Mucus forms the first line of defence of the intestinal mucosa barrier, and mucin is its core component. Glutamine is a vital energy substance for goblet cells; it can promote mucus synthesis and alleviate damage to the intestinal mucus barrier after burn injury, but its mechanism is not fully understood. This study focused on the molecular mechanisms underlying the effects of glutamine on the synthesis and modification of mucin 2 (MUC2) by using animal and cellular models of burn sepsis. We found that anterior gradient-2 (AGR2) plays a key role in the posttranslational modification of MUC2. Oxidative stress induced by burn sepsis enhanced the S-glutathionylation of AGR2, interfered with the processing and modification of MUC2 precursors by AGR2 and blocked the synthesis of mature MUC2. Further studies revealed that NADPH, catalysed by glucose-6-phosphate dehydrogenase (G6PD), is a key molecule in inhibiting oxidative stress and regulating AGR2 activity. Glutamine promotes O-linked N-acetylglucosamine (O-GlcNAc) modification of G6PD via the hexosamine pathway, which facilitates G6PD homodimer formation and increases NADPH synthesis, thereby inhibiting AGR2 S-glutathionylation and promoting MUC2 maturation, ultimately reducing damage to the intestinal mucus barrier after burn sepsis. Overall, we have demonstrated that the central mechanisms of glutamine in promoting MUC2 maturation and maintaining the intestinal mucus barrier are the enhancement of G6PD glycosylation and inhibition of AGR2 S-glutathionylation.

Burns and burn sepsis, characterized by persistent and profound hypercatabolism, cause energy metabolism dysfunction that worsens organ injury and systemic disorders. Glutamine (Gln) is a key nutrient that remarkably replenishes energy metabolism in burn and sepsis patients, but its exact roles beyond substrate supply is unclear. In this study, we demonstrated that Gln alleviated liver injury by sustaining energy supply and restoring redox balance. Meanwhile, Gln also rescued the dysfunctional mitochondrial electron transport chain (ETC) complexes, improved ATP production, reduced oxidative stress, and protected hepatocytes from burn sepsis injury. Mechanistically, we revealed that Gln could activate SIRT4 by upregulating its protein synthesis and increasing the level of Nicotinamide adenine dinucleotide (NAD⁺), a co-enzyme that sustains the activity of SIRT4. This, in turn, reduced the acetylation of shock protein (HSP) 60 to facilitate the assembly of the HSP60-HSP10 complex, which maintains the activity of ETC complex II and III and thus sustain ATP generation and reduce reactive oxygen species release. Overall, our study uncovers a previously unknown pharmacological mechanism involving the regulation of HSP60-HSP10 assembly by which Gln recovers mitochondrial complex activity, sustains cellular energy metabolism and exerts a hepato-protective role in burn sepsis.

Sepsis is life-threatening organ dysfunction caused by a dysregulated host response to infection. Although fish oil has been used as an immunonutritional preparations for the treatment of sepsis patients, there is still controversy as to whether it is beneficial to them. We systematically reviewed published clinical trial data to evaluate the effectiveness of fish oil-containing nutrition supplementation in sepsis patients. A systematic search was undertaken in PubMed, Embase, Chinese Biomedicine Database, the Cochrane Library and the China Knowledge Resource Integrated Database to obtain clinical controlled trails. RCTs on nutrition therapy containing fish oil among adult sepsis patients were selected for analysis in comparison with routine therapy. Twenty-five published trials were included in the meta-analysis. Fish oil-containing nutrition supplementation reduced the mortality compared with the control group (relative risk (RR) 0.74, I² = 0%). Fish oil also shortened the ICU stay (MD −3.57 days; 95% CI −4.54, −2.59; p0.05). Parenteral nutrition containing fish oil could significantly decrease mortality in sepsis patients while enteral administration could not. Fish oil-containing nutrition supplementation.

Beta 3 (β3) integrin plays an important role in the initiation of myogenesis in adult muscle. Protein disulfide isomerases (PDIs) can activate β3 integrin in various cells to promote cell migration, adhesion and fusion. However, the effect of PDIs on myogenesis during muscle regeneration has not been elucidated. Here, we report that PDIA3 expression is induced in regenerating myofibers. The inhibition of PDIA3 in muscle injuries in mice disrupts myoblast differentiation, impairs muscle regeneration, and ultimately aggravates muscle damage. Moreover, PDIA3 expression is upregulated and observed on the cell surfaces of myoblasts during differentiation and fusion. The inhibition of extracellular PDIA3 with an anti-PDIA3 monoclonal antibody attenuates β3 integrin/AKT/mTOR signal activity, inhibits myoblast differentiation, and blocks the fusion of myoblasts. Thus, PDIA3 may be a mediator of myoblast differentiation and fusion during muscle regeneration.