Browsing by Author "Malkhey Verma"

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Aldose Reductase: a cause and a potential target for the treatment of diabetic complications
(Pharmaceutical Society of Korea, 2021) Sapna Thakur; Sonu Kumar Gupta; Villayat Ali; Priyanka Singh; Malkhey Verma
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. © 2021, The Pharmaceutical Society of Korea.
Alterations in cellular metabolisms after Imatinib therapy: a review
(Springer, 2022) Veerandra Kumar; Priyanka Singh; Sonu Kumar Gupta; Villayat Ali; Jyotirmayee; Malkhey Verma
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. © 2022, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
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
(American Chemical Society, 2023) Priyanka Singh; Radheshyam Yadav; Malkhey Verma; Ravindresh Chhabra
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 IM-sensitive 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. © 2023 American Society for Mass Spectrometry. Published by American Chemical Society. All rights reserved.
Antileukemic Activity of hsa-miR-203a-5p by Limiting Glutathione Metabolism in Imatinib-Resistant K562 Cells
(MDPI, 2022) Priyanka Singh; Radheshyam Yadav; Malkhey Verma; Ravindresh Chhabra
Imatinib has been the first and most successful tyrosine kinase inhibitor (TKI) for chronic myeloid leukemia (CML), but many patients develop resistance to it after a satisfactory response. Glutathione (GSH) metabolism is thought to be one of the factors causing the emergence of imatinib resistance. Since hsa-miR-203a-5p was found to downregulate Bcr-Abl1 oncogene and also a link between this oncogene and GSH metabolism is reported, the present study aimed to investigate whether hsa-miR-203a-5p could overcome imatinib resistance by targeting GSH metabolism in imatinib-resistant CML cells. After the development of imatinib-resistant K562 (IR-K562) cells by gradually exposing K562 (C) cells to increasing doses of imatinib, resistant cells were transfected with hsa-miR-203a-5p (R+203). Thereafter, cell lysates from various K562 cell sets (imatinib-sensitive, imatinib-resistant, and miR-transfected imatinib-resistant K562 cells) were used for GC-MS-based metabolic profiling. L-alanine, 5-oxoproline (also known as pyroglutamic acid), L-glutamic acid, glycine, and phosphoric acid (Pi)—five metabolites from our data, matched with the enumerated 28 metabolites of the MetaboAnalyst 5.0 for the GSH metabolism. All of these metabolites were present in higher concentrations in IR-K562 cells, but intriguingly, they were all reduced in R+203 and equated to imatinib-sensitive K562 cells (C). Concludingly, the identified metabolites associated with GSH metabolism could be used as diagnostic markers. © 2022 by the authors.
Combating TKI resistance in CML by inhibiting the PI3K/Akt/mTOR pathway in combination with TKIs: a review
(Springer, 2021) Priyanka Singh; Veerandra Kumar; Sonu Kumar Gupta; Gudia Kumari; Malkhey Verma
Chronic myeloid leukemia (CML), a myeloproliferative hematopoietic cancer, is caused by a genetic translocation between chromosomes 9 and 22. This translocation produces a small Philadelphia chromosome, which contains the Bcr-Abl oncogene. The Bcr-Abl oncogene encodes the BCR-ABL protein, upregulates various signaling pathways (JAK-STAT, MAPK/ERK, and PI3K/Akt/mTOR), and out of which the specifically highly active pathway is the PI3K/Akt/mTOR pathway. Among early treatments for CML, tyrosine kinase inhibitors (TKIs) were found to be the most effective, but drug resistance against kinase inhibitors led to the discovery of novel alternative therapies. At this point, the PI3K/Akt/mTOR pathway components became new targets due to stimulation of this pathway in TKIs-resistant CML patients. The current review article deals with reviewing the scientific literature on the PI3K/Akt/mTOR pathway inhibitors listed in the National Cancer Institute (NCI) drug dictionary and proved effective against multiple cancers. And out of those enlisted inhibitors, the US FDA has also approved some PI3K inhibitors (Idelalisib, Copanlisib, and Duvelisib) and mTOR inhibitors (Everolimus, Sirolimus, and Temsirolimus) for cancer therapy. So far, several inhibitors have been tested, and further investigations are still ongoing. Even in Imatinib, Nilotinib, and Ponatinib-resistant CML cells, a dual PI3K/mTOR inhibitor, BEZ235, showed antiproliferative activity. Therefore, by considering the literature data of these reviews and further examining some of the reported inhibitors, which proved effective against the PI3K/Akt/mTOR signaling pathway in multiple cancers, may improve the therapeutic approaches towards TKI-resistant CML cells where the respective signaling pathway gets upregulated. © 2021, Springer Science+Business Media, LLC, part of Springer Nature.
Computational insights into CHST11 and CHST13: homology modeling, molecular docking, and dynamics simulation for novel therapeutic targeting in cancers
(Elsevier B.V., 2025) Isha Sharma; Vinay Kumar Singh; Rajan Vyas; Malkhey Verma
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and remains a major global health concern due to its high mortality and resistance to current therapies. Emerging evidence highlights the role of carbohydrate sulfotransferases CHST11 and CHST13 in driving tumor progression, activating MAPK signaling, and mediating chemoresistance. In this study, homology modeling, molecular docking, and molecular dynamics (MD) simulations were used to explore the structural and functional properties of CHST11 and CHST13, key sulfotransferases implicated in HCC. Active site analysis and interaction profiling guided the screening of 60 bioactive compounds, with ascorbic acid as a reference. Capsaicin bound strongly to both CHST11 and CHST13, whereas erlotinib exhibited selective affinity for CHST13. Notably, the CHST13-capsaicin complex demonstrated the most favorable binding energy and structural stability in MD simulations. These findings highlight the distinct dynamic behaviors of both targets and support their potential as druggable proteins in HCC, offering a basis for developing selective therapeutic inhibitors. © 2025
Control of Ph+ and additional chromosomal abnormalities in chronic myeloid leukemia by tyrosine kinase inhibitors
(Springer, 2023) Sana Ansari; Malkhey Verma
Chronic myeloid leukemia (CML) is a type of blood cancer that is known to affect hematopoietic stem cells. The presence of the Philadelphia chromosome (Ph+) is the major characteristic of CML. A protein expressed by the Philadelphia chromosome shows elevated tyrosine kinase activity and is considered a tumorigenic factor. The first line of therapy that had been established for CML was “imatinib,” a potent tyrosine kinase inhibitor. Various other second- and third-generation TKIs are taken into account in cases of imatinib failure/resistance. With the subsequent rise in the development of tyrosine kinase inhibitors, optimization in the treatment of CML and amplified total survival were observed throughout TKI dosage. As the disease progresses, additional chromosomal abnormalities (ACAs) have been reported, but their prognostic effect and impact on the response to treatment are still unknown. However, some substantial understandings have been achieved into the disease transformation mechanisms, including the role of somatic mutations, ACAs, and several different genomic mutations that occur during diagnosis or have evolved during treatment. The acquisition of ACAs impedes CML treatment. Due to additional chromosomal lesions, there are greater chances of future disease progression at the time of CML diagnosis beyond the Ph+ translocation. The synchronous appearance of two or more ACAs leads to lower survival and is classified as a poor prognostic group. The key objective of this review is to provide detailed insights into TKIs and their role in controlling Ph+ and ACAs, along with their response, treatment, overall persistence, and survival rate. © 2023, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
CRISPR/Cas9: efficient and emerging scope for Brassica crop improvement
(Springer Science and Business Media Deutschland GmbH, 2025) Shiv Shankar Sharma; Ashwani Pandey; Anamika Kashyap; Lakshay Goyal; Pooja Garg; Ranjeet Kushwaha; Jyoti Sharma; Shikha Tripathi; Sujata Kumari; George Thomas; Malkhey Verma; Navin Chandra Gupta; Ashish Kumar Gupta; Ramcharan C. Bhattacharya; Sandhya Sharma; Mahesh Rao
Main conclusion: CRISPR/Cas9 revolutionizes Brassica crop improvement by enhancing yield, quality, and stress resistance, providing a precise and versatile tool for genetic and agronomic advancements. Abstract: The rapidly advancing CRISPR/Cas9 (Clustered regularly interspaced short palindromic repeats/CRISPR associated protein 9) technologies are being employed in both diploid and polyploid species of Brassica for gene functions and precise genetic improvements. CRISPR/Cas technology has sparked significant attention among the scientific community due to its affordability, precision, and effectiveness compared to other genome editing techniques. The recent discoveries highlight the diverse applications of the CRISPR/Cas9 genome editing tool in enhancing agriculturally important traits in Brassica species. This technology has been utilized to improve yield, quality, and resistance to both biotic and abiotic stresses globally. Here, we present an overview that encourages researchers to explore and improve the functionality and genetic progress of Brassica U-triangle species utilizing genome editing technologies. In addition, ethical considerations and concerns associated with CRISPR technologies are addressed, providing valuable insight into how CRISPR/Cas9 tools and have revolutionized crop improvement with special emphasis on Brassica for various agronomically and nutritionally important traits. © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2025.
Developing therapeutic approaches for chronic myeloid leukemia: a review
(Springer, 2023) Veerandra Kumar; Jyotirmayee; Malkhey Verma
Modern clinical therapy of chronic myeloid leukemia (CML) with TKIs is highly efficacious in most CML patients, while it is not remedial and generally confined due to intolerance or resistance. CML is currently considered a severe disease. Interestingly, stem cell transplantation in the past decade was an attractive clinical therapeutic option in CML patients, but it is not successful due to independently more death rates in older patients. So, the targeting of BCR::ABL oncoprotein is extensively used to enhance the reduction in a higher percentage of CML patients by tyrosine kinase inhibitors (TKIs). However, resistance or intolerance responses to these inhibitors are responsible for future deterioration and further development of disease. At this point, the clinical treatment of CML is a major challenge, and the lack of molecular responses to TKIs are not succeeded with chemotherapy alone. So, the considerable efficacious clinical necessities remain unmet. Therefore, continuous efforts are needed to explore new potential treatment strategies with an increasing understanding of CML biology. Therefore, this review deals with the investigation of TKI treatment with interferon, chemotherapy (Hydroxyurea, Homoharringtonine, Omacetaxine, Cytarabine), and several other new TKIs under beneficial clinical trials. Additionally, the approaches towards TKIs-resistant or intolerant CML cells where the respective signaling pathway gets up-regulated are also targeted with its inhibitor. This review presents evidence that new TKIs under clinical and pre-clinical trials may improve the chemotherapy of CML. © 2022, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
miR-145-5p and miR-203a-5p overcome imatinib resistance in myelogenous leukemic cells through metabolic reprogramming
(National Institute of Science Communication and Policy Research, 2023) Priyanka Singh; Sonu Kumar Gupta; Villayat Ali; Ravindresh Chhabra; Malkhey Verma
Imatinib is the most effective therapy for chronic myeloid leukemia (CML), but many patients eventually develop resistance to it after an initial satisfactory response. This study investigated the potential of three miRNAs (miR-106b-5p, miR-145-5p, miR-203a-5p) in overcoming imatinib resistance in leukemic cells. The imatinib-resistant K562 (IR-K562) cells were developed and transfected with one of the three miRNAs to evaluate their potency in overcoming imatinib resistance. The changes in the metabolic profile were studied using flux balance analysis (FBA) and the data was validated using qRT-PCR.Among the three miRNAs, the ectopic expression of either miR-145-5p or miR-203a-5p was able to sensitize the IR-K562 cells to imatinib. The concentration of key oncometabolites; glucose, lactate, and glutamine, in the culture media of the miR-transfected IR-K562 cells, reverted to the same levels as seen in imatinib-sensitive K562 cells. In addition, the FBA analysis revealed that the metabolism of lipid, fatty acids, and electron transport chain were significantly altered in resistant cells. The FBA data was also validated at the molecular level. Interestingly, the imatinib treatment coupled with the transfection of miR-145-5p or miR-203a-5p cells could reverse the metabolic flux of IR-K562 to the levels seen in imatinib-sensitive K562 cells. This study highlights the key metabolic changes that occur during development of imatinib resistance. It also identifies the specific miRNAs which can be targeted to overcome imatinib resistance in CML. © 2023, National Institute of Science Communication and Policy Research. All rights reserved.
miRNA expression based modulation: A new paradigm for the treatment of chronic myeloid leukemia
(Elsevier B.V., 2025) Sana Ansari; Malkhey Verma
MicroRNAs (miRNAs) are non-coding and internally derived small RNA molecules. They post-transcriptionally direct gene expression either by inhibiting translation or initiating degradation of mRNA. Conserved evolutionarily, these miRNAs have a significant role in several developmental and regulatory functions in organisms including mammalian cell growth, differentiation, and apoptosis. An individual miRNA can modulate a network of mRNA expression by binding to multiple mRNAs through imperfect sequence complementarity. In several types of cancer, dysregulation of miRNAs may contribute to cell initiation, migration, incursion, proliferation, immortality, and drug resistance. Among all leukemia cases, approximately 15 % of patients suffer from chronic myeloid leukemia (CML). miRNA-based modulation offers the idiosyncratic competence for regulating a variety of genes simultaneously; in that way, it could help to modulate accordant signalling pathways that are engaged in cell differentiation, proliferation, and survival. The one-drug, one-target approach thereby evolves into a paradigm of one drug with multiple targets. This review will delve into the understanding of miRNA dysregulation and recent advancements in therapeutic strategies based on miRNAs. © 2025 Elsevier B.V.
Novel pharmacological approach for the prevention of multidrug resistance (MDR) in a human leukemia cell line
(Elsevier Ltd, 2021) Sonu Kumar Gupta; Priyanka Singh; Ravindresh Chhabra; Malkhey Verma
Background: Drug resistance mechanisms are the regulatory factors associated with drug metabolism and drug transport to inward and outward of the target cells. Maybridge fragment (MBF) library is a collection of pharmacophore rich compounds having affinity with membrane transporters. This study has been designed to evaluate the efficacy of MBFs in overcoming the leukemic cells’ resistance to imatinib. Methods: Imatinib resistant cells (K562-R) were prepared using myelogenous leukemia cell line (K562) by titration method. The four MBFs were prioritized for determining their effect on imatinib resistance. The cells were treated with imatinib and MBFs and the MTT assay was performed to evaluate the efficacy of MBFs in enhancing the imatinib mediated cell death. The transcript levels of Bcr-Abl1 gene and efflux transporter genes were determined by RT-qPCR analysis. Results: The MBFs enhanced the imatinib mediated cell death of K562-R cells. There was also a significant decrease in the mRNA levels of the major drug efflux genes (ABCB1, ABCB10, ABCC1 and ABCG2) when treated with a combination of imatinib and MBF in comparison to imatinib treatment alone. Conclusion: The drug efflux is one of the mechanisms of multidrug resistance in cancer cells and the MBFs used in this study were all found to significantly overcome the imatinib resistance by limiting the expression of efflux genes. This study, therefore, highlights the potential of Maybridge compounds in treating the drug resistant leukemia. © 2021 Elsevier Ltd
Organ-targeted drug delivery systems (OTDDS) of poly[(N-acryloylglycine)-co-(N-acryloyl-l-phenylalanine methyl ester)] copolymer library and effective treatment of triple-negative breast cancer
(Royal Society of Chemistry, 2025) Sukanya Patra; None Jyotirmayee; Krishan Kumar; Divya Pareek; Prem Shankar Gupta; Anjali Ramsabad Mourya; Taniya Das; Kirti Wasnik; Malkhey Verma; Ruchi Chawla; Tarun K. Batra; Pradip Paik
Organ-targeted drug delivery systems (OTDDS) are essential for the effective treatment of complicated diseases. Triple-negative breast cancer (TNBC) is an aggressive cancer with high mortality and requires targeted therapeutics. This work was aimed at designing a library of polymeric OTDDS with N-acryloyl-glycine (NAG) and N-acryloyl-l-phenylalanine methyl ester (NAPA) [p(NAG-co-NAPA)(x:y)] and screening its in vivo organ-targeting specificity. Among this library, the best p(NAG-co-NAPA)(x:y) NPs with an x : y ratio of 1 : 4 and size of 160-210 nm targeted breasts to a high extent compared to other organs and thus were optimized for TNBC treatment. A network pharmacology study was performed, which revealed that 14 genes were responsible for TNBC, and a combination of DHA (targets 6 genes) and piperine (targets 8 genes) drugs was used to optimize the formulation, achieving the maximum therapeutic efficiency against TNBC with an IC50 value of 350 μg mL−1. The designed organ-specific polymeric nanoparticle (NP) library, identification of target genes and proteins responsible for TNBC, and the optimized formulation for effective combination therapy established an effective therapeutic option for TNBC. The findings of this work further demonstrate that this polymeric library of NPs shows exciting therapeutic potential for treating TNBC and presents innovative treatment options for critical diseases of the liver, heart, lungs and kidney. © 2025 The Royal Society of Chemistry.
Potential therapeutic targets in chronic myeloid leukemia
(Springer, 2025) Manvi Bansal; Malkhey Verma
Chronic myeloid leukemia (CML) is driven by the BCR::ABL fusion oncoprotein, caused by a reciprocal translocation between chromosomes no. 9 and 22, leading to the formation of the Philadelphia chromosome having aberrant tyrosine kinase activity. Tyrosine kinase inhibitors (TKIs) revolutionized the CML treatment and helped patients to achieve a higher survival rate. However, TKI resistance, leukemia stem cell (LSC) persistence, and disease relapse highlight the necessity for alternative treatment strategies. Furthermore, oxidative stress pathways are critical in promoting leukemic development and resistance, offering an emerging avenue for targeted intervention. This review explores several promising therapeutic targets in CML, such as suppressor pathways, autophagy modulation, the BCL-2 family proteins, and microRNAs (miRNAs) modulation. Restoring the function of tumor suppressors, such as PTPRG and p53, may complement current therapies since they are essential in regulating cell proliferation and apoptosis. Tumor suppressors offer the potential to enhance apoptosis, while the precise modulation of autophagy, a complex cellular process with context-dependent roles, can regulate cell survival under therapeutic pressure. The BCL-2 family proteins regulate apoptosis by the mitochondrial intrinsic apoptosis pathway, representing a critical target for overcoming apoptotic resistance in CML cells. Meanwhile, miRNAs emerge as potent modulators of oncogenic and apoptotic pathways by acting as tumor suppressors or oncomiRs, presenting an opportunity for advanced treatment. This review also includes gene editing to target oncogenic drivers or correcting mutations and USP inhibition to overcome resistance. Finally, it concludes by emphasizing the importance of combining these diverse therapeutic approaches with ongoing next-generation TKIs and comprehensive and personalized approaches for CML treatment, offering a path toward deeper remissions and ultimately achieving curative outcomes for CML patients. © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2025.
Role of miRNAs to control the progression of Chronic Myeloid Leukemia by their expression levels
(Springer, 2024) Manvi Bansal; Sana Ansari; Malkhey Verma
Chronic Myeloid Leukemia (CML) is a myeloproliferative disorder distinguished by a specific genetic anomaly known as a reciprocal translocation between chromosomes 9 and 22. This translocation causes fusion between the BCR and ABL regions. Consequently, BCR::ABL oncoprotein is formed, which plays a significant role in driving CML progression. Imatinib, a tyrosine kinase inhibitor (TKI), became the first line of drugs against CML. However, with continuous treatment, patients developed resistance against it. Indeed, to address this challenge, microRNA-based therapy emerges as a promising approach. miRNAs are 20–25 nucleotides long and hold great significance in various cellular processes, including cell differentiation, proliferation, migration, and apoptosis. In several malignancies, it has been reported that miRNAs might help to promote or prevent tumourigenesis and abnormal expression because they could act as both oncogenes/tumor suppressors. Recently, because of their vital regulatory function in maintaining cell homeostasis, miRNAs might be used to control CML progression and in developing new therapies for TKI-resistant patients. They might also act as potential prognostic, diagnostic, and therapeutic biomarkers based on their expression profiles. Various annotation tools and microarray-based expression profiles can be used to predict dysregulated miRNAs and their target genes. The main purpose of this review is to provide brief insights into the role of dysregulated miRNAs in CML pathogenesis and to emphasize their clinical relevance, such as their significant potential as therapeutics against CML. Utilizing these miRNAs as a therapeutic approach by inhibition or amplification of their activity could unlock new doors for the therapy of CML. © 2024, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
Transport and metabolism of tyrosine kinase inhibitors associated with chronic myeloid leukemia therapy: a review
(Springer, 2022) Veerandra Kumar; Priyanka Singh; Sonu Kumar Gupta; Villayat Ali; Malkhey Verma
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. © 2022, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
Unlocking the Secrets of the King of Spices: Exploring Its Chemistry, Health Benefits, and Medicinal Wonders
(CRC Press, 2025) Sukanya Patra; Jyotirmayee; Pradip Paik; Malkhey Verma
Black pepper, the “King of Spices”, has a rich history of culinary and medicinal uses. This versatile spice contains multiple bioactive compounds, such as alkaloids, essential oils, flavonoids, and lignans, which has been studied extensively for its health benefits, including antioxidant, anti-inflammatory, antimicrobial, and gastroprotective properties. Piperine, an active alkaloid of black pepper, enhances the bioavailability of nutrients and drugs, making it a valuable adjunct in pharmacology and nutrition. However, high doses of piperine may lead to adverse effects, including gastrointestinal irritation, hepatotoxicity, and interference with drug metabolism. This chapter provides a more detailed comprehensive review to completely understand pepper’s therapeutic potential and safety profile. © 2026 selection and editorial matter, Pankaj Kumar Chaurasia, Shashi Lata Bharati, Sunita Singh, and Ashutosh Mani; individual chapters, the contributors.