[Novel role of intracellular ATP in obesity pathology].

ATP is an important energy source for cells. Traditionally, intracellular ATP levels are believed to be relatively stable and will not rise consistently in the physiological conditions. However, new studies suggest that ATP levels may rise in multiple tissues under the condition of energy surplus contributing to the metabolic disorders in obesity. However, the molecular mechanism of ATP elevation remains unknown in obesity except the increase in energy supply. Based on our experimental results and the findings reported in the literature, we discuss the cellular and molecular mechanisms by which ATP levels are regulated in cells by multiple factors, including superoxide ions, mitochondrial flash, antioxidants, anti-apoptotic molecule Bcl-xL, AMP-activated protein kinase (AMPK) and metformin. Contribution of these factors to the alteration of ATP set-point will be discussed together with their impact on insulin resistance in type 2 diabetes mellitus. With a focus on the energy surplus in obesity, we explore the mechanism of insulin resistance induced by ATP elevation and provide an answer to the contradiction between the new experimental results and the traditional viewpoint of intracellular ATP. We propose that elevation of intracellular ATP may lead to metabolic disorder in obesity through activation of a feedback mechanism that inhibits mitochondrial function.

Dihydroartemisinin inhibits the growth and invasion of gastric cancer cells by regulating cyclin D1-CDK4-Rb signaling.

BACKGROUND: Dihydroartemisinin (DHA), a semisynthetic derivative of artemisinin, has a broad range of biological properties, including antitumor activity. However, the mechanisms by which DHA affects the tumorigenesis of gastric carcinoma (GC) are poorly understood. MATERIAL AND METHODS: The targets of DHA were identified by network pharmacology, and the association of CDK4 with clinicopathological characteristics and prognosis in patients with GC was analyzed by using TCGA data. CCK8, Transwell and flow cytometric analyses, as well as a tumor xenograft model, were used to assess the effects of DHA on the growth and migration of GC cells. qRT-PCR and Western blot analyses were used to determine the effects of DHA on the cyclin D1-CDK4-Rb signaling pathway. RESULTS: We identified 13 DHA targets and measured their expression of whichCDK4 expression levels were substantially higher in GC tissues than those in adjacent normal tissues, and high CDK4 expression acted as an independent prognostic factor of poor survival in patients with GC. DHA suppressed cell proliferation, migration and invasion in vitro and in vivo and induced G1 phase cell cycle arrest in a dose-dependent manner by regulating cyclin D1-CDK4-Rb signaling. CONCLUSIONS: DHA inhibits the tumorigenesis and invasion of GC by regulating cyclin D1-CDK4-Rb signaling and may provide therapeutic strategies for the treatment of GC.

Sanguinarine inhibits the tumorigenesis of gastric cancer by regulating the TOX/DNA-PKcs/ KU70/80 pathway.

Sanguinarine (SAG), a benzophenanthridine alkaloid extracted from Sanguinaria canadensis, exerts antioxidant, anti-inflammatory and antiproliferative activities in a variety of malignancies. However, the underlying mechanisms by which SAG affects the tumorigenesis of gastric cancer (GC) are unclear. The common targets of SAG and GC were identified by network pharmacology, and the association of thymocyte selection-associated high mobility group box (TOX) with the clinicopathological characteristics and prognosis of patients with GC was analyzed by using datasets from The Cancer Genome Atlas (TCGA). 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assays, colony formation assays, flow cytometry analysis, and a xenograft tumor model were conducted to assess the effects of SAG on the growth of GC cells, and Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analysis were used to determine the effects of SAG on the TOX/DNA-PKcs/KU70/80 signaling pathway. We identified 9 collective targets of SAG and GC, of which TOX expression levels were dramatically downregulated in GC tissues compared with adjacent normal tissues, and a low expression of TOX served as an independent prognostic factor of poor survival in patients with GC. SAG suppressed cell viability, colony formation and in vivo tumorigenesis and induced cell apoptosis and cell cycle arrest. Furthermore, SAG increased the expression levels of TOX but decreased those of DNA-PKcs and KU70/80 in GC cells. Our findings indicate that SAG inhibits the tumorigenesis of GC cells by regulating TOX/DNA-PKcs/KU70/80 signaling and may provide therapeutic strategies for the treatment of GC.

Intralesional and topical glucocorticoids for pretibial myxedema: A case report and review of literature.

Pretibial myxedema (PTM), an uncommon manifestation of Graves' disease (GD), is a local autoimmune reaction in the cutaneous tissue. The treatment of PTM is a clinical challenge. We herein report on a patient with PTM who achieved complete remission by multipoint subcutaneous injections of a long-acting glucocorticoid and topical glucocorticoid ointment application for a self-controlled study. A 53-year-old male presented with a history of GD for 3.5 years and a history of PTM for 1.5 years. Physical examination revealed slight exophthalmos, a diffusely enlarged thyroid gland, and PTM of both lower extremities. One milliliter of triamcinolone acetonide (40 mg) was mixed well with 9 mL of 2% lidocaine in a 10 mL syringe. Multipoint intralesional injections into the skin lesions of the right lower extremity were conducted with 0.5 mL of the premixed solution. A halometasone ointment was used once daily for PTM of the left lower extremity until the PTM had remitted completely. The patient's PTM achieved complete remission in both legs after an approximately 5-mo period of therpy that included triamcinolone injections once a week for 8 wk and then once a month for 2 mo for the right lower extremity and halometasone ointment application once daily for 8 wk and then once 3-5 d for 2 mo for the left lower extremity. The total dosage of triamcinolone acetonide for the right leg was 200 mg. Our experience with this patient suggests that multipoint subcutaneous injections of a long-acting glucocorticoid and topical glucocorticoid ointment application are safe, effective, and convenient treatments. However, the topical application of a glucocorticoid ointment is a more convenient treatment for patients with PTM.