A transcriptomic and proteomic atlas of obesity and type 2 diabetes in cynomolgus monkeys.

Obesity and type 2 diabetes (T2D) remain major global healthcare challenges, and developing therapeutics necessitates using nonhuman primate models. Here, we present a transcriptomic and proteomic atlas of all the major organs of cynomolgus monkeys with spontaneous obesity or T2D in comparison to healthy controls. Molecular changes occur predominantly in the adipose tissues of individuals with obesity, while extensive expression perturbations among T2D individuals are observed in many tissues such as the liver and kidney. Immune-response-related pathways are upregulated in obesity and T2D, whereas metabolism and mitochondrial pathways are downregulated. Moreover, we highlight some potential therapeutic targets, including SLC2A1 and PCSK1 in obesity as well as SLC30A8 and SLC2A2 in T2D. Our study provides a resource for exploring the complex molecular mechanism of obesity and T2D and developing therapies for these diseases, with limitations including lack of hypothalamus, isolated islets of Langerhans, longitudinal data, and body fat percentage.

Amylin deposition activates HIF1α and 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase 3 (PFKFB3) signaling in failing hearts of non-human primates.

Hyperamylinemia induces amylin aggregation and toxicity in the pancreas and contributes to the development of type-2 diabetes (T2D). Cardiac amylin deposition in patients with obesity and T2D was found to accelerate heart dysfunction. Non-human primates (NHPs) have similar genetic, metabolic, and cardiovascular processes as humans. However, the underlying mechanisms of cardiac amylin in NHPs, particularly related to the hypoxia inducible factor (HIF)1α and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) signaling pathways, are unknown. Here, we demonstrate that in NHPs, amylin deposition in heart failure (HF) contributes to cardiac dysfunction via activation of HIF1α and PFKFB3 signaling. This was confirmed in two in vitro cardiomyocyte models. Furthermore, alterations of intracellular Ca2+, reactive oxygen species, mitochondrial function, and lactate levels were observed in amylin-treated cells. Our study demonstrates a pathological role for amylin in the activation of HIF1α and PFKFB3 signaling in NHPs with HF, establishing amylin as a promising target for heart disease patients.

Serpin peptidase inhibitor clade A member 1-overexpression in gastric cancer promotes tumor progression in vitro and is associated with poor prognosis.

Gastric cancer is the second most common cause of cancer-associated death in Asia. The incidence and mortality rates of gastric cancer have markedly increased in the past few decades. Therefore, the identification of novel gastric cancer biomarkers are needed to determine prognosis. The role of serpin peptidase inhibitor clade A member 1 (SERPINA1) has been studied in several types of cancer; however, little is known about its mechanism in gastric cancer. The present study aimed to evaluate SERPINA1 as a potential prognostic biomarker in gastric cancer and to identify the possible mechanisms underlying its action. The expression levels of SERPINA1 in several gastric cancer datasets were assessed, and it was identified that high expression of SERPINA1 was associated to poor clinical outcomes. Furthermore, using histochemical analysis, western blotting, apoptotic analysis, gap closure and invasion assays in cell lines, it was reported that silencing of SERPINA1 inhibited the formation of cellular pseudopodia and did not affect apoptosis, but promoted cell cycle S-phase entry. In addition, overexpression of SERPINA1 increased the migration and invasion of gastric cancer cells, whereas knockdown of SERPINA1 decreased these functions. Moreover, SERPINA1 overexpression increased the protein levels of SMAD4, which is a key regulator of the transforming growth factor (TGF)-ß signaling pathway. Taken together, the present data demonstrated that SERPINA1 promotes gastric cancer progression through TGF-ß signaling, and suggested that SERPINA1 may be a novel prognostic biomarker from tumor tissue biopsy in gastric cancer.

Targeting Autophagy Facilitates T Lymphocyte Migration by Inducing the Expression of CXCL10 in Gastric Cancer Cell Lines.

Autophagy is a type of cellular catabolic degradation process that occurs in response to nutrient starvation or metabolic stress, and is a valuable resource for highly proliferating cancer cells. Autophagy also facilitates the resistance of cancer cells to antitumor therapies. However, the involvement of autophagy in regulating CXCL10 expression in gastric cancer (GC) cells and T lymphocyte migration remains unclear. In this study, we aimed to investigate the effect of autophagy inhibition on CXCL10 expression and T lymphocyte infiltration in GC and elucidate the underlying mechanism. Analysis of public databases revealed a positive correlation between CXCL10 expression and both prognosis of patients with GC and the expression profile of T lymphocyte markers in the GCs. Chemotaxis and spheroid infiltration assays revealed that CXCL10 induced T lymphocyte migration and infiltration into GC spheroids, an in vitro three-dimensional cell culture model. In addition, in vitro autophagy inhibition in GC cells increased CXCL10 expression under both normal and hypoxic culture conditions. Further investigation on the underlying mechanism showed that in vitro autophagy inhibition suppressed the JNK signaling pathway and further enhanced CXCL10 expression in GC cells. Collectively, our results provide novel insights for understanding the role of autophagy in regulation of intra-tumor immunity.