Rhizoma Alismatis Decoction improved mitochondrial dysfunction to alleviate SASP by enhancing autophagy flux and apoptosis in hyperlipidemia acute pancreatitis.

BACKGROUND: Acute pancreatitis (AP) is an inflammatory disorder of the exocrine pancreas, especially hyperlipidemia acute pancreatitis (HLAP) is the third leading cause of acute pancreatitis which is more severe with a greater incidence of persistent multiorgan failure. HLAP inflicts injury upon the organelles within the acinar cell, particularly mitochondria, the endolysosomal-autophagy system, and is accompanied by senescence-associated secretory phenotype (SASP). RAD, only two consists of Rhizoma Alismatis and Atractylodes macrocephala Rhizoma, which is best known for its ability to anti-inflammatory and lipid-lowering. Nevertheless, the mechanism by which RAD alleviates HLAP remains obscure, necessitating further investigation. PURPOSE: The study aimed to assess the effects of the RAD on HLAP and to elucidate the underlying mechanism in vivo and in vitro, offering a potential medicine for clinical treatment for HLAP. STUDY DESIGN AND METHODS: C57BL/6 mice with hyperlipidemia acute pancreatitis were induced by HFD and CER, then administrated with RAD. AR42J were stimulated by cerulein or conditioned medium and then cultured with RAD. Serums were analyzed to evaluate potential pancreas and liver damage. Furthermore, tissue samples were obtained for histological, and protein investigations by H&E, Oil red staining, and Western blot. In addition, western blot and immunofluorescent staining were utilized to estimate the effect of RAD on mitochondrial function, autophagy flux, and SASP. RESULTS: In vivo, RAD considerably alleviated systemic inflammation while attenuating TC, TG, AMY, LPS, inflammatory cytokines, histopathology changes, oxidative damage, mitochondrial fission, and autophagy markers in HLAP mice. Impaired autophagy flux and mitochondrial dysfunction resulted in a significant enhancement of NLRP3 and IL-1ß in the pancreas. RAD could reverse these changes. In vitro, RAD significantly restored mitochondrial membrane potential and oxidative phosphorylation levels. RAD decreased Beclin-1 and LC3-II expression and increased LAMP-1 and Parkin-Pink expression, which showed that RAD significantly ameliorated HLAP-induced damage to the mitochondria function by suppressing mitochondrial oxidative damage and enhancing autophagy flux and mitophagy to remove the damaged mitochondria. In addition, we found that RAD could up-regulate the expression of BAX, and Bad and down-regulate the expression of p16, and p21, indicating that RAD could promote damaged cell apoptosis and alleviate SASP. CONCLUSIONS: This study revealed that RAD ameliorates mitochondrial function to alleviate SASP through enhancing autophagy flux, mitophagy, and apoptosis which provided a molecular basis for the advancement and development of protection strategies against HLAP.

Inhibition of PDGFRß alleviates endothelial cell apoptotic injury caused by DRP-1 overexpression and mitochondria fusion failure after mitophagy.

Kawasaki disease (KD), described as "mucocutaneous lymph node syndrome", affects infants and toddlers. Patients with KD suffer from an inflammatory cascade leading to vasculitis with a predilection for coronary arteries. While the symptoms and pathogenesis of KD have received more and more attention, the precise mechanisms are still debated. Researches show that endothelial dysfunction process in KD leads to arterial damage and affect clinical outcome. In this study, we constructed a Candida albicans water soluble fraction (CAWS)-induced KD murine model and penetrated investigating the mechanisms behind endothelial dysfunction. CAWS-induced mice presented remarkably elevated vascular endothelial cell growth factor (VEGF) levels. Abundant expression of VEGF was documented in all vessels that showed edema from acute KD. It has been reported that Platelet-derived growth factor (PDGF) co-expression normalizes VEGF-induced aberrant angiogenesis. Hyperexpression of PDGFRß was induced in the thickened medial layer and vascular endothelium of KD mice. Masitinib (Mas) is an oral tyrosine kinase inhibitor of numerous targets, which can selectively target PDGFR signaling. We set out to explore whether Mas could regulate coronary pathology in KD. Mas administration significantly reduced the VEGF-induced endothelial cells migration. NOX4 was activated in vascular endothelial cells to produce more ROS. Mitochondrial dysregulated fission and mitophagy caused by DRP-1 overexpression precipitated the arterial endothelial cells injury. Here, mitophagy seemed to work as the driving force of DRP-1/Bak/BNIP3-dependent endothelial cells apoptosis. In summary, how mitophagy is regulated by DRP-1 under pathologic status is critical and complex, which may contribute to the development of specific therapeutic interventions in cardiovascular diseases patients, for example Masatinib, the inhibitor of PDGFRß. FACTS AND QUESTIONS: Kawasaki disease causing systemic vasculitis, affects infants and toddlers. Coronary artery injury remains the major causes of morbidity and mortality. DRP-1 overexpression induces DRP-1/Bak/BNIP3-dependent endothelial cells apoptosis. PDGFRß was high-expressed in the thickened medial layer of CAWS-induced KD mice. Inhibition of PDGFRß signaling alleviates arterial endothelial cells injury.

Unraveling the metabolic network of organic acids in solid-state fermentation of Chinese cereal vinegar.

Shanxi aged vinegar (SAV) is fermented by multispecies microorganism with solid-state fermentation (SSF) technology, which contains a variety of organic acids. However, the metabolic network of them in SSF is still unclear. In this study, metagenomics technology was used to reveal the microbial community and functional genes in SAV fermentation. The metabolic network of key organic acids with taste active value higher than 1 was reconstructed for the first time, including acetate, lactate, malate, citrate, succinate, and tartrate. The results show pyruvate is the core compound in the metabolic network of organic acids. Metabolic pathway of acetate plays a pivotal role in this network, and acetate has regulatory function on metabolism of other organic acids. Acetobacter and Lactobacillus are the predominant genera for organic acid metabolism in SSF of SAV. This is also the first report on metabolic network of organic acids in cereal vinegar, adding new knowledge on the flavor substance metabolism during multispecies fermentation of traditional fermented food.

Bioaugmentation by Pediococcus acidilactici AAF1-5 Improves the Bacterial Activity and Diversity of Cereal Vinegar Under Solid-State Fermentation.

Bioaugmentation technology may be an effective strategy to improve the solid-state fermentation rate and utilization of raw materials for traditional vinegar production. The relationship between bacteria and fermentation process was analyzed to rationally design and perform bioaugmented solid-state fermentation of the Tianjin Duliu mature vinegar (TDMV). Fermentation process was highly correlated with Acetobacter, Lactobacillus, and Pediococcus contents, which were the core functional microorganisms in TDMV fermentation. Pediococcus acidilactici AAF1-5 was selected from 20 strains to fortify the fermentation due to its acidity and thermal tolerance. Bioaugmentation was performed in the upper layer of TDMV fermentation. P. acidilactici AAF1-5 colonized and then spread into the lower layer to improve the fermentation. Result showed that the fermentation period was 5 days less than that of the control. Meanwhile, the non-volatile acid, lactic acid, amino nitrogen, and reducing sugar contents in the bioaugmented TDMV increased by 53%, 14%, 32%, and 36%, respectively, compared with those in the control. Bioaugmentation with P. acidilactici AAF1-5 not only improved the utilization of starch from 79% to 83% but also increased the bacterial community diversity.