Regulation of Nuclear Factor-KappaB (NF-κB) signaling pathway by non-coding RNAs in cancer: Inhibiting or promoting carcinogenesis?

Background & Aims Nonalcoholic fatty liver disease (NAFLD) is becoming a severe liver disorder worldwide. Autophagy plays a critical role in liver steatosis. However, the role of autophagy in NAFLD remains exclusive and under debate. In this study, we investigated the role of S100 calcium binding protein A11 (S100A11) in the pathogenesis of hepatic steatosis. Methods We performed liver proteomics in a well-established tree shrew model of NAFLD. The expression of S100A11 in different models of NAFLD was detected by Western blot and/or quantitative polymerase chain reaction. Liver S100A11 overexpression mice were generated by injecting a recombinant adenovirus gene transfer vector through the tail vein and then induced by a high-fat and high-cholesterol diet. Cell lines with S100a11 stable overexpression were established with a recombinant lentiviral vector. The lipid content was measured with either Bodipy staining, Oil Red O staining, gas chromatography, or a triglyceride kit. The autophagy and lipogenesis were detected in vitro and in vivo by Western blot and quantitative polymerase chain reaction. The functions of Sirtuin 1, histone deacetylase 6 (HDAC6), and FOXO1 were inhibited by specific inhibitors. The interactions between related proteins were analyzed by a co-immunoprecipitation assay and immunofluorescence analysis. Results The expression of S100A11 was up-regulated significantly in a time-dependent manner in the tree shrew model of NAFLD. S100A11 expression was induced consistently in oleic acid–treated liver cells as well as the livers of mice fed a high-fat diet and NAFLD patients. Both in vitro and in vivo overexpression of S100A11 could induce hepatic lipid accumulation. Mechanistically, overexpression of S100A11 activated an autophagy and lipogenesis process through up-regulation and acetylation of the transcriptional factor FOXO1, consequently promoting lipogenesis and lipid accumulation in vitro and in vivo. Inhibition of HDAC6, a deacetylase of FOXO1, showed similar phenotypes to S100A11 overexpression in Hepa 1–6 cells. S100A11 interacted with HDAC6 to inhibit its activity, leading to the release and activation of FOXO1. Under S100A11 overexpression, the inhibition of FOXO1 and autophagy could alleviate the activated autophagy as well as up-regulated lipogenic genes. Both FOXO1 and autophagy inhibition and Dgat2 deletion could reduce liver cell lipid accumulation significantly. Conclusions A high-fat diet promotes liver S100A11 expression, which may interact with HDAC6 to block its binding to FOXO1, releasing or increasing the acetylation of FOXO1, thus activating autophagy and lipogenesis, and accelerating lipid accumulation and liver steatosis. These findings indicate a completely novel S100A11-HDAC6-FOXO1 axis in the regulation of autophagy and liver steatosis, providing potential possibilities for the treatment of NAFLD.

S100A11 Promotes Liver Steatosis via FOXO1-Mediated Autophagy and Lipogenesis.

The placenta is an endocrine fetal organ, which secretes a plethora of steroid- and proteo-hormones, metabolic proteins, growth factors, and cytokines in order to adapt maternal physiology to pregnancy. Central to the growth of the fetus is the supply with nutrients, foremost with glucose. Therefore, during pregnancy, maternal insulin resistance arises, which elevates maternal blood glucose levels, and consequently ensures an adequate glucose supply for the developing fetus. At the same time, maternal β-cell mass and function increase to compensate for the higher insulin demand. These adaptations are also regulated by the endocrine function of the placenta. Excessive insulin resistance or the inability to increase insulin production accordingly disrupts physiological modulation of pregnancy mediated glucose metabolism and may cause maternal gestational diabetes (GDM). A growing body of evidence suggests that this adaptation of maternal glucose metabolism differs between pregnancies carrying a girl vs. pregnancies carrying a boy. Moreover, the risk of developing GDM differs depending on the sex of the fetus. Sex differences in placenta derived hormones and bioactive proteins, which adapt and modulate maternal glucose metabolism, are likely to contribute to this sexual dimorphism. This review provides an overview on the adaptation and maladaptation of maternal glucose metabolism by placenta-derived factors, and highlights sex differences in this regulatory network.

Placental Endocrine Activity: Adaptation and Disruption of Maternal Glucose Metabolism in Pregnancy and the Influence of Fetal Sex

Nonalcoholic fatty liver disease (NAFLD) has been renamed metabolic dysfunction-associated fatty liver disease (MAFLD), a condition for which there is now no authorized treatment. The search for new medications to treat MAFLD made from natural substances is gaining traction. The function of anti-oxidant, anti-inflammation, hypoglycaemic, antiviral, hypolipidemic, and immunomodulatory actions of Astragalus polysaccharides (APS), a chemical molecule isolated from Astragalus membranaceus, has become the focus of therapeutic attention. We have a large number of papers on the pharmacological effects of APS on NAFLD that have never been systematically reviewed before. According to our findings, APS may help to slow the progression of non-alcoholic fatty liver disease (NAFL) to non-alcoholic steatohepatitis (NASH). Lipid metabolism, insulin resistance (IR), oxidative stress (OS), endoplasmic reticulum stress (ERS), inflammation, fibrosis, autophagy, and apoptosis are some of the pathogenic pathways involved. SIRT1/PPARα/FGF21, PI3K/AKT/IRS-1, AMPK/ACC, mTOR/4EBP-1/S6K1, GRP78/IRE-1/JNK, AMPK/PGC-1/NRF1, TLR4/MyD88/NF-κB, and TGF-β/Smad pathways were the most common molecular protective mechanisms. All of the information presented in this review suggests that APS is a natural medication with a lot of promise for NAFLD, but more study, bioavailability studies, medicine type and dosage, and clinical proof are needed. This review could be useful for basic research, pharmacological development, and therapeutic applications of APS in the management of MAFLD.

/pdf/pharmacological-effects-and-molecular-protective-mechanisms-f98q2vx8.pdf

Pharmacological Effects and Molecular Protective Mechanisms of Astragalus Polysaccharides on Nonalcoholic Fatty Liver Disease

Early detection of lung cancer in screening programs is a rational way to reduce mortality associated with this malignancy. Low-dose computed tomography, a diagnostic tool used in lung cancer screening, generates a relatively large number of false-positive results, and its complementation with molecular biomarkers would greatly improve the effectiveness of such programs. Several biomarkers of lung cancer based on different components of blood, including miRNA signatures, were proposed. However, only a few of them have been positively validated in the context of early cancer detection yet, which imposes a constant need for new biomarker candidates. An emerging source of cancer biomarkers are exosomes and other types of extracellular vesicles circulating in body fluids. Hence, different molecular components of serum/plasma-derived exosomes were tested and showed different levels in lung cancer patients and healthy individuals. Several studies focused on the miRNA component of these vesicles. Proposed signatures of exosome miRNA had promising diagnostic value, though none of them have yet been clinically validated. These signatures involved a few dozen miRNA species overall, including a few species that recurred in different signatures. It is worth noting that all these miRNA species have cancer-related functions and have been associated with lung cancer progression. Moreover, a few of them, including known oncomirs miR-17, miR-19, miR-21, and miR-221, appeared in multiple miRNA signatures of lung cancer based on both the whole serum/plasma and serum/plasma-derived exosomes.

Serum Exosomes and Their miRNA Load-A Potential Biomarker of Lung Cancer.

Non-small cell lung cancer (NSCLC) is the most deadly cancer in the world due to its often delayed diagnosis. Identification of biomarkers with high sensitivity, specificity, and accessibility for early detection, such as circulating microRNAs, is therefore of utmost importance. In the present study, we identified a significantly higher expression of miR-146a-5p in the serum and tissue samples of NSCLC patients than that of the healthy controls. In parallel, miR-146a-5p was also highly expressed in three human NSCLC adenocarcinoma-cell lines (A549, H1299, and H1975) compared to the human bronchial epithelium cell line (HBE). By dual-luciferase reporter assay and manipulation of the expressions of miR-146a-5p and its target gene, tumor necrosis factor receptor-associated factor 6 (TRAF6), we showed that the functional effects of miR-146a-5p on NSCLC cell survival and migration were mediated by direct binding to and suppression of TRAF6. Overexpression of TRAF6 sufficiently reversed miR-146a-5p-induced cancer cell proliferation, migration, and apoptosis resistance. Our data implied that miR-146a-5p/TRAF6/NF-κB-p65 axis could be a promising diagnostic marker and a therapeutic target for NSCLC.

/pdf/mir-146a-5p-plays-an-oncogenic-role-in-nsclc-via-suppression-l7vmoom2ns.pdf

miR-146a-5p Plays an Oncogenic Role in NSCLC via Suppression of TRAF6.

Loss of Adipose Growth Hormone Receptor in Mice Enhances Local Fatty Acid Trapping and Impairs Brown Adipose Tissue Thermogenesis.

Growth hormone (GH) exerts numerous effects on tissues through binding to its receptor, GHR, which resides on cell membranes in many different organs and tissues. Endocrine pancreatic β cells are the only source of insulin secretion in response to metabolic demand, thereby regulating blood glucose and maintaining metabolic homeostasis. β cell dysfunction is the main composition of diabetes mellitus. Numerous studies have provided strong evidence that GHR signaling plays an independent role in β cell function. In this review, we focus on the role of GHR signaling in β cell actions and the underlying molecular mechanisms.

The role of growth hormone receptor in β cell function.

Astragalus polysaccharide (APS) is the main component of Astragalus membranaceus, an anti-diabetic herb being used for thousands of years in Traditional Chinese medicine (TCM). In this study, we aimed to evaluate the impact of APS on hepatic insulin signaling, autophagy and ER stress response in high-fat-diet (HFD)-induced insulin resistance (IR) mice. APS was intra-gastrically administrated and metformin was used as a control medicine. Apart from monitoring the changes in the important parameters of IR progression, the gene and protein expression of the key factors marking the state of hepatic ER stress and autophagic flux were examined. We found that, largely comparable to the metformin regime, APS treatment resulted in an overall improvement of IR, as indicated by better control of body weight and blood glucose/lipid levels, recovery of liver functions and regained insulin sensitivity. In particular, the excessive and pro-apoptotic ER stress response and inhibition of autophagy, as a result of prolonged HFD exposure, were significantly corrected by APS administration, indicating a switch of the cellular fate in favor of cell survival. Using the HepG2/IR cell model, we demonstrated that APS modulated the insulin-initiated phosphorylation cascades in a similar manner to metformin. This study provides a rationale for exploiting the insulin-sensitizing potential of APS, which has a therapeutic performance almost equivalent to metformin, to enrich our options in the treatment of IR.

/pdf/aps-could-potentially-activate-hepatic-insulin-signaling-in-zmdm6msh6b.pdf

APS could potentially activate hepatic insulin signaling in HFD-induced IR mice.

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miR-146a-5p Plays an Oncogenic Role in NSCLC via Suppression of TRAF6.

Loss of Adipose Growth Hormone Receptor in Mice Enhances Local Fatty Acid Trapping and Impairs Brown Adipose Tissue Thermogenesis.

The role of growth hormone receptor in β cell function.

APS could potentially activate hepatic insulin signaling in HFD-induced IR mice.