Curcumin suppresses cell proliferation and reduces cholesterol absorption in Caco-2 cells by activating the TRPA1 channel.

BACKGROUND: Curcumin (Cur) is a bioactive dietary polyphenol of turmeric with various biological activities against several cancers. Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths. Intestinal cholesterol homeostasis is associated with CRC. Chemotherapy for CRC is related to varied adverse effects. Therefore, natural products with anti-cancer properties represent a potential strategy for primary prevention of CRC. METHODS: The present study used Cur as a therapeutic approach against CRC using the Caco-2 cell line. The cells were treated with different concentrations of Cur for different duration of time and then the proliferation ability of cells was assessed using Cell Counting Kit-8 and 5-Ethynyl-2'-deoxyuridine assays. Oil red O staining and cholesterol assay kit were used to evaluate cellular lipid content and cholesterol outward transportation. Finally, the protein expressions of cholesterol transport-related protein and signal transduction molecules were assessed using Western blot assay. RESULTS: Cur inhibited cell proliferation in Caco-2 cells in a dose- and time-dependent manner by activating the transient receptor potential cation channel subfamily A member 1 (TRPA1) channel. Activation of the TRPA1 channel led to increased intracellular calcium, peroxisome proliferator-activated receptor gamma (PPARγ) upregulation, and the subsequent downregulation of the specificity protein-1 (SP-1)/sterol regulatory element-binding protein-2 (SREBP-2)/Niemann-Pick C1-like 1 (NPC1L1) signaling pathway-related proteins, and finally reduced cholesterol absorption in Caco-2 cells. CONCLUSIONS: Cur inhibits cell proliferation and reduces cholesterol absorption in Caco-2 cells through the Ca2+/PPARγ/SP-1/SREBP-2/NPC1L1 signaling by activating the TRPA1 channel, suggesting that Cur can be used as a dietary supplement for the primary prevention of CRC. In Caco-2 cells, Cur first stimulates calcium influx by activating the TRPA1 channel, further upregulates PPARγ and downregulates SP-1/SREBP-2/NPC1L1 signaling pathway, and finally inhibits the absorption of cholesterol. TRPA1, transient receptor potential cation channel subfamily A member 1; NPC1L1, Niemann-Pick C1-like 1; PPARγ, peroxisome proliferator-activated receptor gamma; SP-1, specificity protein-1; SREBP-2, sterol regulatory element-binding protein-2; Cur, curcumin.

Ghrelin improves endothelial function and reduces blood pressure in Ang II-induced hypertensive mice: Role of AMPK.

BACKGROUND: Endothelial dysfunction is a major pathophysiology observed in hypertension. Ghrelin, a key regulator of metabolism, has been shown to play protective roles in cardiovascular system. However, whether it has the effect of improving endothelial function and lowering blood pressure in Ang II-induced hypertensive mice remains unclear. METHODS: In this study, hypertension was induced by continuous infusion of Ang II with a subcutaneous osmotic pumps and ghrelin (30 µg/kg/day) was intraperitoneal injection for 4 weeks. Acetylcholine-induced endothelium-dependent relaxation in aortae was measured on wire myograph and superoxide production in mouse aortae was assessed by fluorescence imaging. RESULTS: We found that ghrelin had protective effects on Ang II-induced hypertension by inhibiting oxidative stress, increasing NO production, improving endothelial function, and lowering blood pressure. Furthermore, ghrelin activated AMPK signaling in Ang II-induced hypertension, leading to inhibition of oxidative stress. Compound C, a specific inhibitor of AMPK, reversed the protective effects of ghrelin on the reduction of oxidative stress, the improvement of endothelial function and the reduction of blood pressure. CONCLUSIONS: our findings indicated that ghrelin protected against Ang II-induced hypertension by improving endothelial function and lowering blood pressure partly through activating AMPK signaling. Thus, ghrelin may be a valuable therapeutic strategy for hypertension.

A Novel Heterozygous NF1 Variant in a Neurofibromatosis-Noonan Syndrome Patient with Growth Hormone Deficiency: A Case Report

Neurofibromatosis-Noonan syndrome (NFNS), a rare autosomal-dominant hereditary disease, is characterized by clinical manifestations of both neurofibromatosis type 1 (NF1) and NS. We present a case of NFNS with short stature caused by a heterozygous nonsense variant of the NF1 gene. A 12-year-old boy was admitted because of short stature, numerous café-au-lait spots, low-set and posteriorly rotated ears, sparse eyebrows, broad forehead, and inverted triangular face. Cranial and spinal magnetic resonance imaging showed abnormal nodular lesions. Molecular analysis revealed a novel heterozygous c.6189 C > G (p.(Tyr2063*)) variant in the NF1 gene. The patient was not prescribed recombinant growth hormone (GH) therapy because exogenous GH may have enlarged the abnormal skeletal lesions. During follow-up, Lisch nodules were found in the ophthalmologic examination. NFNS, a variant form of NF1, is caused by heterozygous mutations in the NF1 gene. The mechanism of GH deficiency caused by NF1 is still unclear. Whether NFNS patients should be treated with exogenous GH remains controversial.

Effects of circulating member B of the family with sequence similarity 3 on the risk of developing metabolic syndrome and its components: A 5-year prospective study.

AIMS/INTRODUCTION: Member B of the family with sequence similarity 3 (FAM3B), also known as pancreatic-derived factor, is mainly synthesized and secreted by islet ß-cells, and plays a role in abnormal metabolism of glucose and lipids. However, the prospective association of FAM3B with metabolic disorders remains unclear. The present study aimed to reveal the predictive relationship between pancreas-specific cytokine and metabolic syndrome (MetS). MATERIALS AND METHODS: A total of 210 adults (88 men and 122 women) without MetS, aged between 40 and 65 years, were recruited and received a comprehensive health examination. Baseline serum FAM3B levels were determined by sandwich enzyme-linked immunosorbent assay. Subsequently, all participants underwent a follow-up examination after 5 years. MetS was identified in accordance with the International Diabetes Federation criteria. RESULTS: During follow up, 35.7% participants developed MetS. In comparison with the non-MetS group, participants with MetS had an increased serum FAM3B at baseline (21.85 ng/mL [19.38, 24.17 ng/mL] vs 28.56 ng/mL [25.32, 38.10 ng/mL], P < 0.001). Moreover, serum FAM3B was significantly associated with variations in fasting plasma insulin (r = -0.306, P < 0.001), homeostasis model assessment of ß-cell function (r = -0.328, P < 0.001) and homeostasis model assessment of insulin resistance (r = -0.191, P = 0.006). Furthermore, a positive correlation between baseline FAM3B and the incidence of MetS was observed, even after multivariable adjustment (relative risk 1.23 [1.15, 1.31], P < 0.001). Furthermore, the optimal cut-off values of FAM3B was 23.98 ng/mL for predicting MetS based on the Youden Index. CONCLUSIONS: Elevated circulating FAM3B might be considered as a predictor of newly-onset MetS and its progression.