Pharmacokinetics and clinical efficacy of 6'-sialyllactose in patients with GNE myopathy: Randomized pilot trial.

GNE myopathy, caused by biallelic mutations in the GNE gene, is characterized by initial ankle dorsiflexor weakness and rimmed vacuoles in the muscle histopathology, resulting in reduced sialic acid production. Sialyllactose is a source of sialic acid. We performed a pilot clinical trial to analyze the pharmacokinetic properties of 6'-sialyllactose (6SL) and evaluated the safety, and efficacy of oral 6SL in patients with GNE myopathy. Ten participants were in the pharmacokinetic study, and 20 in the subsequent clinical trial. For the pharmacokinetic study, participants were administered either 3 g (low-dose) or 6 g (high-dose) of 6SL in a single dose. Plasma concentrations of 6SL, sialic acid, and sialic acid levels on the surface of red blood cells were periodically assessed in blood samples. Patients were randomly allocated to test (low- and high-dose groups) or placebo groups for the trial. Motor function, ambulation, plasma 6SL and sialic acid concentrations, GNE myopathy-functional activity scale scores, and MRI findings were assessed. 6SL was well tolerated, except for self-limited gastrointestinal discomfort. Free sialic acid in both low- and high-dose groups significantly increased at 6 and 12 weeks, but not in the placebo group. In the high-dose group, proximal limb powers improved with daily 6SL. Considering the fat fraction on muscle MRI, results in the high-dose group were superior to those in the low-dose group. 6SL may be a good candidate for GNE myopathy therapeutics as it induces an increase or reduces the decrease in limb muscle power, attenuates muscle degeneration, and improves the biochemical properties of sialic acid.

Sauchinone inhibits the proliferation, migration and invasion of breast cancer cells by suppressing Akt-CREB-MMP13 signaling pathway.

Sauchinone, a lignan isolated from Saururus chinenesis, is known to exhibit anti-inflammatory and anti-oxidant effects. Recently, sauchinone has been reported to inhibit the growth of various cancer cells, but its effects on breast cancer cells remain poorly understood. In the present study, we investigated the effects of sauchinone on the growth of breast cancer cells along with the underlying molecular mechanisms. Our results show that sauchinone treatment markedly inhibited the proliferation, migration, and invasion of breast cancer cells. Sauchinone reduced the phosphorylation of Akt, ERK, and CREB increased by transforming growth factor-ß (TGF-ß). In particular, sauchinone treatment suppressed the expression of matrix metalloproteinase (MMP)-13 (MMP13) by regulating the Akt-CREB signaling pathway. Sauchinone was less effective in inhibiting cell migration in Mmp13-knockdown cells than in control cells, suggesting that MMP13 may be a novel target for sauchinone. Our study suggests that sauchinone inhibits the growth of breast cancer cells by attenuating the Akt-CREB-MMP13 pathway. In addition, the targeted inhibition of MMP13 by sauchinone represents a promising approach for the treatment of breast cancer.

Gremlin-1 Promotes Metastasis of Breast Cancer Cells by Activating STAT3-MMP13 Signaling Pathway.

Gremlin-1 (GREM1), one of the bone morphogenetic protein (BMP) antagonists, can directly bind to BMPs. GREM1 is involved in organogenesis, tissue differentiation, and organ fibrosis. Recently, numerous studies have reported the oncogenic role of GREM1 in cancer. However, the role of GREM1 in metastasis of breast cancer cells and its underlying mechanisms remain poorly understood. The role of GREM1 in breast cancer progression was assessed by measuring growth, migration, and invasion of breast cancer cells. An orthotopic breast cancer mouse model was used to investigate the role of GREM1 in lung metastasis of breast cancer cells. GREM1 knockdown suppressed the proliferation of breast cancer cells, while its overexpression increased their growth, migration, and invasion. Cells with Grem1-knockdown showed much lower tumor growth rates and lung metastasis than control cells. GREM1 enhanced the expression of matrix metalloproteinase 13 (MMP13). A positive correlation between GREM1 and MMP13 expression was observed in breast cancer patients. GREM1 activated signal transducer and activator of transcription 3 (STAT3) transcription factor involved in the expression of MMP13. Our study suggests that GREM1 can promote lung metastasis of breast cancer cells through the STAT3-MMP13 pathway. In addition, GREM1 might be a promising therapeutic target for breast cancer metastasis.

Gremlin-1 activates Akt/STAT3 signaling, which increases the glycolysis rate in breast cancer cells.

Gremlin-1 (GREM1), one of the antagonists of bone morphogenetic proteins (BMPs), has recently been reported to be overexpressed in a variety of cancers including breast cancer. GREM1 is involved in tumor promotion, but little is known about its role in the glycolysis of cancer cells. In this study, we investigated the role of GREM1 in glycolysis of breast cancer cells and its underlying molecular mechanisms. We first observed that glucose uptake and lactate production were increased in GREM1-overexpressing breast cancer cells. GREM1 increased the expression of hexokinase-2 (HK2), which catalyzes the phosphorylation of glucose, the first step in glycolysis. In addition, GREM1 activated STAT3 transcription factor through the ROS-Akt signaling pathway. The ROS-Akt-STAT3 axis activated by GREM1 was involved in promoting glucose uptake by increasing the expression of HK2 in breast cancer cells. Therefore, our study suggested a new mechanism by which GREM1 is involved in breast cancer promotion by increasing glycolysis in breast cancer cells.

Gremlin-1 augments the oestrogen-related receptor α signalling through EGFR activation: implications for the progression of breast cancer.

BACKGROUND: Gremlin-1 (GREM1), one of the bone morphogenetic protein antagonists, is involved in organogenesis, tissue differentiation and kidney development. However, the role of GREM1 in cancer progression and its underlying mechanisms remain poorly understood. METHODS: The role of GREM1 in breast cancer progression was assessed by measuring cell viability, colony formation, 3D tumour spheroid formation/invasion and xenograft tumour formation. Chromatin immunoprecipitation, a luciferase reporter assay and flow cytometry were performed to investigate the molecular events in which GREM1 is involved. RESULTS: GREM1 expression was elevated in breast cancer cells and tissues obtained from breast cancer patients. Its overexpression was associated with poor prognosis in breast cancer patients, especially those with oestrogen receptor (ER)-negative tumours. GREM1 knockdown inhibited the proliferation of breast cancer cells and xenograft mammary tumour growth, while its overexpression enhanced their viability, growth and invasiveness. Oestrogen-related receptor α (ERRα), an orphan nuclear hormone receptor, directly interacted with the GREM1 promoter and increased the expression of GREM1. GREM1 also enhanced the promoter activity of ESRRA encoding ERRα, comprising a positive feedback loop. Notably, GREM1 bound to and activated EGFR, a well-known upstream regulator of ERRα. CONCLUSIONS: Our study suggests that the GREM1-ERRα axis can serve as a potential therapeutic target in the management of cancer, especially ER-negative tumour.

DHA inhibits Gremlin-1-induced epithelial-to-mesenchymal transition via ERK suppression in human breast cancer cells.

Docosahexaenoic acid (DHA) is an omega-3 fatty acid abundant in fish oils. It is known to have an inhibitory effect on various diseases such as inflammation, diabetes, and cancer. Epithelial-to-mesenchymal transition (EMT) is a process that epithelial cells gain migratory property to become mesenchymal cells involved in wound healing, organ fibrosis, and cancer progression. Gremlin-1 (GREM1) is a bone morphogenetic protein antagonist known to play a role in EMT. However, the role of GREM1 in the induction of EMT in human breast cancer cells and the effect of DHA on GREM1-induced EMT remain unclear. Establishment of GREM1 knockdown cell lines was performed using lentiviral shRNAs. Expression of EMT markers was determined by qRT-PCR and Western blotting. Effect of GREM1 and/or DHA on cell migration was investigated using wound healing assay. The level of GREM1 expression in human breast cancer tissues was determined by Oncomine database mining. GREM1 induced the expression of genes including N-cadherin, vimentin, and Slug. GREM1 promoted the migration of human breast cancer cells. GREM1 enhanced the expression of phosphorylated extracellular signal-regulated kinase (p-ERK) and the ERK activation was involved in EMT. Interestingly, DHA reduced the expression of GREM1. DHA also inhibited the expression of mesenchymal cell-associated genes and cell migration induced by GREM1. Furthermore, DHA suppressed the expression of p-ERK induced by GREM1. These results indicate that GREM1-ERK axis plays a role in EMT in human breast cancer cells and DHA is a putative compound that can inhibit EMT by inhibiting GREM1 signal transduction.

Suppressive effects of dehydrocostus lactone on the toll-like receptor signaling pathways.

Toll-like receptors (TLRs) are a group of pattern-recognition receptors (PRRs) that are at the core of innate and adaptive immune responses. TLRs activation triggers the activation of two downstream signaling pathways, the myeloid differential factor 88 (MyD88)- and toll-interleukin-1 receptor domain-containing adapter inducing interferon-ß (TRIF)-dependent pathways. To evaluate the therapeutic potential of DHL, a natural sesquiterpene lactone derived from Inulahelenium L. and Saussurea lappa, we examined its effect on signal transduction via the TLR signaling pathways. DHL inhibited the activation of nuclear factor-κB (NF-κB) and interferon regulatory factor 3 (IRF3), the representative transcription factors involved in the inflammatory response, induced by TLR agonists, as well as the expression of cyclooxygenase-2 and interferon inducible protein-10. DHL also inhibited the activation of NF-κB and IRF3 induced by the overexpression of downstream signaling components of the TLRs signaling pathways. All results suggest that DHL might become a new therapeutic drug for a variety of inflammatory diseases.