomly sampling that we believe is useful for future study of the problem

High mobility group box 1 (HMGB1) is a widely-expressed and highly-abundant protein that acts as an extracellular signal upon active secretion by immune cells or passive release by dead, dying, and injured cells. Both intracellular and extracellular HMGB1 play pivotal roles in regulation of the cellular response to stress. Targeting the translocation, release, and activity of HMGB1 can limit inflammation and reduce tissue damage during infection and sterile inflammation. Although the mechanisms contributing to HMGB1 biology are still under investigation, it appears that oxidative stress is a central regulator of HMGB1's translocation, release, and activity in inflammation and cell death (e.g., necrosis, apoptosis, autophagic cell death, pyroptosis, and NETosis). Thus, targeting HMGB1 with antioxidant compounds may be an attractive therapeutic strategy for inflammation-associated diseases such as sepsis, ischemia and reperfusion injury, arthritis, diabetes, and cancer.

Seeing is believing: A direct, selective, and sensitive strategy for colorimetric visualization of cerebral dopamine has been developed for the first time using gold nanoparticles through the design of double molecular recognition (see picture). The simplicity of this method establishes a facile and reliable approach for monitoring cerebral species in brain chemistry, which may be related to physiological and pathological events.