Ataxia-Telangiectasia Mutated Is Involved in Autolysosome Formation.

Ataxia-telangiectasia mutated (ATM), a master kinase of the DNA damage response (DDR), phosphorylates a multitude of substrates to activate signaling pathways after DNA double-strand breaks (DSBs). ATM inhibitors have been evaluated as anticancer drugs to potentiate the cytotoxicity of DNA damage-based cancer therapy. ATM is also involved in autophagy, a conserved cellular process that maintains homeostasis by degrading unnecessary proteins and dysfunctional organelles.

EI24, as a Component of Autophagy, Is Involved in Pancreatic Cell Proliferation.

Autophagy is a highly conserved cellular process in which cytoplasmic materials are degraded and recycled as energy sources when nutrient supplies are lacking. Established tumor cells require autophagy for cell growth and tumor promotion. In particular, the survival of pancreatic tumor cells appears to be strongly dependent on autophagy, referred to as autophagy addiction.

Fanconi anemia protein FANCD2 is activated by AICAR, a modulator of AMPK and cellular energy metabolism.

FANCD2 is a pivotal molecule in the pathogenesis of Fanconi anemia (FA), an autosomal recessive human syndrome with diverse clinical phenotypes, including cancer predisposition, short stature, and hematological abnormalities. In our previous study, we detected the functional association of FANC proteins, whose mutations are responsible for the onset of FA, with AMPK in response to DNA interstrand crosslinking lesions. Because AMPK is well known as a critical sensing molecule for cellular energy levels, we checked whether FANCD2 activation occurs after treatments affecting AMPK and/or cellular energy status.

DDRI-9: a novel DNA damage response inhibitor that blocks mitotic progression.

The DNA damage response (DDR) is an emerging target for cancer therapy. By modulating the DDR, including DNA repair and cell cycle arrest, the efficacy of anticancer drugs can be enhanced and side effects reduced. We previously screened a chemical library and identified novel DDR inhibitors including DNA damage response inhibitor-9 (DDRI-9; 1H-Purine-2,6-dione,7-[(4-fluorophenyl)methyl]-3,7-dihydro-3-methyl-8-nitro).

Ouabain, a cardiac glycoside, inhibits the Fanconi anemia/BRCA pathway activated by DNA interstrand cross-linking agents.

Modulation of the DNA repair pathway is an emerging target for the development of anticancer drugs. DNA interstrand cross-links (ICLs), one of the most severe forms of DNA damage caused by anticancer drugs such as cisplatin and mitomycin C (MMC), activates the Fanconi anemia (FA)/BRCA DNA repair pathway. Inhibition of the FA/BRCA pathway can enhance the cytotoxic effects of ICL-inducing anticancer drugs and can reduce anticancer drug resistance.

Exercise and dexamethasone oppositely modulate beta-cell function and survival via independent pathways in 90% pancreatectomized rats.

Long-term dexamethasone (DEX) treatment is well known for its ability to increase insulin resistance in liver and adipose tissues leading to hyperinsulinemia. On the other hand, exercise enhances peripheral insulin sensitivity. However, it is not clear whether DEX and/or exercise affect beta-cell mass and function in diabetic rats, and whether their effects can be associated with the modulation of the insulin/IGF-I signaling cascade in pancreatic beta-cells.

Exercise enhances insulin and leptin signaling in the cerebral cortex and hypothalamus during dexamethasone-induced stress in diabetic rats.

Exercise and dexamethasone (DEX) are known to have opposite effects on peripheral insulin resistance. However, their effects and mechanism on brain glucose metabolism have been poorly defined. We investigated the modulation of the hypothalamo-pituitary-adrenal (HPA) axis and insulin/leptin signaling associated with glucose utilization in the brains of 90% pancreatectomized diabetic rats, which had been administered two dosages of DEX and exercised for 8 weeks.

Improvement of insulin resistance and insulin secretion by water extracts of Cordyceps militaris, Phellinus linteus, and Paecilomyces tenuipes in 90% pancreatectomized rats.

The effect of supplementation with Phellinus linteus (P. linteus), Paecilomyces tenuipes (P. tenuipes), and Cordyceps militaris (C.

The insulin sensitizing effect of homoisoflavone-enriched fraction in Liriope platyphylla Wang et Tang via PI3-kinase pathway.

In the present study, we screened candidates for enhancing insulin action, using glucose uptake as an indicator, from Liriope platyphylla Wang et Tang (LPWT) extract, Liliaceae, in 3T3-L1 adipocytes. The mechanism of insulin sensitizing action in the fractions was also investigated. LPWT extract with 70% MeOH was sequentially separated with Diaion HP-20 and silica gel column chromatography.

A high carbohydrate diet induces insulin resistance through decreased glucose utilization in ovariectomized rats.

Background: Recent research has reported that high sugar diets increase insulin resistance, without abdominal obesity, in male, but not female Wistar rats. Whether a high sucrose (SU) diet increased insulin resistance in ovariectomized (OVX) rats was determined.

Methods: Female Sprague Dawley rats, weighing 273 +/- 20 g, had either an ovariectomy or a sham operation (sham).