bims-bramad 2020-09-20 papers

J Hepatobiliary Pancreat Sci. 2020 Sep 19.

Effects of Branched-chain Amino Acids on Postoperative Tumor Recurrence in Patients Undergoing Curative Resection for Hepatocellular Carcinoma: A Randomized Clinical Trial.

Hiroyuki Hachiya, Taku Aoki, Yukihiro Iso, Takayuki Shimizu, Kazuma Tago, Kyung Hwa Park, Yuhki Sakuraoka, Takayuki Shiraki, Shozo Mori, Keiichi Kubota.

BACKGROUND: No effective postoperative adjuvant therapies have been established for patients with hepatocellular carcinoma (HCC). The aim of this study was to investigate the effect of oral administration of branched-chain amino acids (BCAA) on the recurrence-free survival (RFS) after hepatic resection in HCC patients.
METHODS: In this randomized clinical trial, HCC patients undergoing curative resections were randomly assigned in a 1:1 ratio to the BCAA group or surgery-alone group. The BCAA group received BCAA (Livact® ) for up to 4 years. The primary endpoint was the RFS. The secondary endpoint was the overall survival (OS). Multivariate analysis was performed to detect the clinical characteristics significantly associated with RFS.
RESULTS: Between January 2010 and October 2014, 156 patients (75 in BCAA group and 81 in surgery-alone group) were enrolled in the study. Of these, 2 patients were excluded from the efficacy analysis. Comparison of the survival curves by the log rank test demonstrated no significant difference in the RFS (P=0.579) or OS (P=0.268) between the BCAA and the control group. Multivariate analysis revealed that the RFS was significantly associated with age and number of tumors. A beneficial effect of BCAA on the RFS was found in patients younger than 72 years old with a HbA1c level of <6.4%.
CONCLUSIONS: Oral BCAA supplementation could not reduce the risk of recurrence after hepatic resection in HCC patients; however, the results suggested that BCAA supplementation may be beneficial for selected patients who were younger and had mildly impaired glucose tolerance.

Keywords: Branched-chain amino acids; Hepatectomy; Hepatocellular carcinoma; Overall survival; Recurrence-free survival

DOI: https://doi.org/10.1002/jhbp.830

Food Chem Toxicol. 2020 Sep 10. pii: S0278-6915(20)30634-7. [Epub ahead of print]145 111744

Comparative analysis of fecal metabolite profiles in HFD-induced obese mice after oral administration of huangjinya green tea extract.

Mingxi Li, Jialin Xu, Yi Zhang, Suo Chu, Shizhuo Sun, Yan Huo, Jie Zhao, Xiaodi Hu, Chunpeng Wan, Liya Li.

To explore the impact of Huangjinya on metabolic disorders and host endogenous metabolite profiles, high-fat diet (HFD)-fed mice were administrated with Huangjinya green tea extract (HGT) at the dose of 150 or 300 mg/kg for 9 weeks. Epigallocatechin gallate was the main catechin derivative, followed by epigallocatechin and catechin presented in HGT, which contained high levels of free amino acids (50.30 ± 0.60 mg/g). HGT significantly alleviated glucose and insulin intolerance, reduced hepatic lipid accumulation and liver steatosis, and prevented white adipose tissue expansion in HFD-fed mice. Untargeted mass spectrometry-based metabolomics analysis revealed that HGT reduced the abundance of fecal branched-chain amino acids, aromatic amino acids, sphingolipids, and most acyl cholines, modulated bile acid metabolism by increasing chenodeoxycholate and reducing cholic acid content, and increased unsaturated fatty acids content. Fatherly, HGT activated insulin/PI3K/Akt and AMPK signaling pathways in the liver, reduced adipogenic and lipogenic genes expression, and promoted the genes expression related to lipolysis and adipocyte browning in white adipose tissue, contributed to improving metabolic syndrome in HFD-fed mice. The current study reported the impact of HGT supplementation on endogenous metabolite profiles, and highlights the positive roles of HGT in preventing diet-induced obesity and the related metabolic disorders.

Keywords: Green tea; Huangjinya; Liver steatosis; Metabolome; Obesity

DOI: https://doi.org/10.1016/j.fct.2020.111744

Cancers (Basel). 2020 Sep 10. pii: E2576. [Epub ahead of print]12(9):

Amino Acids Regulate Cisplatin Insensitivity in Neuroblastoma.

Venugopal Gunda, Anup S Pathania, Srinivas Chava, Philip Prathipati, Nagendra K Chaturvedi, Don W Coulter, Manoj K Pandey, Donald L Durden, Kishore B Challagundla.

Neuroblastoma are pediatric, extracranial malignancies showing alarming survival prognosis outcomes due to their resilience to current aggressive treatment regimens, including chemotherapies with cisplatin (CDDP) provided in the first line of therapy regimens. Metabolic deregulation supports tumor cell survival in drug-treated conditions. However, metabolic pathways underlying cisplatin-resistance are least studied in neuroblastoma. Our metabolomics analysis revealed that cisplatin-insensitive cells alter their metabolism; especially, the metabolism of amino acids was upregulated in cisplatin-insensitive cells compared to the cisplatin-sensitive neuroblastoma cell line. A significant increase in amino acid levels in cisplatin-insensitive cells led us to hypothesize that the mechanisms upregulating intracellular amino acid pools facilitate insensitivity in neuroblastoma. We hereby report that amino acid depletion reduces cell survival and cisplatin-insensitivity in neuroblastoma cells. Since cells regulate their amino acids levels through processes, such as autophagy, we evaluated the effects of hydroxychloroquine (HCQ), a terminal autophagy inhibitor, on the survival and amino acid metabolism of cisplatin-insensitive neuroblastoma cells. Our results demonstrate that combining HCQ with CDDP abrogated the amino acid metabolism in cisplatin-insensitive cells and sensitized neuroblastoma cells to sub-lethal doses of cisplatin. Our results suggest that targeting of amino acid replenishing mechanisms could be considered as a potential approach in developing combination therapies for treating neuroblastomas.

Keywords: MYCN; amino acids; cisplatin-sensitivity; hydroxychloroquine; metabolism; neuroblastoma

DOI: https://doi.org/10.3390/cancers12092576

Anal Methods. 2020 May 28. 12(20): 2555-2559

Analysis of intracellular α-keto acids by HPLC with fluorescence detection.

Takuya Fujiwara, Ayuna Hattori, Takahiro Ito, Takashi Funatsu, Makoto Tsunoda.

Branched-chain keto acids and branched-chain amino acids are metabolites of branched-chain amino acid aminotransferases (BCATs), which catalyzes reversible transamination between them. We found that BCAT1 plays an important role in the progression of myeloid leukaemia, and a method for the analysis of intracellular α-keto acids including branched-chain keto acids was necessary to further investigate their role. In this study, we developed a method to analyze six α-keto acids (α-ketoglutaric acid (KG), pyruvic acid, α-ketobutyric acid, α-ketoisovaleric acid, α-ketoisocaproic acid, and α-keto-β-methylvaleric acid) in K562 cells by HPLC with fluorescence detection, using 1,2-diamino-4,5-methylenedioxybenzene (DMB) as a derivatization reagent. Because split peaks of DMB-KG were observed when injection samples were too acidic, the derivatization solution was diluted with NaOH solution to obtain a single peak. Limits of detection and limits of quantification were 1.3-5.4 nM and 4.2-18 nM, respectively. Intracellular concentrations of α-keto acids were 1.55-316 pmol/1 × 106 K562 cells. The developed method realized reproducible and sensitive analysis of intracellular α-keto acids. Thus, the method could be used to elucidate the role of BCAT in myeloid leukaemia.

DOI: https://doi.org/10.1039/d0ay00556h

Cureus. 2020 Aug 12. 12(8): e9706

Maple Syrup Urine Disease Masquerading as Urea Cycle Disorder: A Tale of Two Clinical Mimics.

Shahzad Rauf, Talal Almas, Irfan Ullah, Norina Usman, Muhammad Irfan.

Maple syrup urine disease, an inherited disorder of metabolism, is characterised by deficient activity of the branched-chain alpha-keto acid dehydrogenase complex (BCKAD) enzyme, resulting in an accumulation of branched-chain amino acids. While it is classically diagnosed by the means of a neonatal screening panel, it can sometimes remain undetected. In such cases, maple syrup urine disease is noted to elicit a constellation of clinical symptoms characterised by a plethora of neurological and respiratory impairments. A prompt diagnosis and management of the disease therefore remains imperative. Due to the remarkable semblance in the clinical symptoms elicited by maple syrup urine disease and urea cycle disorders, both the ailments should be considered in the list of differential diagnosis in patients presenting with elevated serum ammonia levels in the context of the overarching clinical picture. We chronicle the case of a 25-day-old neonate who presented with unabated seizures. An initial diagnosis of a urea cycle disorder was suspected; however, further diagnostic workup divulged an underlying diagnosis of maple syrup urine disease.

Keywords: inborn errors of metabolism; maple syrup urine disease; urea cycle disorder

DOI: https://doi.org/10.7759/cureus.9706