Aristolochic acid mutational signature defines the low-risk subtype in upper tract urothelial carcinoma.

Rationale: Dietary exposure to aristolochic acids and similar compounds (collectively, AA) is a significant risk factor for nephropathy and subsequent upper tract urothelial carcinoma (UTUC). East Asian populations, who have a high prevalence of UTUC, have an unusual genome-wide AA-induced mutational pattern (COSMIC signature 22). Integrating mutational signature analysis with clinicopathological information may demonstrate great potential for risk ranking this UTUC subtype. Methods: We performed whole-genome sequencing (WGS) on 90 UTUC Chinese patients to extract mutational signatures. Genome sequencing data for urinary cell-free DNA from 26 UTUC patients were utilized to noninvasively identify the mutational signatures. Genome sequencing for primary tumors on 8 out of 26 patients was also performed. Metastasis-free survival (MFS) and cancer-specific survival (CSS) were measured using Kaplan-Meier methods. Results: Data analysis showed that a substantial proportion of patients harbored the AA mutational signature and were associated with AA-containing herbal drug intake, female gender, poor renal function, and multifocality. Field cancerization was found to partially contribute to multifocality. Nevertheless, AA Sig subtype UTUC patients exhibited favorable outcomes of CSS and MFS compared to the No-AA Sig subtype. Additionally, AA Sig subtype patients showed a higher tumor mutation burden, higher numbers of predicted neoantigens, and infiltrating lymphocytes, suggesting the potential for immunotherapy. We also confirmed the AA signature in AA-treated human renal tubular HK-2 cells. Notably, the AA subtype could be ascertained using a clinically applicable sequencing strategy (low coverage) in both primary tumors and urinary cell-free DNA as a basis for therapy selection. Conclusion: The AA mutational signature as a screening tool defines low-risk UTUC with therapeutic relevance. The AA mutational signature, as a molecular prognostic marker using either ureteroscopy and/or urinary cell-free DNA, is especially useful for diagnostic uncertainty when kidney-sparing treatment and/or immune checkpoint inhibitor therapy were considered.

Effect of 2,4-dichlorophenoxyacetic acid on the activities of some metabolic enzymes for generating pyridine nucleotide pool of cells from mouse liver.

2,4-Dichlorophenoxyacetic acid (2,4-D), which is a plant auxin analogue, is lethal to broad leaved weeds within days at high dosages and is considered as having low toxicity to mammals. Some studies have reported that exposure to this compound may cause damage to organs such as liver. The aim of this study was to investigate the effects of 2,4-D in mouse liver on chromosomes as well as hexokinase (HK), glucose-6-phosphate dehydrogenase (G6PD), 6-phosphogluconate dehydrogenase (6PGD), lactate dehydrogenase (LDH) and malate dehydrogenase (MDH) which are required for the generation of the pyridine nucleotide pool. The experiments were carried out with a 2,4-D group, an ethanol control for 2,4-D, and saline group for ethanol control group on three generations of mice. Only female parents were given 2,4-D during the gestation period, lactation period and for 33 days following the lactation period. In females of the first cross, 2,4-D caused a significant increase in the activity of LDH, and ethanol alone caused a significant increase in the activities of HK and LDH. In the male offspring of the first cross maternal, 2,4-D caused a significant increase in the activity of LDH, and ethanol alone caused a significant decrease in the activity of 6PGD. In the female offspring of the first cross maternal, ethanol caused a significant increase in the activities of G6PD and MDH. In the female offsprings of the third cross maternal, 2,4-D caused a significant increase in the activity of MDH. No gross morphological changes were observed in internal organs, such as liver, kidney and spleen of the affected animals. Also, a chromosomal study from bone marrow cells indicated no anomalies in chromosomal sets and structures. As a result, 2,4-D had an effect on the first cross maternal and their offsprings. The compound did not affect the parameters studied except MDH enzyme activity in the second and third generation of mice.

The effects of n-3 polyunsaturated fatty acids by gavage on some metabolic enzymes of rat liver.

In this experimental study, the effect of fish n-3 fatty acids was studied on the some important enzymes of carbohydrate metabolism, hexokinase (HK), glucose-6-phosphate dehydrogenase (G6PD), 6-phosphogluconate dehydrogenase (6PGD), lactate dehydrogenase (LDH), and malate dehydrogenase (MDH) in rat liver. Wistar albino rats of experimental group (n= 9) were supplemented fish omega-3 fatty acids (n-3 PUFA) as 0.4 g/kg bw. by gavage for 30 days in addition to their normal diet. Isotonic solution was given to the control group (n= 8) by the same way. At 30th day, the rats were killed by decapitation under ether anesthesia, autopsied and liver was removed. Spectrophotometric methods were used to determine the activities of above-mentioned enzymes in the liver. The n-3 PUFA caused increases in the activities of HK, G6PD, LDH, and MDH in comparison with control. These increases were statistically significant (P < 0.01) except 6PGD activity. As a result, n-3 PUFA may regulate the metabolic function of liver effectively by increasing HK, G6PD, 6PGD, LDH, and MDH enzyme activities of rat liver when added in enough amounts to the regular diet.

Recuperative effect of Semecarpus anacardium linn. nut milk extract on carbohydrate metabolizing enzymes in experimental mammary carcinoma-bearing rats.

Semecarpus anacardium Linn. of the family Anacardiaceae has many applications in the Ayurvedic and Siddha systems of medicine. We have tested the antitumour activity of Semecarpus anacardium nut extract against experimental mammary carcinoma in animals. As there is a direct relationship between the proliferation of tumour cells and the activities of the glycolytic and gluconeogenic enzymes, we studied changes in the activities of enzymes involved in this metabolic pathway in the liver and kidney. The enzymes investigated were glycolytic enzymes, namely hexokinase, phosphoglucoisomerase, aldolase and the gluconeogenic enzymes, namely glucose-6-phosphatase and fructose-1,6-biphosphatase in experimental rats. A significant rise in glycolytic enzyme activities and a simultaneous fall in gluconeogenic enzyme activities were found in mammary carcinoma bearing rats. Drug administration returned these enzyme activities to their respective control activities.

The effect of dietary selenium on lead neurotoxicity.

Lead, when administered to male rats for 8 weeks in a dose of 20 mg/kg body weight, resulted in the impairment of the enzymes hexokinase and total ATPase in the cerebral and cerebellar regions of the brain. The changes were, however, more pronounced in the cerebellar region. Along with these, a decrease in acetylcholine esterase (AchE) and monoamine oxidase (MAO) was seen, thus affecting both cholinergic and adrenergic neurotransmitters. When selenium was administered concomitantly with lead, the values of total ATPase and hexokinase activities approached normal values in both brain regions. A significant improvement in acetylcholine esterase activity and MAO was also seen.