Papers by Manikandan Palrasu
PubMed, Oct 1, 2008
Introduction: We investigated the combinatorial chemopreventive efficacy of Azadirachta indica (A... more Introduction: We investigated the combinatorial chemopreventive efficacy of Azadirachta indica (AI) and Ocimum sanctum (OS) against N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced gastric carcinogenesis, based on changes in oxidant-antioxidant status, cell proliferation, apoptosis and angiogenesis. Methods: Male Wistar rats were assigned to four groups. Rats in groups 1 and 2 received MNNG (150 mg/kg body weight i.g.) three times with a gap of two weeks in between the treatment. Group 2 rats additionally received ethanolic AI (100 mg/kg body weight i.g.) and OS (150 mg/kg body weight i.g.) leaf extract three times per week for 26 weeks. Group 3 animals were given AI and OS leaf extract alone, whereas group 4 served as the control. Results: Lipid and protein oxidation and status of the antioxidants, superoxide dismutases, catalase, reduced glutathione (GSH) and GSH-dependent enzymes together with markers of proliferation (proliferating cell nuclear antigen [PCNA], glutathione S-transferase-Pi [GST-P]), invasion (cytokeratin [CK]), angiogenesis (vascular endothelial growth factor [VEGF]) and apoptosis (Bcl-2, Bax, cytochrome C and caspase-3) were used to biomonitor chemoprevention. Rats administered MNNG developed forestomach carcinomas that displayed low lipid and protein oxidation coupled to enhanced antioxidant activities, and overexpression of PCNA, GST-P, CK, VEGF and Bcl-2 with downregulation of Bax, cytochrome C and caspase-3. Coadministration of AI and OS extract suppressed MNNG-induced gastric carcinomas accompanied by modulation of the oxidant-antioxidant status, inhibition of cell proliferation and angiogenesis, and induction of apoptosis. Conclusion: The results of the present study suggest that chemoprevention by AI and OS combination may be mediated by their antioxidant, antiangiogenic, antiproliferative and apoptosis inducing properties.
PubMed, Jul 1, 2007
Introduction: This study was designed to evaluate the chemopreventive effects of ethanolic Ocimum... more Introduction: This study was designed to evaluate the chemopreventive effects of ethanolic Ocimum sanctum (OS) leaf extract on cell proliferation, apoptosis and angiogenesis during N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced gastric carcinogenesis. Methods: The rats were divided into four groups of ten each. Rats in group one were given MNNG (150 mg/kg body weight) by intragastric intubation three times, with a two-week interval between treatments. Rats in group two were administered MNNG as in group one, and in addition, they received intragastric intubation of ethanolic OS extract (300 mg/kg body weight) three times per week, starting on the day following the first exposure to MNNG. The intubation of ethanolic OS extract continued until the end of the experimental period. Rats in group three were given ethanolic OS leaf extract only. Group four served as controls. All the rats were killed after an experimental period of 26 weeks. Results: Intragastric administration of MNNG-induced well-differentiated squamous cell carcinomas that showed increased cell proliferation, and angiogenesis with evasion of apoptosis, as revealed by the upregulation of proliferating cell nuclear antigen (PCNA), glutathione S-transferase-pi (GST-pi), Bcl-2, cytokeratin (CK) and vascular endothelial growth factor (VEGF) and with downregulation of Bax, cytochrome C and caspase 3 protein expression. Administration of ethanolic OS leaf extract reduced the incidence of MNNG-induced gastric carcinomas. This was accompanied by decreased expression of PCNA, GST-pi, Bcl-2, CK and VEGF, and overexpression of Bax, cytochrome C, and caspase 3. Conclusion: This study provides evidence that, in MNNG-induced gastric carcinogenesis, the key proteins involved in the proliferation, invasion, angiogenesis and apoptosis, are viable molecular targets for chemoprevention using ethanolic OS leaf extract.
Journal of Agricultural and Food Chemistry, 2009
We evaluated the protective effects of subfractions of the ethyl acetate fraction (EAF) and the m... more We evaluated the protective effects of subfractions of the ethyl acetate fraction (EAF) and the methanolic fraction (MF) from the crude ethanolic extract (CEE) of Azadirachta indica A. Juss (neem) leaves against various free radicals and hydrogen peroxide (H 2 O 2)-induced oxidative damage to red blood cells (RBCs) and pBR322 DNA. Neem leaf fractions reduced DPPH • , ABTS •þ , superoxide (O •-), hydroxyl (OH •), and nitric oxide radicals to nonradical forms in a concentrationdependent manner. Treatment with the benzene insoluble fraction from EAF (EBIF), the chloroform insoluble fraction from EAF (ECIF), the chloroform insoluble fraction from MF (MCIF), and the ethyl acetate insoluble fraction from MF (MEIF) significantly mitigated H 2 O 2-induced oxidative damage to RBCs and pBR322 DNA. Although we found low in vitro free radical scavenging activity for the benzene insoluble fraction from EAF (EBSF), the chloroform soluble fraction from EAF (ECSF), the chloroform soluble fraction from MF (MCSF), and the ethyl acetate soluble fraction from MF (MESF), these fractions showed no effect on H 2 O 2-induced lipid peroxidation and pBR322 DNA damage. High-performance liquid chromatography (HPLC) and TLC-Iatroscan analysis revealed that the greater efficacy of EBIF, ECIF, MCIF, and MEIF may be due to the presence of more polar compounds such as nimbolide and quercetin. Our studies suggest that the antioxidant and protective effects of active neem leaf fractions against H 2 O 2-induced lipid peroxidation and pBR322 DNA damage can be attributed to their ability to inhibit various free radicals.
PLOS Pathogens
Helicobacter pylori (H. pylori) is a common gastric pathogen that infects approximately half of t... more Helicobacter pylori (H. pylori) is a common gastric pathogen that infects approximately half of the world’s population. Infection with H. pylori can lead to diverse pathological conditions, including chronic gastritis, peptic ulcer disease, and cancer. The latter is the most severe consequence of H. pylori infection. According to epidemiological studies, gastric infection with H. pylori is the strongest known risk factor for non-cardia gastric cancer (GC), which remains one of the leading causes of cancer-related deaths worldwide. However, it still remains to be poorly understood how host-microbe interactions result in cancer development in the human stomach. Here we focus on the H. pylori bacterial factors that affect the host ubiquitin proteasome system. We investigated E3 ubiquitin ligases SIVA1 and ULF that regulate p14ARF (p19ARF in mice) tumor suppressor. ARF plays a key role in regulation of the oncogenic stress response and is frequently inhibited during GC progression. Expr...
Cancers, 2021
Gastric cancer (GC) is one of the deadliest malignancies worldwide. In contrast to many other tum... more Gastric cancer (GC) is one of the deadliest malignancies worldwide. In contrast to many other tumor types, gastric carcinogenesis is tightly linked to infectious events. Infections with Helicobacter pylori (H. pylori) bacterium and Epstein–Barr virus (EBV) are the two most investigated risk factors for GC. These pathogens infect more than half of the world’s population. Fortunately, only a small fraction of infected individuals develops GC, suggesting high complexity of tumorigenic processes in the human stomach. Recent studies suggest that the multifaceted interplay between microbial, environmental, and host genetic factors underlies gastric tumorigenesis. Many aspects of these interactions still remain unclear. In this review, we update on recent discoveries, focusing on the roles of various gastric pathogens and gastric microbiome in tumorigenesis.
243Background: Helicobacter pylori (H. pylori) is the strongest known risk factor for gastric can... more 243Background: Helicobacter pylori (H. pylori) is the strongest known risk factor for gastric cancer. Bacterial degradation of tumor suppressor proteins affect the host microbe’s interactions and h...
Gastroenterology, 2019
and pharmacological interrogation. Results: Human fetal gut samples displayed robust TuJ1 immunoh... more and pharmacological interrogation. Results: Human fetal gut samples displayed robust TuJ1 immunohistochemistry by embryonic week (EW) 12 with a dense neural network at the level of the myenteric plexus including expression of excitatory neurotransmitter (VAChT and SubP) and synaptic markers (SYN). By contrast, inhibitory neurotransmitter (nNOS and VIP) markers were not observed until EW14. Electrical train stimulation (40V, 2s, 20Hz of 300čs electrical pulses) of internodal strands did not evoke activity within the myenteric plexus of EW12 fetal gut (n=0/3). Similarly, the majority of EW14 gut tissues (80%), assessed by calcium imaging, demonstrated no response to electrical stimulation (n=4/5). By contrast, at EW16 the emergence of evoked calcium transients (Fh/F0=1.21±0.03; n=3), upon electrical stimulation (n=3/3), was observed which were abolished after the addition of 1čM tetrodotoxin (TTX; n=3/3). To investigate if postsynaptic specialization was a limiting factor in the development of evoked activity, pharmacological activation and blockade of nicotinic acetylcholine receptors was performed at EW14 and EW16 respectively. At EW14 application of 1čM acetylcholine did not elicit compound activation within the presumptive ENS. Furthermore, by EW16 application of 300čM hexamethonium did not diminish electrically evoked calcium transients whereas subsequent application of 1čM TTX abolished compound activation of the fetal ENS. Expression analyses using RNAseq and qRT-PCR further showed that the development of evoked activity, within the developing ENS, is coincident with increases in expression of various genes encoding proteins involved in neurotransmission and action potential modulation. Conclusion: These findings provide the first direct evidence of developing neuronal diversity, electrical excitability and network formation in the human intestine.
Journal of Clinical Investigation, 2020
Approximately half of the world's population is infected with the stomach pathogen Helicobacter p... more Approximately half of the world's population is infected with the stomach pathogen Helicobacter pylori. Infection with H. pylori is the main risk factor for distal gastric cancer. Bacterial virulence factors, such as the oncoprotein CagA, augment cancer risk. Yet despite high infection rates, only a fraction of H. pylori-infected individuals develop gastric cancer. This raises the question of defining the specific host and bacterial factors responsible for gastric tumorigenesis. To investigate the tumorigenic determinants, we analyzed gastric tissues from human subjects and animals infected with H. pylori bacteria harboring different CagA status. For laboratory studies, well-defined H. pylori strain B128 and its cancerogenic derivative strain 7.13, as well as various bacterial isogenic mutants were employed. We found that H. pylori compromises key tumor suppressor mechanisms: the host stress and apoptotic responses. Our studies showed that CagA induces phosphorylation of XIAP E3 ubiquitin ligase, which enhances ubiquitination and proteasomal degradation of the host proapoptotic factor Siva1. This process is mediated by the PI3K/Akt pathway. Inhibition of Siva1 by H. pylori increases survival of human cells with damaged DNA. It occurs in a strain-specific manner and is associated with the ability to induce gastric tumor.
Oncogene, Jan 30, 2018
Infection with Helicobacter pylori is one of the strongest risk factors for development of gastri... more Infection with Helicobacter pylori is one of the strongest risk factors for development of gastric cancer. Although these bacteria infect approximately half of the world's population, only a small fraction of infected individuals develops gastric malignancies. Interactions between host and bacterial virulence factors are complex and interrelated, making it difficult to elucidate specific processes associated with H. pylori-induced tumorigenesis. In this study, we found that H. pylori inhibits p14ARF tumor suppressor by inducing its degradation. This effect was found to be strain-specific. Downregulation of p14ARF induced by H. pylori leads to inhibition of autophagy in a p53-independent manner in infected cells. We identified TRIP12 protein as E3 ubiquitin ligase that is upregulated by H. pylori, inducing ubiquitination and subsequent degradation of p14ARF protein. Using isogenic H. pylori mutants, we found that induction of TRIP12 is mediated by bacterial virulence factor CagA....
Organic & Biomolecular Chemistry, 2014
The structures of the newly synthesized 4-methyl-N′-(3-alkyl-2r,6c-diarylpiperidin-4-ylidene)-1,2... more The structures of the newly synthesized 4-methyl-N′-(3-alkyl-2r,6c-diarylpiperidin-4-ylidene)-1,2,3-thiadiazole-5-carbohydrazide (5a–5l) were confirmed by spectral and elemental analysis.
Journal of Medicinal Chemistry
Nimbolide, a major limonoid constituent of Azadirachta indica, commonly known as neem, has attrac... more Nimbolide, a major limonoid constituent of Azadirachta indica, commonly known as neem, has attracted increasing research attention owing to its wide spectrum of pharmacological properties, predominantly anticancer activity. Nimbolide is reported to exert potent antiproliferative effects on a myriad cancer cell lines and chemotherapeutic efficacy in preclinical animal tumor models. The potentiality of nimbolide to circumvent multidrug resistance and aid in targeted protein degradation broaden its utility in enhancing therapeutic modalities and outcome. Accumulating evidence indicates that nimbolide prevents the acquisition of cancer hallmarks such as sustained proliferation, apoptosis evasion, invasion, angiogenesis, metastasis, and inflammation by modulating kinase-driven oncogenic signaling networks. Nimbolide has been demonstrated to abrogate aberrant activation of cellular signaling by influencing the subcellular localization of transcription factors and phosphorylation of kinases in addition to influencing the epigenome. Nimbolide, with its ever-expanding repertoire of molecular targets, is a valuable addition to the anticancer drug arsenal.
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Papers by Manikandan Palrasu