Browsing by Author "Lokesh Yadav"

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FNC (4′-azido-2′-deoxy-2′-fluoro(arbino)cytidine) as an Effective Therapeutic Agent for NHL: ROS Generation, Cell Cycle Arrest, and Mitochondrial-Mediated Apoptosis
(Springer, 2024) Naveen Kumar; Alok Shukla; Sanjay Kumar; Ilya Ulasov; Rishi Kant Singh; Sandeep Kumar; Anand Patel; Lokesh Yadav; Ruchi Tiwari; Rachana Paswan; Shivashish Priyadarshi Mohanta; Kaushalendra; Jyeoti Antil; Arbind Acharya
Cytotoxic nucleoside analogs (NAs) hold great promise in cancer therapeutics by mimicking endogenous nucleosides and interfering with crucial cellular processes. Here, we investigate the potential of the novel cytidine analog, 4′-azido-2′-deoxy-2′-fluoro(arbino)cytidine (FNC), as a therapeutic agent for Non-Hodgkin lymphoma (NHL) using Dalton’s lymphoma (DL) as a T-cell lymphoma model. FNC demonstrated dose- and time-dependent inhibition of DL cell growth and proliferation. IC-50 values of FNC were measured at 1 µM, 0.5 µM, and 0.1 µM after 24, 48, and 72 h, respectively. Further elucidation of FNC’s mechanism of action uncovers its role in inducing apoptosis in DL cells. Notable DNA fragmentation and nuclear condensation point to activated apoptotic pathways. FNC-induced apoptosis was concomitant with changes in cellular membranes, characterized by membrane rupture and altered morphology. The robust anticancer effects of FNC are linked to its capacity to induce reactive oxygen species (ROS) production, prompting oxidative stress-mediated apoptosis. Additionally, FNC disrupted mitochondrial membrane potential (MMP), leading to mitochondrial dysfunction, further promoting apoptosis. Dysregulation of apoptotic genes, with upregulation of Bax and downregulation of Bcl-2 and Bcl-xl, implicates the mitochondrial-mediated apoptosis pathway. Furthermore, FNC-induced G2/M phase cell cycle arrest was mediated through modulation of the cell cycle inhibitor p21. Overall, this study highlights the potential of FNC as a promising therapeutic agent for NHL. © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2024.
Mitochondrial-mediated apoptosis as a therapeutic target for FNC (2′-deoxy-2′-b-fluoro-4′-azidocytidine)-induced inhibition of Dalton’s lymphoma growth and proliferation
(Springer Science and Business Media B.V., 2024) Naveen Kumar; Sanjeev Kumar; Alok Shukla; Sanjay Kumar; Rishi Kant Singh; Ilya Ulasov; Sandeep Kumar; Anand Kumar Patel; Lokesh Yadav; Ruchi Tiwari; Rachana; Shivashish Priyadarshi Mohanta; Kaushalendra; Vikram Delu; Arbind Acharya
Purpose: T-cell lymphomas, refer to a diverse set of lymphomas that originate from T-cells, a type of white blood cell, with limited treatment options. This investigation aimed to assess the efficacy and mechanism of a novel fluorinated nucleoside analogue (FNA), 2′-deoxy-2′-β-fluoro-4′-azidocytidine (FNC), against T-cell lymphoma using Dalton’s lymphoma (DL)-bearing mice as a model. Methods: Balb/c mice transplanted with the DL tumor model received FNC treatment to study therapeutic efficacy against T-cell lymphoma. Behavioral monitoring, physiological measurements, and various analyses were conducted to evaluate treatment effects for mechanistic investigations. Results: The results of study indicated that FNC prevented DL-altered behavior parameters, weight gain and alteration in organ structure, hematological parameters, and liver enzyme levels. Moreover, FNC treatment restored organ structures, attenuated angiogenesis, reduced DL cell viability and proliferation through apoptosis. The mechanism investigation revealed FNC diminished MMP levels, induced apoptosis through ROS induction, and activated mitochondrial-mediated pathways leading to increase in mean survival time of DL mice. These findings suggest that FNC has potential therapeutic effects in mitigating DL-induced adverse effects. Conclusion: FNC represents an efficient and targeted treatment strategy against T-cell lymphoma. FNC’s proficient ability to induce apoptosis through ROS generation and MMP reduction makes it a promising candidate for developing newer and more effective anticancer therapies. Continued research could unveil FNC’s potential role in designing a better therapeutic approach against NHL. © 2023, The Author(s).
Moringa oleifera L. leaf extract induces cell cycle arrest and mitochondrial apoptosis in Dalton's Lymphoma: An in vitro and in vivo study
(Elsevier Ireland Ltd, 2023) Sandeep Kumar; Praveen Kumar Verma; Alok Shukla; Rishi Kant Singh; Anand Kumar Patel; Lokesh Yadav; Sanjay Kumar; Naveen Kumar; Kaushalendra; Arbind Acharya
Ethnopharmacological relevance: The present work is based on a wide spectrum of evidences available from scientific literature which reflects nutritional and medicinal values of natural products such as plants and their extracts. Moringa oleifera is one such popular plant species amidst indigenous tribal communities which is frequently used to treat ailments such as piles, sore throat, eye and ear infections and even poisonous bites of tropical fauna such as insects or snakes. Furthermore decoction of leaf and bark was used to cure fever and cough. Evidences further reveal that Moringa oleifera L. (Family Moringaceae), is widely distributed not only over the Indian sub-continent, but also over Philippines, Central America, Saudi Arabia and the Caribbean Islands and have been traditionally used to treat cancers since ancient times. However, therapeutic effects of Moringa oleifera on Non-Hodgkin Lymphoma (NHL) are yet to be established. Aim of the study: The study aims to investigate the anti-cancer effects of Moringa oleifera leaf extract against murine NHL Non-Hodgkin cells in vitro and in vivo. Material and methods: The pharmacologically active compounds of Moringa oleifera leaf extract were identified by GC-HRMS analysis. Tests of Moringa oleifera leaf extract's cytotoxicity against DL cells were carried out using the MTT assay. Chromatin condensation along with other morphological alterations were visualized through Fluorescence microscopy. Changes in the mitochondrial membrane potential (ΔΨm), the cell cycle, and apoptosis were analysed through flow cytometer. We tried to identify proteins involved in apoptosis and cell cycle through Western blotting using BALB/c mice as a model organism. Results: GC-HRMS study revealed that a methanol based leaf extract of Moringa oleifera (MOML) comprises of a variety of bioactive chemicals. Our results indicate that MOML successfully reduced the proliferation of DL cells by lowering ΔΨm, changing overall cell morphology. DL cells treated with MOML showed arrested cell cycle at the G2/M phase and substantially up-regulated the expression of p53 and p21. Elevated levels of Bax, Cyt-c, and Caspase-3 and lowered expression levels of Bcl-2 protein suggested induction of apoptosis. Mechanistically, the anticancer efficacy of MOML is attributed to MEK/ERK-mediated pathway inactivation in DL cells. It is also interesting to note that MOML-mediated inhibition of DL growth was accompanied by apoptosis induction and improvement in hematological parameters in DL-bearing mice. Conclusion: Our finding suggested that MOML induces apoptosis and abrogates the growth of Dalton's lymphoma both in vitro and in vivo. © 2022 Elsevier B.V.
Pharmacological Insights: Mitochondrial ROS Generation by FNC (Azvudine) in Dalton’s Lymphoma Cells Revealed by Super Resolution Imaging
(Springer, 2024) Naveen Kumar; Vikram Delu; Ilya Ulasov; Sanjay Kumar; Rishi Kant Singh; Sandeep Kumar; Alok Shukla; Anand Kumar Patel; Lokesh Yadav; Ruchi Tiwari; Kumari Rachana; Shivashish Priyadarshi Mohanta; Varsha Singh; Anuradha Yadav; Kaushalendra Kaushalendra; Arbind Acharya
Nucleoside analogs are a common form of chemotherapy that disrupts DNA replication and repair, leading to cell cycle arrest and apoptosis. Reactive oxygen species (ROS) production is a significant mechanism through which these drugs exert their anticancer effects. This study investigated a new nucleoside analog called FNC or Azvudine, and its impact on ROS production and cell viability in Dalton’s lymphoma (DL) cells. The study found that FNC treatment resulted in a time- and dose-dependent increase in ROS levels in DL cells. After 15 and 30 min of treatment with 2 and 1 mg/ml of FNC, mitochondrial ROS production was observed in DL cells. Furthermore, prolonged exposure to FNC caused structural alterations and DNA damage in DL cells. The results suggest that FNC’s ability to impair DL cell viability may be due to its induction of ROS production and indicate a need for further investigation. © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2024.
Safety Assessment of a Nucleoside Analogue FNC (2’-deoxy-2’-β-fluoro-4’-azidocytidine ) in Balb/c Mice: Acute Toxicity Study
(Asian Pacific Organization for Cancer Prevention, 2023) Naveen Kumar; Vikram Delu; Alok Shukla; Rishi Kant Singh; Ilya Ulasov; Daria Fayzullina; Sandeep Kumar; Anand Kumar Patel; Lokesh Yadav; Ruchi Tiwari; Kumari Rachana; Shivashish Priyadarshi Mohanta; Sanjay Kumar; Kaushalendra Kaushalendra; Arbind Acharya
Objectives: The present study aimed to provide an insight into the acute toxicity of a novel fluorinated nucleoside analogue (FNA), FNC (Azvudine or2’-deoxy-2’-β-fluoro-4’-azidocytidine). FNC showed potent anti-viral and anticancer activities and approved drug for high-load HIV patients, despite, its acute toxicity study being lacking. Materials and Methods: OECD-423 guidelines were followed during this study and the parameters were divided into four categories - behavioral parameters, physiological parameters, histopathological parameters, and supplementary tests. The behavioral parameters included feeding, body weight, belly size, organ weight and size, and mice behavior. The physiological parameters consisted of blood, liver, and kidney indicators. In histopathological parameters hematoxylin and eosin staining was performed to analyse the histological changes in the mice organs after FNC exposure. In addition, supplementary tests were conducted to assess cellular viability, DNA fragmentation and cytokine levels (IL-6 and TNF-α) in response to FNC. Results: In the behavioral parameters FNC induced changes in the mice-to-mice interaction and activities. Mice’s body weight, belly size, organ weight, and size remained unchanged. Physiological parameters of blood showed that FNC increased the level of WBC, RBC, Hb, and neutrophils and decreased the % count of lymphocytes. Liver enzymes SGOT (AST), and ALP was increased. In the renal function test (RFT) cholesterol level was significantly decreased. Histopathological analysis of the liver, kidney, brain, heart, lungs, and spleen showed no sign of tissue damage at the highest FNC dose of 25 mg/kg b.wt. Supplementary tests for cell viability showed no change in viability footprint, through our recently developed dilution cum-trypan (DCT) assay, and Annexin/PI. No DNA damage or apoptosis was observed in DAPI or AO/EtBr studies. Pro-inflammatory cytokines IL-6 and TNF-α increased in a dose-dependent manner. Conclusion: This study concluded that FNC is safe to use though higher concentration shows slight toxicity. © This work is licensed under a Creative Commons Attribution-Non Commercial 4.0 International License.
Spatial Heterogeneity in Health Risk Assessment of Heavy Metals During North-East Monsoon and South-West Monsoon over India
(Springer, 2024) Martina Rani; Sakshi Ahlawat; N. Vijayan; Lokesh Yadav; Tirthankar Banerjee; Abhijeet Chatterjee; Manpreet Singh Bhatti; Trupti Das; Amit Dhir; Sangita Goel; Altaf Husain Khan; Ravindra Khaiwal; Jagdish Chandra Kuniyal; Anita Lakhani; Abhishek Gupta; Srimanta Pal; Prasenjit Saikia; B.M. Vyas; Suman Mor; Tuhin Kumar Mandal
The present study reports the health risk assessment in heavy metals (Cr, Cd, Pb, As, Mn, and Ni) in particulate matter (< 2.5 µm) measured at 18 different sites of five climatic zones India during the distinct seasons namely the northeast monsoon (NEM) and the southwest monsoon (SWM) in campaign mode for the period of 2014–2019. The concentration of these heavy metals in PM2.5 was determined using WD-X-ray fluorescence (XRF). Health risk assessment of heavy metals was performed estimating Hazard quotient (HQ) and carcinogenic risk (CR) assessment for adults and children for the heavy metals. HI < 1 implies no health hazard, and HI > 1 indicates that adverse health impacts may occur. Exposure to harmful toxic metals for adults and children, the total excess cancer risk higher than the threshold range (10–4–10–6) of heavy metals is considered significant. Since airmass movement during the two seasons (NEM and SWM) is completely different, a variation is expected in the concentration of heavy metals and associated health risk factors. During NEM the CR for children (2–4 × 10–6) is more observed at several sites namely Patiala, Lucknow, Varanasi, Bhuvneshwar, Jaisalmer, and Rajkot, whereas, for adults, the moderate CR (1–9 × 10–6) is at sites Darjeeling, Jorhat, Giridh, Delhi, Udaipur, Jaisalmer, and Bikaner. CR value for children and adults is comparatively lower during SWM than NEM. © The Author(s) under exclusive licence to Institute of Earth Environment, Chinese Academy Sciences 2024.
Spatial Heterogeneity in Health Risk Assessment of Heavy Metals During North-East Monsoon and South-West Monsoon over India
(Springer, 2025) Martina Rani; Sakshi Ahlawat; Narayanasamy Vijayan; Lokesh Yadav; Tirthankar Banerjee; Abhijit Chatterjee; Manpreet Singh Bhatti; Trupti Das; Amit Dhir; Sangita Goel; Altaf Hussain Khan; Ravindra Khaiwal; Jagdish Chandra Kuniyal; Anita Lakhani; A. Gupta; Srimanta K. Pal; Prasenjit C. Saikia; Brij Mohan Vyas; Suman Mor; Tuhin Kumar Mandal
The present study reports the health risk assessment in heavy metals (Cr, Cd, Pb, As, Mn, and Ni) in particulate matter (< 2.5 µm) measured at 18 different sites of five climatic zones India during the distinct seasons namely the northeast monsoon (NEM) and the southwest monsoon (SWM) in campaign mode for the period of 2014–2019. The concentration of these heavy metals in PM2.5 was determined using WD-X-ray fluorescence (XRF). Health risk assessment of heavy metals was performed estimating Hazard quotient (HQ) and carcinogenic risk (CR) assessment for adults and children for the heavy metals. HI < 1 implies no health hazard, and HI > 1 indicates that adverse health impacts may occur. Exposure to harmful toxic metals for adults and children, the total excess cancer risk higher than the threshold range (10–4–10–6) of heavy metals is considered significant. Since airmass movement during the two seasons (NEM and SWM) is completely different, a variation is expected in the concentration of heavy metals and associated health risk factors. During NEM the CR for children (2–4 × 10–6) is more observed at several sites namely Patiala, Lucknow, Varanasi, Bhuvneshwar, Jaisalmer, and Rajkot, whereas, for adults, the moderate CR (1–9 × 10–6) is at sites Darjeeling, Jorhat, Giridh, Delhi, Udaipur, Jaisalmer, and Bikaner. CR value for children and adults is comparatively lower during SWM than NEM. © The Author(s) under exclusive licence to Institute of Earth Environment, Chinese Academy Sciences 2024.
Synthesis, characterizations, crystal structure and anticancer activity of Mn(II), Co(II) and Ni(II) complexes of N′-cyclohexyl-2-thiophene-carbonyl hydrazine carbothioamide
(Elsevier Ltd, 2023) Shubham Jaiswal; Lokesh Yadav; Shivendra Kumar Pandey; Suryansh Chandra; M.K. Bharty; L.B. Prasad; A. Acharya
The current century has witnessed continuous and exponential increase in the number of patients suffering from different types of sarcomas. To cure these sarcomas, there are continuous efforts to develop more efficient and less cytotoxic anti-cancerous and antitumor drugs. A thiosemicarbazide derived N-cyclohexyl-2-thiophene-carbonyl hydrazine carbothioamide (Htach) and its metal complexes [Mn(tach)2(o-phen)] (1), [Co(tach)2(o-phen)] (2), [Ni(tach)2(o-phen)] (3) were synthesized and reported here. In these complexes, o-phen was used as secondary ligand for coordinatively saturation of metal ions. The synthesized ligand and complexes are well characterized with different elemental analysis FT-IR, and UV–visible and HR-MS spectroscopy. Further, Complex 1 was characterized by single XRD and crystallized in monoclinic system with space group P 21/n. The anti-proliferative potential of ligand and its complexes were evaluated against Dalton's lymphoma (DL) cancer cell lines through MTT, AO/EtBr and DAPI based assays. The effect of these metal complexes on normal cell lines (splenocyte) has been also investigated. Our investigation reveals that metal–ligand complexes have significant strong anticancer activity against tumor cells in a dose-dependent mode, whereas minimal effect on normal cell lines. For ligand and complexes 1–3, the IC50 values were found as 20, 10, 20 and 5 µM, respectively. These results suggest that among Mn, Co and Ni complexes, nickel complex will be more effective for the functionalization of anticancer agents. © 2023 Elsevier Ltd
Tumor-derived Hsp70-CD14 interaction enhances the antitumor potential of cytotoxic T cells by activating tumor-associated macrophages to express CC chemokines and CD40 costimulatory molecules
(Elsevier B.V., 2024) Sanjay Kumar; Vijay Mohan; Rishi Kant Singh; Pramod Kumar Gautam; Sandeep Kumar; Alok Shukla; Anand Kumar Patel; Lokesh Yadav; Arbind Acharya
Heat shock proteins are a widely distributed group of proteins. It is constitutively expressed in almost all organisms and shows little variation throughout evolution. Previously, HSPs, particularly Hsp70, were recognized as molecular chaperones that aid in the proper three-dimensional folding of newly synthesized polypeptides in cells. Recently, researchers have focused on the potential induction of immune cells, including macrophages, antigen-specific CD8+ cytotoxic T cells, and PBMCs. It induces the expression of CC chemokines such as MIP-1α and RANTES, which are responsible for the chemotactic movement and migration of immune cells at the site of infection to neutralize foreign particles in vivo and in vitro in several cell lines but their effect on tumor-associated macrophages is still not known. These cytokines are also known to influence the movement of several immune cells, including CD8+ cytotoxic T cells, toward inflammatory sites. Therefore, the effect of tumor-derived autologous Hsp70 on the expression of MIP-lα and RANTES in tumor-associated macrophages (TAMs) was investigated. Our results indicated that Hsp70 treatment-induced MIP-lα and RANTES expression was significantly greater in TAMs than in NMOs. According to the literature, the CC chemokine shares the same receptor, CCR5, as HIV does for their action, and therefore could provide better completion to the virus for ligand binding. Furthermore, Hsp70-preactivated TAMs induced increased IL-2 and IFN-γ expression in T cells during coculture for 48 h and upregulated the antitumor immune response of the host. Therefore, the outcome of our study could be useful for developing a better approach to restricting the growth and progression of tumors. © 2024