Patulin and LL-Z1640-2 induce apoptosis of cancer cells by decreasing endogenous protein levels of Zic family member 5.

Zic family member 5 (ZIC5) is a transcription factor that promotes the survival of several cancer cell types. As ZIC5 is expressed at minimal levels in normal human adult tissues, it is a potential therapeutic target. In this study, we screened a chemical library containing 3398 compounds that includes pre-existing drugs and compounds with known effects to identify ZIC5 inhibitors. In the first screening, 18 hit compounds decreased GFP intensity in melanoma A375 cells overexpressing GFP-tagged ZIC5. In the second screening, five compounds that attenuated ZIC5 protein levels in A375 cells were identified. Among them, LL-Z1640-2 and patulin selectively induced apoptosis in melanoma cells expressing ZIC5, while only inducing very low levels of apoptosis in normal human melanocytes, which have no detectable ZIC5 expression. LL-Z1640-2 and patulin also induced apoptosis in BRAF inhibitor-resistant melanoma, pancreatic cancer, cholangiocarcinoma and colorectal cancer cells. LL-Z1640-2- and patulin-mediated suppression of melanoma proliferation were rescued by ZIC5 overexpression. These results suggest that LL-Z1640-2 and patulin are promising compounds that decrease ZIC5 expression to induce apoptosis in cancer cells.

Trehalose accumulation and radiation resistance due to prior heat stress in Saccharomyces cerevisiae.

In this study, we examined the accumulation of trehalose, a stress-responsive substance, upon gamma-ray irradiation by evaluating the cause of trehalose accumulation and the development of gamma-ray resistance through intracellular trehalose accumulation. Saccharomyces cerevisiae cells cultured to the logarithmic growth phase were irradiated with gamma rays, and the intracellular trehalose content was measured. However, trehalose was not detectable. The yeast cells with trehalose accumulation caused by pre-treatment at 40 °C were irradiated with gamma rays, and the resistance of these cells to gamma radiation was compared with that of cells without heat treatment. Trehalose accumulation resulted in gamma-ray resistance and suppressed the increase in reactive oxygen species, lipid peroxidation, and DNA double-strand break production in yeast cells. The tests were also performed with a trehalose-6-phosphate-synthase (TPS1)-deficient mutant strain (Δtps1) unable to synthesize trehalose, and the results revealed that TPS1 was involved in protection against oxidative stress.

The Impact of Carbohydrate Management on Coleoptile Elongation in Anaerobically Germinating Seeds of Rice (Oryza sativa L.) under Light and Dark Cycles.

The ability of rice to elongate coleoptiles under oxygen deprivation is a determinant of anaerobic germination tolerance, critical for successful direct seeding. Most studies on anaerobic coleoptile elongation have been performed under constant darkness or in flooded soils because a drilling method was the primary approach for direct seeding of rice. However, aerial seeding is becoming popular, in which seeds which land on flooded soils are exposed to light during the daytime. Here, we investigated physiological mechanisms underlying anaerobic elongation of coleoptiles under light and dark cycles. This study identified two novel varieties, LG and L202, enabling the development of long coleoptiles under oxygen limitation, comparable to well-characterized varieties with strong anaerobic germination tolerance. Germination experiments using these two tolerant and two intolerant varieties, including Takanari and IR64, revealed that light and dark cycles increased coleoptile length in LG, Takanari, and IR64 relative to constant darkness. Interestingly, even in intolerant lines, dramatic starch breakdown and soluble carbohydrate accumulation occurred under oxygen limitation. However, intolerant lines were more susceptible to a representative soluble sugar, glucose, than tolerant lines under oxygen deprivation, suggesting that coleoptile growth can be inhibited in intolerant lines due to hypersensitivity to soluble sugars accumulated in anaerobically germinating seeds.

Zic family member 5 promotes survival in human pancreatic cancer and cholangiocarcinoma cells.

Pancreatic ductal adenocarcinoma (PDAC) and cholangiocarcinoma (CCA) are malignant tumors with poor prognosis because of the limited effectiveness of traditional chemotherapy and few effective molecular therapeutic agents. Here, we determined the essential roles of Zic family member 5 (ZIC5) in the survival of PDAC and CCA cells. The results showed that ZIC5 is strongly expressed in PDAC and CCA tissues, while ZIC5 expression is barely observed in most normal human adult tissues. Furthermore, ZIC5 expression is related to poor prognosis of patients with PDAC. ZIC5 knockdown via small interfering RNA decreased the phosphorylation of signal transducer and activator of transcription 3 (STAT3), a protein that is associated with PDAC and CCA aggressiveness. However, ZIC5 knockdown induced cell death regardless of STAT3 activation, which is promoted by interleukin (IL) -6, a factor associated with inflammation. Furthermore, knockdown of ZIC5 in PDAC and CCA cells additively or synergistically induced apoptosis with the anti-cancer drug gemcitabine. Thus, ZIC5 constitutes a potential therapeutic target for the treatment of PDAC and CCA.

[A case of small-cell lung carcinoma accompanied by the syndrome of inappropriate secretion of antidiuretic hormone and Lambert-Eaton myasthenic syndrome].

Although the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and Lambert-Eaton myasthenic syndrome (LEMS) are often individually accompanied by small-cell lung carcinoma, simultaneous occurrence of the 2 syndromes is rare. A 61-year-old man was admitted to our hospital because of fatigue and myasthenia in the extremities, and small-cell lung carcinoma with pulmonary metastasis was diagnosed, together with SIADH and LEMS. These syndromes markedly ameliorated following tumor shrinkage, with 4 cycles of chemotherapy consisting of carboplatin and etoposide. On progression of the tumor thereafter, neither syndrome recurred. A literature review disclosed that these syndromes frequently resolve with tumor shrinkage.

Roles of Catalase and Trehalose in the Protection from Hydrogen Peroxide Toxicity in Saccharomyces cerevisiae.

The roles of catalase and trehalose in Saccharomyces cerevisiae subject to hydrogen peroxide (H2O2) treatment were examined by measuring the catalase activity and intracellular trehalose levels in mutants lacking catalase or trehalose synthetase. Intracellular trehalose was elevated but the survival rate after H2O2 treatment remained low in mutants with deletion of the Catalase T gene. On the other hand, deletion of the trehalose synthetase gene increased the catalase activity in mutated yeast to levels higher than those in the wild-type strain, and these mutants exhibited some degree of tolerance to H2O2 treatment. These results suggest that Catalase T is critical in the yeast response to oxidative damage caused by H2O2 treatment, but trehalose also plays a role in protection against H2O2 treatment.

DMAP as an effective catalyst to accelerate the solubilization of waste fiber-reinforced plastics.

Waste fiber-reinforced plastics (FRPs), which are formidable composite plastics for chemical treatment, can be efficiently depolymerized by treatment with supercritical methanol in the presence of catalytic amounts of 4-(dimethylamino)pyridine (DMAP), which is a well-known catalyst for the formation of esters and amides. This novel depolymerization reaction also provides ready separation of the depolymerized products into three components: methanol-soluble oil, CHCl3-soluble solid, and an inorganic residue. Thus, almost complete decomposition of FRP as well as useful separation of the decomposed products was achieved with the present method, and the latter were ready for chemical recycling. Investigation of the reaction profile revealed that the reaction rate increased as the amount of DMAP increased. Unfortunately, DMAP employed in the reaction could not be recovered because of its decomposition catalyzed by dimethyl phthalate, a depolymerized product from waste FRP, under the reaction conditions employed.