Differential chemo-sensitivity of cancer cells, which is attributed to the cellular heterogeneity and phenotypic variation of cancer cells, is considered to be the main reason for tumor recurrence ...after chemotherapy. Here, we generated small cell lung cancer patient-derived tumor organoids and subjected them to long-term expansion with the addition of WNT3A or R-spondin1. We confirmed that the organoids have similar genetic profiles, molecular characteristics, and morphological architectures to the corresponding patient tumor tissue during and after long-term expansion. Interestingly, the cellular heterogeneity of organoids is reflected in their differential response to cisplatin or etoposide. We propose to utilize the organoids as small cell lung cancer patient avatar models that would be ideal for investigating the mechanisms underlying tumor recurrence after chemotherapy, and would ultimately help to develop personalized medicine.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
HER family receptors are frequently deregulated in breast cancer and the deregulation of these receptors is associated with poor prognosis. Thus, these receptors are considered therapeutic targets. ...In the present study, we found that piperlongumine (PL) downregulates the expression of HER family receptors HER1, HER2, and HER3 in breast cancer cells. Downregulation of these receptors by PL is mediated through the generation of reactive oxygen species (ROS), as N-acetyl-cysteine blocks it. Interestingly, the HER2-overexpressing cell lines BT474 and SkBr3 are somewhat more sensitive to PL than the low HER2-expressing cell line MCF7. In addition, the overexpression of HER2 increases the sensitivity of MCF7 cells to PL. Collectively, our data indicate the therapeutic potential of PL in the treatment of breast cancer.
•Piperlongumine downregulates the expression of HER family receptors.•Downregulation of these receptors by piperlongumine is mediated by ROS.•Overexpression of HER2 increases the cell sensitivity to piperlongumine.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
3-Hydroxypropionic acid (3-HP) is an important platform chemical to be converted to acrylic acid and acrylamide. Aldehyde dehydrogenase (ALDH), an enzyme that catalyzes the reaction of ...3-hydroxypropionaldehyde (3-HPA) to 3-HP, determines 3-HP production rate during the conversion of glycerol to 3-HP. To elucidate molecular mechanism of 3-HP production, we determined the first crystal structure of a 3-HP producing ALDH, α-ketoglutarate-semialdehyde dehydrogenase from Azospirillum basilensis (AbKGSADH), in its apo-form and in complex with NAD
. Although showing an overall structure similar to other ALDHs, the AbKGSADH enzyme had an optimal substrate binding site for accepting 3-HPA as a substrate. Molecular docking simulation of 3-HPA into the AbKGSADH structure revealed that the residues Asn159, Gln160 and Arg163 stabilize the aldehyde- and the hydroxyl-groups of 3-HPA through hydrogen bonds, and several hydrophobic residues, such as Phe156, Val286, Ile288, and Phe450, provide the optimal size and shape for 3-HPA binding. We also compared AbKGSADH with other reported 3-HP producing ALDHs for the crucial amino acid residues for enzyme catalysis and substrate binding, which provides structural implications on how these enzymes utilize 3-HPA as a substrate.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
A method for the separation and quantification of three flavonoids and one isocoumarin by reverse-phase high performance liquid chromatography (HPLC) has been developed and validated. Four ...constituents present in a crude ethanolic extract of the flowers of Coryloposis coreana Uyeki, were analyzed. Bergenin, quercetin, quercitrin and isosalipurposide were used as calibration standards. In the present study, an excellent linearity was obtained with an r² higher than 0.999. The chromatographic peaks showed good resolution. In combination with other validation data, including precision, specificity, and accuracy, this method demonstrated good reliability and sensitivity, and can be conveniently used for the quantification of bergenin, quercetin, quercitrin and isosalipurposide in the crude ethanolic extract of C. coreana Uyeki flos. Furthermore, the plant extracts were analyzed with HPLC to determine the four constituents and compositional differences in the extracts obtained under different extraction conditions. Several extracts of them which was dependent on the ethanol percentage of solvent were also analyzed for their antimicrobial and antioxidant activities. One hundred % ethanolic extract from C. coreana Uyeki flos showed the best antimicrobial activity against the methicillin-resistant Staphylococcus aureus (MRSA) strain. Eighty % ethanolic extract showed the best antioxidant activity and phenolic content. Taken of all, these results suggest that the flower of C. coreana Uyeki flos may be a useful source for the cure and/or prevention of septic arthritis, and the validated method was useful for the quality control of C. coreana Uyeki.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Acyl-CoA oxidases (ACOXs) play important roles in lipid metabolism, including peroxisomal fatty acid β-oxidation by the conversion of acyl-CoAs to 2-trans-enoyl-CoAs. The yeast Yarrowia lipolytica ...can utilize fatty acids as a carbon source and thus has extensive biotechnological applications. The crystal structure of ACOX3 from Y. lipolytica (YlACOX3) was determined at a resolution of 2.5 A. It contained two molecules per asymmetric unit, and the monomeric structure was folded into four domains; Nα, Nβ, Cα1, and Cα2 domains. The cofactor flavin adenine dinucleotide was bound in the dimer interface. The substrate-binding pocket was located near the cofactor, and formed at the interface between the Nα, Nβ, and Cα1 domains. Comparisons with other ACOX structures provided structural insights into how YlACOX has a substrate preference for short-chain acyl-CoA. In addition, the structure of YlACOX3 was compared with those of medium- and long-chain ACOXs, and the structural basis for their differences in substrate specificity was discussed.
Objectives
To evaluate the surgical feasibility of laparoscopic adrenalectomy using the lateral retroperitoneal approach for the treatment of large pheochromocytomas, and to identify the preoperative ...risk factors for intraoperative hypertension.
Methods
We retrospectively reviewed 51 patients who underwent laparoscopic adrenalectomy using the lateral retroperitoneal approach for the treatment of pheochromocytomas. Patient characteristics and perioperative outcomes were analyzed and compared between the two study groups based on tumor size: group A (n = 27, ≤6 cm) and group B (n = 24, ˃6 cm).
Results
There was no significant difference in preoperative characteristics between the two groups except for tumor size (P = 0.001) and urinary metanephrine (P = 0.011). Group B patients required longer operating time (P = 0.008), had a greater estimated blood loss (P = 0.001) and hemoglobin change (P = 0.002). However, no significant differences were observed in perioperative complications and mortality. Multivariate analysis showed that symptomatic pheochromocytomas (P = 0.004) and tumor size (P = 0.007) were significant risk factors for intraoperative hypertension.
Conclusions
Laparoscopic adrenalectomy using the lateral retroperitoneal approach for pheochromocytomas can be regarded as a treatment option, even for tumors measuring >6 cm. Symptomatic pheochromocytomas and large tumor size seem to represent risk factors for intraoperative hypertension.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Steam reforming of methanol over a commercial Cu/ZnO/Al2O3 catalyst was studied at atmospheric pressure and in a temperature range between 160 and 260 DGC. The reaction rate depended upon methanol ...and hydrogen partial pressures, and was independent of the partial pressures of carbon oxides and water, which was in excess of the methanol partial pressure. Small amounts of carbon monoxide, less than 1 % in the product gas, were formed at high temperatures; the amounts were well below the equilibrium amounts of reverse water-gas-shift reaction (RWGS). This was in support of the reaction sequence of methanol steam reforming followed by the RWGS. A power-law and a Langmuir-Hinselwood rate expression were developed for the reforming reaction by fitting the expressions to the experimental data. As the data were found to be affected by internal diffusion at high temperatures, the effectiveness factor of the catalyst particle was estimated in the fitting in order to obtain the intrinsic kinetics. Details of the estimation of the factor are elucidated. In order to predict a non-zero, finite rate in the absence of hydrogen, the hydrogen partial pressure term in the power-law expression was corrected by a fitted constant to avoid an infinite reaction rate, since the exponent of the hydrogen partial pressure was a negative number due to the hydrogen inhibition effect in the reforming; in the reaction mechanism for the Langmuir-Hinselwood expression, it was necessary to assume two different kinds of active sites on the catalyst: one for adsorbed methoxy and the other for adsorbed hydrogen. In addition, an excellent fitting of the data by the Langmuir-Hinselwood expression indicates that dehydrogenation of the adsorbed methoxy to the adsorbed oxymethylene is the rate-determining step (RDS), and that adsorption of all the species other than methoxy and hydrogen on the active sites is negligible.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Tyrosinases (TYRs) catalyze two-step consecutive oxidation reactions of monophenolic compounds. Since known TYRs have optimal pH at neutral to somewhat basic pH, they have limitations to be used for ...production of catechol derivatives. In this study, we identified TYR from Burkholderia thailandensis (BtTYR), which exhibited high tyrosinase activity at low pH. We determined the crystal structure of BtTYR and provided the structural basis for the regulation of its activity in response to pH change. At high pH, BtTYR is inactivated due to the tight binding of its TYR and CAP domains, although it is stable in monomer form; at low pH, however, the protein is activated by the typical opening of the CAP domain, and the formation of tetramers maintains the stability of the protein. Such unique tyrosinase activity of BtTYR at acidic pH was successfully applied to highly efficient production of catechol derivatives and fabrication of an adhesive hydrogel.
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IJS, KILJ, NUK, PNG, UL, UM
Hepatic lipid accumulation is a major risk factor for dyslipidemia, nonalcoholic fatty liver disease, and insulin resistance. The present study was conducted to evaluate hypolipidemic effects of ...meso-dihydroguaiaretic acid (MDA), anti-oxidative and anti-inflammatory compound isolated from the Myristica fragrans HOUTT., by oil red O staining, reverse transcription-polymerase chain reaction (RT-PCR), and Western blot. MDA significantly inhibited insulin-induced hepatic lipid accumulation in a dose-dependent manner. The lipid-lowering effect of MDA was accompanied by increased expression of proteins involved in fatty acid oxidation and decreased expression of lipid synthetic proteins. In addition, MDA activated AMP-activated protein kinase (AMPK) as determined by phosphorylation of acetyl-CoA carboxylase (ACC), a downstream target of AMPK. The effects of MDA on lipogenic protein expression were suppressed by pretreatment with compound C, an AMPK inhibitor. Taken together, these findings show that MDA inhibits insulin-induced lipid accumulation in human HepG2 cells by suppressing expression of lipogenic proteins through AMPK signaling, suggesting a potent lipid-lowering agent.
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