Stage-specific metabolomics suggests a trade-off between primary and secondary metabolites for nutritional advantage in Lepidium latifolium L.

Lepidium latifolium L. is an established phytofood of the Ladakh Himalayas that contains differential content of important glucosinolates (GLS) in specific stages of sprouts. Therefore, in order to harness its nutraceutical potential, a comprehensive mass spectrometry-based stage-specific untargeted metabolomic analysis was performed. A total of 318 metabolites were detected, out of which 229 were significantly (p ≤ 0.05) changed during different stages. The Principal Component Analysis plot clearly differentiated different growth stages into three clusters. The nutritionally important metabolites, including amino acids, sugars, organic acids, and fatty acids, were found significantly (p ≤ 0.05) higher in the first cluster consisting of 1st, 2nd and 3rd week sprouts. The higher energy requirements during the early growth stages were observed with the higher metabolites of glycolysis and the TCA cycle. Further, the trade-off between primary and secondary sulfur-containing metabolites was observed, which may explain the differential GLS content in different growth stages.

Alterations in cellular metabolisms after Imatinib therapy: a review.

Chronic myeloid leukemia (CML) is characterized by the possession of the Philadelphia chromosome, which contains the Bcr-Abl oncogene that codes for the oncoprotein BCR-ABL. Through glucose metabolism, glycolysis, and the translocation of the high-affinity glucose transporter to the cell surface, BCR-ABL modulates various signaling pathways in CML cells and maintains ATP turnover in tumor cells. Given the effective results of anti-tumor drugs in normalizing abnormal cellular metabolism, Imatinib (IM) has begun to be investigated and proven to be a highly potent tyrosine kinase inhibitor (TKI) in CML therapy. Initially, IM was tested for aberrant glucose metabolism, but all four metabolisms (glucose, lipid, amino acid, and nucleotide) are interrelated and enhance tumor growth under stress; eventually, the other three metabolisms were investigated. Subsequent effects of IM therapy showed a switch from glycolysis to the tricarboxylic acid cycle, upregulation of pentose phosphate pathway-associated oxidative pathways, and internal translocation of glucose transporters. In terms of lipid metabolism, IM had contradictory results: in one study, it served as a triglyceride and total cholesterol regulator, while in another study, it had no impact. The effect of IM on altered amino acid and nucleotide metabolisms was investigated using a multi-omics approach, which revealed a decrease in sulfur-containing amino acids, aromatic amino acids, and nucleotide biosynthesis. So, despite the mixed effect on cellular metabolism, IM has more positive effects, and therefore, the drug proved to be better than other TKIs. The present study is one approach to determine the transformative activities of IM against CML-associated metabolic changes, but further investigation is still needed to uncover more potentials of IM.

Transport and metabolism of tyrosine kinase inhibitors associated with chronic myeloid leukemia therapy: a review.

Imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and asciminib are FDA-approved tyrosine kinase inhibitors (TKIs) for chronic myeloid leukemia (CML), each of which has a specific pharmacological profile. Asciminib has been recently (2021) approved for patients resistant to former TKIs, and because the binding site of this drug (the myristoyl pocket in the ABL1 kinase) is different from that of other TKIs (ATP-binding sites), it is, therefore, effective against T315I mutation of BCR-ABL oncoprotein. All TKIs have a different pharmacological profile due to different chemical structures. Imatinib is the only TKI whose absorption depends on both influx (OCT1 and OATP1A2) and efflux (ABCB1 and ABCG2) transporters, whereas the others rely only on efflux transporters. The efflux of dasatinib is also regulated by ABCC4 and ABCC6 transporters. Nilotinib and ponatinib are transported passively, as no role of transporters has been found in their case. A phenomenon common to all in the metabolic aspect is that the CYP3A4 isoform of CYP450 primarily metabolizes TKIs. Not only does CYP3A4, flavin-containing monooxygenase 3 (FMO3), and uridine 5'-diphospho-glucuronosyltransferase (UGT) also metabolize dasatinib, and similarly, by glucuronidation process, asciminib gets metabolized by UGT enzymes (UGT1A3, UGT1A4, UGT2B7, and UGT2B17). Additionally, the side effects of TKIs are categorized as hematological (thrombocytopenia, neutropenia, anemia, and cardiac dysfunction) and non-hematological (diarrhea, nausea, vomiting, pleural effusion, and skin rash). However, few toxicities are drug-specific, like degradation of biomolecules by ponatinib-glutathione (P-GSH) conjugates and clinical pancreatitis (dose-limited toxicity and manageable by dosage alterations) are related to ponatinib and asciminib, respectively. This review focuses on the pharmacokinetics of approved TKIs related to CML therapy to comprehend their specificity, tolerability, and off-target effects, which could help clinicians to make a patient-specific selection of CML drugs by considering concomitant diseases and risk factors to the patients.

Aldose Reductase: a cause and a potential target for the treatment of diabetic complications.

Diabetes mellitus, a disorder of metabolism, results in the elevation of glucose level in the blood. In this hyperglycaemic condition, aldose reductase overexpresses and leads to further complications of diabetes through the polyol pathway. Glucose metabolism-related disorders are the accumulation of sorbitol, overproduction of NADH and fructose, reduction in NAD+, and excessive NADPH usage, leading to diabetic pathogenesis and its complications such as retinopathy, neuropathy, and nephropathy. Accumulation of sorbitol results in the alteration of osmotic pressure and leads to osmotic stress. The overproduction of NADH causes an increase in reactive oxygen species production which leads to oxidative stress. The overproduction of fructose causes cell death and non-alcoholic fatty liver disease. Apart from these disorders, many other complications have also been discussed in the literature. Therefore, the article overviews the aldose reductase as the causative agent and a potential target for the treatment of diabetic complications. So, aldose reductase inhibitors have gained much importance worldwide right now. Several inhibitors, like derivatives of carboxylic acid, spirohydantoin, phenolic derivatives, etc. could prevent diabetic complications are discussed in this article.

Nickel excess affects phenology and reproductive attributes of Asterella wallichiana and Plagiochasma appendiculatum growing in natural habitats.

Bryophytes are potent metal absorbers, thriving well on heavy metal (HM)-polluted soils. Mechanisms controlling uptake, compartmentalization and impacts of HMs on bryophytes life cycle are largely unknown. The current study is an effort to decipher mechanisms of nickel (Ni) excess-induced effects on the phenological events of two bryophytes, Asterella wallichiana and Plagiochasma apendiculatum growing in natural habitats. Observations revealed Ni-excess induced negative impacts on abundance, frequency of occurrence of reproductive organs, population viability and morphological traits, spore viability and physiological attributes of both the liverworts. Results led us conclude that P. appendiculatum survived better with the lowest impact on its life cycle events than A. wallichiana under Ni excess in natural habitats. Our findings collectively provide insights into the previously unknown mechanisms of Ni-induced responses in liverworts with respect to phenological attributes, as well as demonstrate the potential of P. appendiculatum to survive better in Ni excess habitats.

Effect of temperature and insect herbivory on the regulation of glucosinolate-myrosinase system in Lepidium latifolium.

The glucosinolate-myrosinase (GLS-MYR) system is an important component of plant-insect interactions. However, there is no report on its performance in field conditions where the plants are subjected to both abiotic and biotic pressures simultaneously. We investigated the GLS-MYR system in a Himalayan ecotype of Lepidium latifolium that is recognized for its adaptive potential in field conditions. In order to understand the independent contribution of temperature and Pieris brassicae herbivory on the components of the GLS-MYR system, different conditions were simulated in the growth chamber. During field conditions, the final GLS hydrolysis products were found to be regulated by the metabolic GLS levels, the temperature conditions, and the density of insect interactions. These factors influence the expression of the hydrolyzing and specifier proteins, which further affects the GLS hydrolysis products. Our results suggest that the production of hydrolysis products is differentially affected under field conditions. While allyl isothiocyanate is significantly (P ≤ 0.05) affected by temperature but not insect density, 1-cyano-2,3-epithiopropane is not affected by either. The study shows that the outcome of the GLS-MYR system in a plant is a consequence of the combinatorial effect of ecophysiological factors and the insect interactions that eventually decide the performance of a plant in an environment.

GC-MS based metabolomic approach to understand nutraceutical potential of Cannabis seeds from two different environments.

Cannabis sativa L. is a valuable plant that has regained its importance for medicinal use. Gas chromatography-mass spectrometry based untargeted metabolomic study was conducted in seeds of two accessions from different environments. A total of 236 metabolites were observed, and 43 metabolites were found differentially significant (p ≤ 0.05) in both the accessions. Based on the qualitative and quantitative accumulation of the nutraceutically important amino acids, cannabinoids, alkaloids, and fatty acids, the high altitude temperate Himalayan accession (CAN2) was found to have an advantage over the low altitude subtropical accession (CAN1). Seed oil from CAN2 showed the exclusive presence of linoleic acid and α- linolenic acid. The reducing power and DNA nicking assay on the methanolic extracts suggested higher antioxidant and nutraceutical potential in CAN2 and corroborated with the metabolic content of phenols and flavonoids. The environmental effect on the antioxidant and nutraceutical value in seeds is further discussed.

Role of membrane-embedded drug efflux ABC transporters in the cancer chemotherapy.

One of the major problems being faced by researchers and clinicians in leukemic treatment is the development of multidrug resistance (MDR) which restrict the action of several tyrosine kinase inhibitors (TKIs). MDR is a major obstacle to the success of cancer chemotherapy. The mechanism of MDR involves active drug efflux transport of ABC superfamily of proteins such as Pglycoprotein (P-gp/ABCB1), multidrug resistance-associated protein 2 (MRP2/ABCC2), and breast cancer resistance protein (BCRP/ABCG2) that weaken the effectiveness of chemotherapeutics and negative impact on the future of anticancer therapy. In this review, the authors aim to provide an overview of various multidrug resistance (MDR) mechanisms observed in cancer cells as well as the various strategies developed to overcome these MDR. Extensive studies have been carried out since last several years to enhance the efficacy of chemotherapy by defeating these MDR mechanisms with the use of novel anticancer drugs that could escape from the efflux reaction, MDR modulators or chemosensitizers, multifunctional nanotechnology, and RNA interference (RNAi) therapy.