Browsing by Author "Gautam Sethi"

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Activation of c-Jun N-terminal kinase is required for ultraviolet B-induced apoptosis of murine peritoneal macrophages in vitro
(2004) Gautam Sethi; Ajit Sodhi
The mechanisms of ultraviolet B (UVB)-induced apoptosis and the role of c-Jun N-terminal kinase (JNK) mitogen activated protein kinase (MAPK) in murine peritoneal macrophages, the terminally differentiated non-dividing cells were investigated. Exposure of macrophages to UVB 100 mJ/cm2 induced rapid apoptosis concurrent with activation of JNK and mitochondrial cytochrome c release leading to procaspase-3 activation. Late into the UVB-induced apoptosis, a caspase-mediated cleavage of Bid was observed. Caspase inhibitors N-Benzylocarbonyl-Val-Asp-fluoromethyl ketone and N-Acetyl-Asp-Glu-Val-Asp-aldehyde inhibited the UVB-induced apoptosis without preventing the release of cytochrome c and JNK activation. The inhibition of JNK MAPK prevented UVB-induced apoptosis, concomitant with inhibition in cytochrome c release and procaspase-3 activation. However, it had no effect on procaspase-8 activation. These results indicate that activation of JNK MAPK upstream of caspases might play an important role in the apoptotic process of macrophages exposed to UVB irradiation. © 2003 Elsevier B.V. All rights reserved.
Caspase-9 and Bax/Bcl-2 regulation in ultraviolet B-induced apoptosis of murine peritoneal macrophages
(2004) Ajit Sodhi; Gautam Sethi
This study was performed to determine the effect of UVB radiation on the activation of apoptosis regulatory proteins using murine peritoneal macrophages, which are terminally, differentiated non-dividing cells. UVB (100 mJ/cm 2) irradiation induced apoptosis in murine peritoneal macrophages concurrent with expression of p53, Apaf-1, upregulation of Bax, downregulation of Bcl-2, activation of caspases-9, -3, -2 and DNA fragmentation. Pretreatment of macrophages with serine protease inhibitors TPCK and TLCK inhibited UVB irradiation induced apoptosis. Interestingly, caspase-9 inhibitor Z-LEHD-FMK blocked caspase-2 activation suggesting that caspase-2 activation is not due to death receptor activation but results from activation of other caspases that are dependent on caspase-9 such as caspase-3. The data showed that the regulation of the Bcl-2 family and caspase-9 might work together to activate a caspase-3 mediated apoptotic pathway following UVB irradiation of macrophages.
Cell cycle dysregulation in cancer
(Elsevier Inc., 2025) Antonino Glaviano; Samarendra Kumar Singh; Eugine Hui Clarissa Lee; Elena Okina; Hiu Yan Lam; Daniela Carbone; E. Premkumar Reddy; Mark J. O'Connor; Andrew Koff; Garima Singh; Justin Stebbing; Gautam Sethi; Karen C. Crasta; Patrizia Diana; Khandan K. Keyomarsi; Michael B. Yaffe; Seth Andrew Wander; Aditya Bardia; Alan Prem Kumar
Cancer is a systemic manifestation of aberrant cell cycle activity and dysregulated cell growth. Genetic mutations can determine tumor onset by either augmenting cell division rates or restraining normal controls such as cell cycle arrest or apoptosis. As a result, tumor cells not only undergo uncontrolled cell division but also become compromised in their ability to exit the cell cycle accurately. Regulation of cell cycle progression is enabled by specific surveillance mechanisms known as cell cycle checkpoints, and aberrations in these signaling pathways often culminate in cancer. For instance, DNA damage checkpoints, which preclude the generation and augmentation of DNA damage in the G1, S, and G2 cell cycle phases, are often defective in cancer cells, allowing cell division in spite of the accumulation of genetic errors. Notably, tumors have evolved to become dependent on checkpoints for their survival. For example, checkpoint pathways such as the DNA replication stress checkpoint and the mitotic checkpoint rarely undergo mutations and remain intact because any aberrant activity could result in irreparable damage or catastrophic chromosomal missegregation leading to cell death. In this review, we initially focus on cell cycle control pathways and specific functions of checkpoint signaling involved in normal and cancer cells and then proceed to examine how cell cycle control and checkpoint mechanisms can provide new therapeutic windows that can be exploited for cancer therapy. Significance Statement: DNA damage checkpoints are often defective in cancer cells, allowing cell division in spite of the accumulation of genetic errors. Conversely, DNA replication stress and mitotic checkpoints rarely undergo mutations because any aberrant activity could result in irreparable damage or catastrophic chromosomal missegregation, leading to cancer cell death. This review focuses on the checkpoint signaling mechanisms involved in cancer cells and how an emerging understanding of these pathways can provide new therapeutic opportunities for cancer therapy. © 2024 American Society for Pharmacology and Experimental Therapeutics
Corrigendum to “Cell cycle dysregulation in cancer” [Pharmacological Reviews 77 (2025) 100030] (Pharmacological Reviews (2025) 77(2), (S0031699724126300), (10.1016/j.pharmr.2024.100030))
(Elsevier Inc., 2025) Antonino Glaviano; Samarendra Kumar Singh; E. Hui Clarissa Lee; Elena Okina; Hiu Yan Lam; Daniela Carbone; E. Premkumar Reddy; Mark J. O'Connor; Andrew Koff; Garima Singh; Justin Stebbing; Gautam Sethi; Karen C. Crasta; Patrizia Diana; Khandan K. Keyomarsi; Michael B. Yaffe; Seth Andrew Wander; Aditya Bardia; Alan Prem Kumar
The authors would like to add a current affiliation for author Justin Stebbing. The following footnote has been added to the original article: Current affiliation (J.S.): School of Life Sciences, Anglia Ruskin University, Cambridge, United Kingdom. © 2025 American Society for Pharmacology and Experimental Therapeutics
In vitro activation of murine peritoneal macrophages by ultraviolet B radiation: Upregulation of CD18, production of NO, proinflammatory cytokines and a signal transduction pathway
(2004) Gautam Sethi; Ajit Sodhi
In the present study, we report the activation of murine peritoneal macrophages in vitro on irradiation with sublethal dose of UVB (50mJ/cm 2). The activation involves enhanced expression of CD18 molecule and production of nitric oxide (NO), tumor necrosis factor (TNF-α) and interleukin-1 (IL-1). Production of NO, TNF-α and IL-1 by the macrophages on UVB irradiation was found to peak at 24h of incubation post UVB irradiation. Increased iNOS, TNF-α and IL-1β mRNAs expression was also observed by reverse transcription and polymerase chain reaction (RT-PCR). The RT-PCR results also showed the increased transcription of IL-6, IL-12, TLR2 and TLR4 genes in UVB-irradiated macrophages. Increased expression of phospho-IκB was also observed by immunoblotting in UVB-irradiated macrophages. Investigating the signal transduction pathway responsible for the NO, TNF-α and IL-1 production by the UVB-irradiated macrophages, it was observed that the pharmacological inhibitors pertussis toxin, wortmannin, PD98059, SB202190 and genistein blocked NO, TNF-α and IL-1 production suggesting the probable involvement of G-proteins, phosphoinositol-3-kinase, p42/44, p38 mitogen activated protein kinases and tyrosine kinases in the above process. © 2004 Elsevier Ltd. All rights reserved.
Involvement of Fas/Fas ligand in ultraviolet B-induced apoptosis of murine peritoneal macrophages
(2004) Ajit Sodhi; Gautam Sethi
The role of Fas/Fas ligand in ultraviolet B (UVB)-induced apoptosis of murine peritoneal macrophages, the terminally differentiated, non-dividing cells was investigated. UVB (100 mJ/cm2) irradiation induced apoptosis in macrophages concurrent with expression of Fas, Fas ligand, Fas-associated death domain (FADD), activation of caspase-8, -3 and cleavage of poly (ADP-ribose) polymerase (PARP). Pretreatment of macrophages with a p38 mitogen activated protein kinase (MAPK) inhibitor SB202190, and c-Jun N-terminal kinase (JNK) inhibitor SP600125, inhibited UVB irradiation induced Fas expression and apoptosis. Alternatively, pretreatment with MAP kinase kinase (MEK) inhibitor PD98059, and phosphatidylinositol 3-kinase (PI3-K) inhibitor wortmannin, enhanced UVB induced expression of Fas and apoptosis. Apoptosis-inducing factor (AIF) release from mitochondria and Bcl-2 down-regulation is also observed during apoptosis in UVB-irradiated macrophages. The data suggests that UVB-induced apoptosis is at least in part mediated by Fas/FasL system, and that MAPKs and PI3-K play an important role in the apoptotic process of macrophages exposed to UVB irradiation.
Involvement of MAP kinase signal transduction pathway in UVB-induced activation of macrophages in vitro
(Elsevier B.V., 2003) Ajit Sodhi; Gautam Sethi
Ultraviolet B (UVB) radiation causes a variety of biological effects that can be either beneficial or harmful for human health. To exert these effects on a cellular basis, UVB induces a variety of signaling pathways, which act in an independent and additive ways. However, the UVB-induced signal transduction mechanism(s) till date remains not well understood. In the current investigation, we demonstrate p42/44, p38 and JNK MAPK activation in murine peritoneal macrophages on irradiation with UVB as determined by the expression of phospho-p42/44 MAPK, -p38 and -JNK. These responses were found to be rapid and time-dependent, detectable as early as 5min post UVB irradiation 50mJ/cm2 and reached a peak by 15min. UVB-induced phosphorylation of p42/44, p38 and JNK MAPKs was found to be blocked by Gαi-protein inhibitor, pertussis toxin; tyrosine kinase inhibitor, genistein; and PI3-K inhibitor, wortmannin. The activation of downstream transcription factors, c-jun and c-fos was also observed in response to UVB irradiation. The role of PD98059, SB202190, genistein, and wortmannin in regulating UVB-induced c-jun and c-fos activation and transcription was also investigated. The functional consequences of UVB-induced p42/44 MAPK and p38 MAPK activity were studied using TNF-α and NO production in the macrophages. The data suggests the involvement of p42/44, p38 and JNK MAPK pathway and subsequent induction of c-fos and c-jun in the signal transduction process leading to the activation of macrophages exposed to UVB. © 2003 Elsevier B.V. All rights reserved.
Long non-coding RNAs are emerging targets of phytochemicals for cancer and other chronic diseases
(Springer Science and Business Media Deutschland GmbH, 2019) Shruti Mishra; Sumit S. Verma; Vipin Rai; Nikee Awasthee; Srinivas Chava; Kam Man Hui; Alan Prem Kumar; Kishore B. Challagundla; Gautam Sethi; Subash C. Gupta
The long non-coding RNAs (lncRNAs) are the crucial regulators of human chronic diseases. Therefore, approaches such as antisense oligonucleotides, RNAi technology, and small molecule inhibitors have been used for the therapeutic targeting of lncRNAs. During the last decade, phytochemicals and nutraceuticals have been explored for their potential against lncRNAs. The common lncRNAs known to be modulated by phytochemicals include ROR, PVT1, HOTAIR, MALAT1, H19, MEG3, PCAT29, PANDAR, NEAT1, and GAS5. The phytochemicals such as curcumin, resveratrol, sulforaphane, berberine, EGCG, and gambogic acid have been examined against lncRNAs. In some cases, formulation of phytochemicals has also been used. The disease models where phytochemicals have been demonstrated to modulate lncRNAs expression include cancer, rheumatoid arthritis, osteoarthritis, and nonalcoholic fatty liver disease. The regulation of lncRNAs by phytochemicals can affect multi-steps of tumor development. When administered in combination with the conventional drugs, phytochemicals can also produce synergistic effects on lncRNAs leading to the sensitization of cancer cells. Phytochemicals target lncRNAs either directly or indirectly by affecting a wide variety of upstream molecules. However, the potential of phytochemicals against lncRNAs has been demonstrated mostly by preclinical studies in cancer models. How the modulation of lncRNAs by phytochemicals produce therapeutic effects on cancer and other chronic diseases is discussed in this review. © Springer Nature Switzerland AG 2019.
Long noncoding RNAs in triple-negative breast cancer: A new frontier in the regulation of tumorigenesis
(John Wiley and Sons Inc, 2021) Krishan K. Thakur; Aviral Kumar; Kishore Banik; Elika Verma; Elina Khatoon; Choudhary Harsha; Gautam Sethi; Subash C. Gupta; Ajaikumar B. Kunnumakkara
In recent years, triple-negative breast cancer (TNBC) has emerged as the most aggressive subtype of breast cancer and is usually associated with increased mortality worldwide. The severity of TNBC is primarily observed in younger women, with cases ranging from approximately 12%–24% of all breast cancer cases. The existing hormonal therapies offer limited clinical solutions in completely circumventing the TNBC, with chemoresistance and tumor recurrences being the common hurdles in the path of TNBC treatment. Accumulating evidence has correlated the dysregulation of long noncoding RNAs (lncRNAs) with increased cell proliferation, invasion, migration, tumor growth, chemoresistance, and decreased apoptosis in TNBC. Various clinical studies have revealed that aberrant expression of lncRNAs in TNBC tissues is associated with poor prognosis, lower overall survival, and disease-free survival. Due to these specific characteristics, lncRNAs have emerged as novel diagnostic and prognostic biomarkers for TNBC treatment. However, the underlying mechanism through which lncRNAs perform their actions remains unclear, and extensive research is being carried out to reveal it. Therefore, understanding of mechanisms regulating the modulation of lncRNAs will be a substantial breakthrough in effective treatment therapies for TNBC. This review highlights the association of several lncRNAs in TNBC progression and treatment, along with their possible functions and mechanisms. © 2021 Wiley Periodicals LLC
Role of p38 Mitogen-activated Protein Kinase and Caspases in UV-B-induced Apoptosis of Murine Peritoneal Macrophages
(2004) Gautam Sethi; Ajit Sodhi
The mechanisms of ultraviolet-B (UV-B)-induced apoptosis and the role of p38 mitogen-activated protein kinase (MAPK) were investigated in murine peritoneal macrophages. Exposure of murine peritoneal macrophages to UV-B irradiation induced rapid apoptosis concurrent with DNA fragmentation and activation of caspase-3 but did not activate caspase-1. UV-B irradiation (100 mJ/cm2) also induced expression of phospho-p38 and -c-Jun N-terminal kinase (JNK) MAPK; however, no significant expression of phospho-p42/44 was observed 120 min after exposure. Pretreatment of macrophages with a p38 MAPK inhibitor, 4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)-1H-imidazole (SB202190), and a caspase-3 inhibitor, N-acetyl-Asp-Glu-Val-Asp-CHO, suppressed UV-B irradiation-induced apoptosis as observed by DNA laddering and DNA fragmentation estimation quantitatively. Pretreatment with caspase-1 inhibitor, N-acetyl-Tyr-Val-Ala-Asp-CHO, had no effect. UV-B-induced caspase-3 activation resulted in the cleavage of poly-(ADP-ribose) polymerase (PARP), which was inhibited by the caspase-3 inhibitor. SB202190 pretreatment also prevented activation of caspase-3 and the cleavage of PARP. However, the caspase-3 and -1 inhibitors did not affect UV-B-induced expression of phospho-p38 and -JNK. These results suggest that activation of p38 MAPK upstream of caspases might play an important role in the apoptotic process of macrophages exposed to UV-B irradiation.
Role of protein kinase Cδ in UV-B-induced apoptosis of macrophages in vitro
(2005) Ajit Sodhi; Gautam Sethi
We have previously reported that murine peritoneal macrophages exposed to ultraviolet B (UV-B; 100 mJ/cm 2) undergo apoptosis, as indicated by alterations in cell morphology, caspase-3 activation, poly (ADP-ribose) polymerase (PARP) cleavage, DNA fragmentation, sustained activation of p38/c-Jun N-terminal kinase (JNK) mitogen-activated protein kinases (MAPKs) and inactivation of p42/44 MAPKs. It is now reported that macrophages undergoing UV-B-induced apoptosis show enhanced expression of protein kinase Cδ (PKCδ) in a time-dependent manner. Pretreatment of macrophages with PKCδ-specific inhibitor rottlerin prior to the UV-B irradiation inhibits activation of caspase-3, PARP cleavage, DNA fragmentation and release of intracellular Ca 2+. Inhibition of PKCδ also blocks the sustained activation of p38 and JNK MAPKs as well as inactivation of p42/44 MAPKs. PKCα and PKCβ1 expression also increases during UV-B-induced apoptosis in macrophages. Inhibition of these two isoforms with Go6976 slightly suppresses caspase-3 activation, PARP cleavage, DNA fragmentation and release of intracellular Ca 2+, but has no effect on the sustained activation of p38/JNK MAPKs or inactivation of p42/44 MAPKs. It is, therefore, suggested that activation of PKCδ might play an important role in the UV-B-induced apoptosis and that specific activated isoforms of PKC may have distinct functions in cell death. © 2004 Elsevier Inc. All rights reserved.