The role of dietary salt in metabolism and energy balance: Insights beyond cardiovascular disease.

Dietary salt (NaCl) is essential to an organism's survival. However, today's diets are dominated by excessive salt intake, which significantly impacts individual and population health. High salt intake is closely linked to cardiovascular disease (CVD), especially hypertension, through a number of well-studied mechanisms. Emerging evidence indicates that salt overconsumption may also be associated with metabolic disorders. In this review, we first summarize recent updates on the mechanisms of salt-induced CVD, the effects of salt reduction and the use of salt substitution as a therapy. Next, we focus on how high salt intake can impact metabolism and energy balance, describing the mechanisms through which this occurs, including leptin resistance, the overproduction of fructose and ghrelin, insulin resistance and altered hormonal factors. A further influence on metabolism worth noting is the reported role of salt in inducing thermogenesis and increasing body temperature, leading to an increase in energy expenditure. While this result could be viewed as a positive metabolic effect because it promotes a negative energy balance to combat obesity, caution must be taken with this frame of thinking given the deleterious consequences of chronic high salt intake on cardiovascular health. Nevertheless, this review highlights the importance of salt as a noncaloric nutrient in regulating whole-body energy homeostasis. Through this review, we hope to provide a scientific framework for future studies to systematically address the metabolic impacts of dietary salt and salt replacement treatments. In addition, we hope to form a foundation for future clinical trials to explore how these salt-induced metabolic changes impact obesity development and progression, and to elucidate the regulatory mechanisms that drive these changes, with the aim of developing novel therapeutics for obesity and CVD.

Discovery of New Glucose Uptake Inhibitors as Potential Anticancer Agents by Non-Radioactive Cell-Based Assays.

Tumor cells rely on aerobic glycolysis to support growth and survival, thus require more glucose supply. Glucose transporters GLUTs, primarily GLUT1, are overexpressed in various cancers. Targeting GLUTs has been regarded as a promising anticancer strategy. In this study, we first evaluated 75 potential GLUT1 inhibitors obtained from virtual screening of the NCI chemical library by a high-throughput cell-based method using a fluorescent glucose analogue 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxy-d-glucose (2-NBDG) in COS-7 and SKOV3 cells that express high levels of GLUT1. Four compounds, #12, #16, #43 and #69, that significantly inhibited glucose uptake were further evaluated using flow cytometry directly measuring 2-NBDG uptake at the single-cell level and a Glucose Uptake-GloTM assay indirectly measuring 2-deoxy-d-glucose uptake in SKOV3, COS-7 or MCF-7 cells. The inhibitory effect on cancer cell growth was also determined in SKOV3 and MCF-7 cells, and #12 exhibited the best growth inhibitory effect equivalent to a known GLUT1 inhibitor WZB117. Although the anticancer effect of the identified potential GLUT1 inhibitors was moderate, they may enhance the activity of other anticancer drugs. Indeed, we found that #12 synergistically enhanced the anticancer activity of metformin in SKOV3 ovarian cancer cells.

MKRN1 promotes colorectal cancer metastasis by activating the TGF-ß signalling pathway through SNIP1 protein degradation.

BACKGROUND: The Makorin ring finger protein 1 (MKRN1) gene, also called RNF61, is located on the long arm of chromosome 7 and is a member of the RING finger protein family. The E3 ubiquitin ligase MKRN1 is closely linked to tumour development, but the exact mechanism needs to be elucidated. In this study, we aimed to investigate the specific mechanism and role of MKRN1 in colorectal cancer (CRC) development. METHODS: MKRN1 expression in CRC was analysed using the Cancer Cell Line Encyclopaedia and the Cancer Genome Atlas (TCGA) databases. Rectal tumour tissues were frozen to explore the MKRN1 expression in CRC and its clinical significance. The impact of MKRN1 on CRC cell proliferation and migration was observed using CCK8, colony formation, wound healing, and transwell assays. A combination of MKRN1 quantitative proteomics, ubiquitination modification omics analysis, and a string of in vitro and in vivo experiments revealed the potential mechanisms by which MKRN1 regulates CRC metastasis. RESULTS: MKRN1 expression was significantly elevated in CRC tissues compared to paracancerous tissues and was positively linked with prognosis (P < 0.01). MKRN1 downregulation inhibits CRC cell proliferation, migration, and invasion. Conversely, MKRN1 overexpression promotes the proliferation, migration, and invasion of CRC cells. Mechanistically, MKRN1 induces epithelial-mesenchymal transition (EMT) in CRC cells via ubiquitination and degradation of Smad nuclear-interacting protein 1 (SNIP1). Furthermore, SNIP1 inhibits transforming growth factor-ß (TGF-ß) signalling, and MKRN1 promotes TGF-ß signalling by degrading SNIP1 to induce EMT in CRC cells. Finally, using conditional knockout mice, intestinal lesions and metastatic liver microlesions were greatly reduced in the intestinal knockout MKRN1 group compared to that in the control group. CONCLUSIONS: High MKRN1 levels promote TGF-ß signalling through ubiquitination and degradation of SNIP1, thereby facilitating CRC metastasis, and supporting MKRN1 as a CRC pro-cancer factor. The MKRN1/SNIP1/TGF-ß axis may be a potential therapeutic target in CRC.

[Establishment of Drug-Resistant Cell Lines of Acute Myeloid Leukemia and Correlation of Sirt1 and PGC-1α Expression Levels with Drug Resistance].

OBJECTIVE: To construct cytarabine-resistant acute myeloid leukemia (AML) cell lines, and explore the correlation between Sirt1, PGC-1α expression levels and drug resistance. METHODS: Human acute promyelocytic leukemia Kasumi-1 cells were induced by the method of gradually increasing the concentration of Ara-C drug. The IC50 value of Kasumi-1 cells before and after drug addition was detected by CCK-8 method, so as to construct Ara-C resistant cell lines. The expression levels of Sirt1 and PGC-1α mRNA in Kasumi-1 drug-resistant cell lines and their parental cell lines were detected by real-time fluorescence quantitative PCR, and the expression levels of Sirt1 and PGC-1α protein in kasumi-1 drug-resistant cell lines and their parental cell lines were detected by Western blot. RESULTS: The constructed Kasumi-1 cell line had common morphological characteristics of drug-resistant cell lines under microscope, and the drug resistance index was greater than 5, indicating that Kasumi-1 drug-resistant cells had good drug resistance after the construction. The RT-qPCR and Western blot assays showed that the expression levels of Sirt1 and PGC-1α mRNA and protein in the drug-resistant cell lines were higher than those of the parental cell lines (P<0.001). CONCLUSION: AML cell lines resistant to Ara-C can be successfully induced by the method of gradually increasing the concentration, and the co-high expression of Sirt1 and PGC-1α may mediate the drug resistance of AML cells.

[Melatonin Induced Apoptosis of RPMI 8226 Cells through Endoplasmic Reticulum Stress].

OBJECTIVE: To investigate the effect of melatonin (MLT) on the proliferation and apoptosis of human multiple myeloma cell line RPMI 8226 and its possible mechanism. METHODS: RPMI 8226 cells were cultured in vitro, and different concentrations of MLT were treated on RPMI 8226 cells. The effects of MLT on RPMI 8226 cell proliferation were detected by CCK-8 assay and methylcellulose cloning assay, and the effects of MLT on cell apoptosis were detected by AnnexinV-FITC /PI, flow cytometry. Western blot was used to determine the expression of apoptosis and endoplasmic reticulum stress-related proteins in each group, and CCK-8 assay was used to determine the effect of MLT combined with bortezemib on the viability of RPMI 8226 cells. RESULTS: MLT inhibited the proliferation of RPMI 8226 cells in a dose- and time-dependent manner (r=-0.9777，r=-0.9951). With the increase of MLT concentration, the number of clones decreased, the apoptosis of RPMI 8226 cells increased (P<0.05), the expression of anti-apoptotic protein XIAP decreased, the expression of apoptotic proteins Bax and Caspase3 increased, and the expression of endoplasmic reticulum stress-related proteins increased. Compared with the control group, the survival of RPMI 8226 cells in the MLT and BTZ combined group significantly decreased (P<0.01). CONCLUSION: MLT can inhibit the proliferation of RPMI 8226 cells, promote the apoptosis of RPMI 8226 cells, and enhance the anti-tumor effect of BTZ on RPMI 8226 cells. The mechanism may be related to endoplasmic reticulum stress.

Study on laminar viscosity and zero shear viscosity of latex systems.

The flowing nature and rheological properties of polymethyl methacrylate latex systems in a coaxial cylinder viscometer were studied on the basis of laminar shear flow model and rheological experimental data. The physical meaning of laminar viscosity (eta(i,j)) and zero shear viscosity (eta(0)) were described. We assumed that laminar shear flows depended on position and shear time, so microrheological parameters were the function of position and shear time. eta(i,j) was the viscosity of any shear sheet i between two neighboring laminar shear flows at time t; j was denoted as j=t/Deltat; and Deltat was the interacting time of two particles or two laminar shear flows. tau(i,j) and gamma(i,j) were shear stress and shear rate of any shear sheet i at j moment. According to Newton regulation tau(i,j)=eta(i,j)gamma(i,j), apparent viscosity eta(a) should be a statistically mean value of j shear sheets laminar viscosity at j moment, i.e., eta(a)= summation operator(i=j)eta(i,j)gamma(i,j)/ summation operator(i=j)gamma(i,j). eta(0) was defined as shear viscosity between a laminar shear flow and a still fluid surface, i.e., eta(0)=(tau(i,j)/gamma(i,j))(j-i-->0). These new ideas described above may be helpful in the study of the micromechanisms of latex particle systems and worthy of more research.