Investigation of pathogenesis and therapeutic targets of acute myeloid leukemia based on untargeted plasma metabolomics and network pharmacology approach

Zhao

Biomedical Chromatography

et al. 2022

Self Cite

Terrestrosin D (TED) is the active ingredient of Tribulus terrestris L., which is used in traditional Chinese medicine (TCM) formulations and has a wide range of pharmacological activities. A previous study showed that TED alleviated bleomycin (BLM)‐induced pulmonary fibrosis (PF) in mice. However, the mechanisms underlying the therapeutic effect of TED are still unclear and need further investigation. In this study, we evaluated the effect of TED in a mice of BLM‐induced PF in terms of histopathological and biochemical indices. UHPLC–MS‐based plasma metabolomics combined with network pharmacology was used to explore the pathological basis of PF and the mechanism of action of TED. Histological and biochemical analyses showed that TED mitigated inflammatory injury in the lungs, especially at the dosage of 20 mg/kg. Furthermore, BLM changed the plasma metabolite profile in the mice, which was reversed by TED via regulation of amino acid and lipid metabolism. Subsequently, a biomarkers‐targets‐disease network was constructed, and tumor necrosis factor (TNF)‐α and transforming growth factor (TGF)‐β1 were identified as the putative therapeutic targets of TED. Both factors were quantitatively analyzed using enzyme‐linked immunosorbent assay (ELISA). Taken together, the combination of UHPLC–MS‐based metabolomics and network pharmacology can unveil the mechanisms of diseases and drug action.

Section: Plasma Sample Preparationmentioning

confidence: 99%

Section: Establishment Of Biomarkers-targets-disease Networkmentioning

confidence: 99%

Mechanisms exploration of terrestrosin D on pulmonary fibrosis based on plasma metabolomics and network pharmacology

Zhao

Biomedical Chromatography

et al. 2022

Self Cite

J. Am. Soc. Mass Spectrom.

“…In recent years, metabolomics has emerged as an alternative approach for early cancer detection through a detailed analysis of changes in metabolite levels. The altered metabolites may be developed as biomarkers, and the unique metabolic profiles could be translated into personalized therapeutic strategies. , In-depth research into the metabolic profile of leukemia has received a lot of attention recently, , though this approach has been employed for many years in the treatment of several malignancies including ovarian, breast, colorectal, kidney, and hepatocellular carcinoma. − The reports involving CML patients revealed that metabolic profiling could be utilized to diagnose CML and a list that includes specific metabolites may be useful for assessing how well TKI therapy is working. , …”

Section: Introductionmentioning

confidence: 99%

Analysis of the Inhibitory Effect of hsa-miR-145-5p and hsa-miR-203a-5p on Imatinib-Resistant K562 Cells by GC/MS Metabolomics Method

Singh,

Yadav,

Verma

et al. 2023

Imatinib (IM) resistance is considered to be a significant challenge in the management of chronic myeloid leukemia (CML). Previous studies have reported that hsa-miR-145-5p and hsa-miR-203a-5p can overcome IM resistance and hsa-miR-203a-5p can alter glutathione metabolism in IM-resistant cells. The purpose of this study was to examine whether hsa-miR-145-5p or hsa-miR-203a-5p counters IM resistance by targeting the overall metabolic profile of IM-resistant K562 cells. The metablic profiling of cell lysates obtained from IM-sensitive, IM-resistant, and miR-transfected IM-resistant K562 cells was carried out using the GC-MS technique. Overall, 75 major metabolites were detected, of which 32 were present in all samples. The pathway analysis of MetaboAnalyst 5.0 revealed that the majorly enriched pathways included glucose metabolism, fatty acid biosynthesis, lipogenesis, and nucleotide metabolism. Eleven of identified metabolites, L-glutamine, L-glutamic acid, L-lactic acid, phosphoric acid, 9,12-octadecadienoic acid, 9-octadecenoic acid, myristic acid, palmitic acid, cholesterol, and β-alanine, appeared in enriched pathways. IM-resistant cells had comparatively higher concentrations of all of these metabolites. Notably, the introduction of hsa-miR-145-5p or hsa-miR-203a-5p into resistant cells resulted in a decrease in levels of these metabolites. The efficacy of miR-203a-5p was particularly remarkable in comparison with miR-145-5p, as evidenced by partial least-squares-discriminant analysis (PLS-DA), which showed a high level of similarity in metabolic profile between IMsensitive K562 cells and IM-resistant cells transfected with hsa-miR-203a-5p. The results indicate that GC-MS-based metabolic profiling has the potential to distinguish between drug-resistant and -sensitive cells. This approach can also be used to routinely monitor therapeutic response in drug-resistant patients, thus, enabling personalized therapy.

“…AML accounts for 10-20% of infant leukemia and less than 30% of adults have a survival rate of AML for 5 years. In addition, older persons with AML are poorly tolerated and contagious (Yuan et al, 2021). The acute promyelocytic leukemia variant should be treated as a distinct entity with distinct genetic defects, different treatment, and a better prognosis than patients with nonpromyelocytic variants, and the term AML applies to nonpromyelocytic variants (Hernandez-Valladares et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

Screening of V617F mutation in JAK2 gene with acute myeloid leukemia in the Saudi population

Farasani

2022

Acta Biochim Pol

Progress in pathogenesis and therapy of acute myeloid leukemia (AML) is presently accelerating. The Janus kinase 2 gene (JAK2) mutations are rare in de novo AML. The gene codes for the tyrosine kinase that has a significant role in the signal transduction in hematopoietic cells. The aim of this study was to induce V617F mutation in the JAK2 gene in the AML patients diagnosed in the Saudi population. In this case-control study, 100 AML patients and 100 healthy controls were recruited. Genotyping was performed with polymerase chain reaction followed with restriction fragment length polymorphism analysis. The mean age of the AML patients and healthy controls was found to be almost similar (p=0.60). In this study, 15% of VF mutation was documented in the AML cases and none of the mutations were documented either in FF mutation in AML cases or VF and FF mutations in the healthy control subjects. VF mutations [VF vs VV; OR-18.79; (95%CIs: 2.442–144.6) and p=0.0001; F vs V; OR-87.76; (95% CIs: 11.76–654.7) and p<0.0001] were found to be significantly associated when compared between AML cases and healthy controls. In conclusion, the V617F mutation showed the positive association in the AML patients diagnosed in the Saudi population.