Surendra Kumar Shukla - Academia.edu (original) (raw)

Papers by Surendra Kumar Shukla

Scientific Reports, Jan 31, 2022

determined using the Human IL-6 High Sensitivity ELISA kit (BMS213HS, Invitrogen, Carlsbad, CA), ... more determined using the Human IL-6 High Sensitivity ELISA kit (BMS213HS, Invitrogen, Carlsbad, CA), and Mouse IL-6 ELISA kit (BMS603-2, Invitrogen). All experiments were performed in duplicates. Cell culture and conditioned medium collection. hTERT-HPNE, a normal cell line of intermediary cells formed during acinar-to-ductal metaplasia, was established and granted permission for usage by Dr. Michel M.

Pharmaceuticals, Aug 16, 2023

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

Frontiers in Molecular Biosciences

Editorial on the Research Topic Identification and characterization of molecular targets in hepat... more Editorial on the Research Topic Identification and characterization of molecular targets in hepatocellular carcinoma Hepatic malignancies remain a global challenge with an increasing disease burden worldwide. According to an estimate by 2025, more than 1 million people will be affected by it annually (Llovet et al., 2016), GLOBOCAN 2018. IARC). Hepatocellular carcinoma is the most common type of liver cancer representing about 90% of all the cases of hepatic malignancy (Llovet et al., 2021), and according to World Health Organization 2020 record, it is the third leading cause of cancer-related deaths worldwide World Health Organization 2020. Most of the HCC-related mortality occurs in Asian and African countries but the incidences of HCC are on the rise in European countries and the United States. According to the report of the SEER (Surveillance Epidemiology End Results), mortalities related to HCC are on the rise in the United States (McGlynn et al., 2015), and it will become the third leading cause of cancer-related deaths by 2030 (Rahib et al., 2014). Along with viral infection (Hepatitis B Virus-HBV and Hepatitis C Virus-HCV) metabolic diseases such as non-alcoholic steatohepatitis (NASH), diabetes, and obesity are considered key risk factors for HCC development (Global Burden of Disease Liver Cancer et al., 2017; Gupta et al., 2018). The molecular mechanism of HCC pathogenesis varies depending on the genotoxic insults and altered physiological conditions of the body. The advancement of different molecular and biochemical technologies to explore the disease pathogenesis at the cellular level as well as in a systemic way provides plenty of opportunities to explore novel biomarkers of disease progression and identify new therapeutic targets. Metabolic alterations are considered a hallmark of cancer (Hanahan, 2022). Tian et al., by utilizing in silico and in vitro studies, have shown that patients with higher expression of key metabolic enzymes such as LDHA and CHAC2 exhibit poor survival. However, higher expression of some metabolic enzymes like ADPGK, GOT2, MTHFS, and FDCD was associated with a better prognosis. They have also established the correlation between metabolic alteration and the TP53 mutation rate. In a similar line of studies, Zhou et al.,

Pyrimidine nucleotide biosynthesis is a druggable metabolic dependency of cancer cells, and chemo... more Pyrimidine nucleotide biosynthesis is a druggable metabolic dependency of cancer cells, and chemotherapy agents targeting pyrimidine metabolism are the backbone of treatment for many cancers. Dihydroorotate dehydrogenase (DHODH) is an essential enzyme in the de novo pyrimidine biosynthesis pathway that can be targeted by clinically approved inhibitors. However, despite robust preclinical anticancer efficacy, DHODH inhibitors have shown limited single-agent efficacy in phase I clinical trials. Therefore, novel combination therapy strategies are necessary to realize the potential of these drugs. To search for therapeutic vulnerabilities induced by DHODH inhibition, we examined gene expression changes in cancer cells treated with the potent and selective DHODH inhibitor brequinar (BQ). This revealed that BQ treatment causes upregulation of antigen presentation pathway genes and cell surface MHC class I expression. Mechanistic studies showed that this effect is 1) strictly dependent on ...

FEBS Journal, Sep 7, 2012

Viral and cellular oncogenes are well known to enhance rRNA synthesis, leading to increased ribos... more Viral and cellular oncogenes are well known to enhance rRNA synthesis, leading to increased ribosome biogenesis and cell proliferation. Our study on the molecular underpinnings of the interaction between viral HBx and c-Myc, which is implicated in the development of hepatocellular carcinoma, showed a marked increase in the biosynthesis of rRNA, ribosomes and protein in hepatoma cells. A profound alteration in the nucleolar morphology and biochemical content of these cells was also observed. Increased biosynthetic activity was associated with increased cell proliferation and transformation of immortalized human hepatocytes. Furthermore, inhibition of RNA polymerase III activity impaired the proliferative advantage of hepatoma cells and transformation of immortalized hepatocytes as effectively as cisplatin treatment. These findings were corroborated in a transgenic HBx-myc microenvironment, in which an elevated hepatic level of rRNA was associated with conspicuous morphological and biochemical changes in the hepatocytic nucleoli. Thus, HBx and c-Myc seem to work cooperatively to support ribosome biogenesis and cellular transformation.

Abstract Polyphenols are the most abundant bioactive compounds present in fruits, vegetables, and... more Abstract Polyphenols are the most abundant bioactive compounds present in fruits, vegetables, and other plant-derived dietary substances. Owing to their strong antioxidant and antiinflammatory properties, polyphenols have been shown to exhibit protective effect in several chronic diseases. Numerous epidemiological and preclinical studies suggest a strong role of oxidative stress and inflammation in various liver diseases. Here we have discussed the potential role of plant-derived polyphenols in the prevention and treatment of liver diseases including hepatocellular carcinoma (HCC). Among various liver diseases, this article focuses primarily on non–alcoholic fatty liver disease, alcohol-induced liver diseases, and HCC. We have described the biological effect of polyphenols and explained their underlying molecular mechanisms associated with protective effects of these bioactive compounds, as reported in different studies. Further, we have summarized the potential application of these bioactive molecules as preventive and therapeutic agents in different ailments of liver.

Cancers, Sep 7, 2019

Pancreatic ductal adenocarcinoma (PDAC) has a five-year survival rate of <10% due in part to a la... more Pancreatic ductal adenocarcinoma (PDAC) has a five-year survival rate of <10% due in part to a lack of effective therapies. Pan-histone deacetylase (HDAC) inhibitors have shown preclinical efficacy against PDAC but have failed in the clinic due to toxicity. Selective HDAC inhibitors may reduce toxicity while retaining therapeutic efficacy. However, their use requires identification of the specific HDACs that mediate the therapeutic effects of HDAC inhibitors in PDAC. We determined that the HDAC1/2/3 inhibitor Mocetinostat synergizes with the HDAC4/5/6 inhibitor LMK-235 in a panel of PDAC cell lines. Furthermore, while neither drug alone synergizes with gemcitabine, the combination of Mocetinostat, LMK-235, and gemcitabine showed strong synergy. Using small interfering (si)RNA-mediated knockdown, this synergy was attributed to inhibition of HDACs 1, 2, and 6. Pharmacological inhibition of HDACs 1 and 2 with Romidepsin and HDAC6 with ACY-1215 also potently synergized with gemcitabine in a panel of PDAC cell lines, and this drug combination potentiated the antitumor effects of gemcitabine against PDAC xenografts in vivo. Collectively, our data show that inhibition of multiple HDACs is required for therapeutic effects of HDAC inhibitors and support the development of novel strategies to inhibit HDACs 1, 2, and 6 for PDAC therapy.

Current Developments in Nutrition, 2020

Background The mechanistic target of rapamycin complex 1 (mTORC1) is a nutrient-sensing pathway a... more Background The mechanistic target of rapamycin complex 1 (mTORC1) is a nutrient-sensing pathway and a key regulator of amino acid and glucose metabolism. Dysregulation of the mTOR pathways is implicated in the pathogenesis of metabolic syndrome, obesity, type 2 diabetes, and pancreatic cancer. Objectives We investigated the impact of inhibition of mTORC1/mTORC2 and synergism with metformin on pancreatic tumor growth and metabolomics. Methods Cell lines derived from pancreatic tumors of the KPC (KrasG12D/+; p53R172H/+; Pdx1-Cre) transgenic mice model were implanted into the pancreas of C57BL/6 albino mice (n = 10/group). Two weeks later, the mice were injected intraperitoneally with daily doses of 1) Torin 2 (mTORC1/mTORC2 inhibitor) at a high concentration (TH), 2) Torin 2 at a low concentration (TL), 3) metformin at a low concentration (ML), 4) a combination of Torin 2 and metformin at low concentrations (TLML), or 5) DMSO vehicle (control) for 12 d. Tissues and blood samples were ...

Journal of Experimental Medicine, 2020

Approximately one third of cancer patients die due to complexities related to cachexia. However, ... more Approximately one third of cancer patients die due to complexities related to cachexia. However, the mechanisms of cachexia and the potential therapeutic interventions remain poorly studied. We observed a significant positive correlation between SIRT1 expression and muscle fiber cross-sectional area in pancreatic cancer patients. Rescuing Sirt1 expression by exogenous expression or pharmacological agents reverted cancer cell–induced myotube wasting in culture conditions and mouse models. RNA-seq and follow-up analyses showed cancer cell–mediated SIRT1 loss induced NF-κB signaling in cachectic muscles that enhanced the expression of FOXO transcription factors and NADPH oxidase 4 (Nox4), a key regulator of reactive oxygen species production. Additionally, we observed a negative correlation between NOX4 expression and skeletal muscle fiber cross-sectional area in pancreatic cancer patients. Knocking out Nox4 in skeletal muscles or pharmacological blockade of Nox4 activity abrogated tum...

Cancer Letters, 2020

Cancer cachexia patients experience significant muscle wasting, which impairs the quality of life... more Cancer cachexia patients experience significant muscle wasting, which impairs the quality of life and treatment efficacy for patients. Skeletal muscle protein turnover is imparted by increased expression of ubiquitin-proteasome pathway components. Mitogen-activated protein kinases p38 and ERK have been shown to augment E3 ubiquitin ligase expression. Utilizing reverse phase protein arrays, we identified pancreatic cancer cell-conditioned media-induced activation of JNK signaling in myotubes differentiated from C2C12 myoblasts. Inhibition of JNK signaling with SP600125 reduced cancer cell-conditioned media-induced myotube atrophy, myosin heavy chain 2 protein turnover, and mRNA expression of cachexia-specific ubiquitin ligases Trim63 and Fbxo32.

Journal of Proteome Research, 2017

Pancreatic cancer cells overexpressing Mucin 1 (MUC1) rely on aerobic glycolysis and, correspondi... more Pancreatic cancer cells overexpressing Mucin 1 (MUC1) rely on aerobic glycolysis and, correspondingly, are dependent on glucose for survival. Our NMR metabolomics comparative analysis of control (S2−013.Neo) and MUC1-overexpressing (S2−013.MUC1) cells demonstrates that MUC1 reprograms glutamine metabolism upon glucose limitation. The observed alteration in glutamine metabolism under glucose limitation was accompanied by a relative decrease in the proliferation of MUC1-overexpressing cells compared with steady-state conditions. Moreover, glucose limitation induces G1 phase arrest where S2−013.MUC1 cells fail to enter S phase and synthesize DNA because of a significant disruption in pyrimidine nucleotide biosynthesis. Our metabolomics analysis indicates that glutamine is the major source of oxaloacetate in S2−013.Neo and S2−013.MUC1 cells, where oxaloacetate is converted to aspartate, an important metabolite for pyrimidine nucleotide biosynthesis. However, glucose limitation impedes the flow of glutamine carbons into the pyrimidine nucleotide rings and instead leads to a significant accumulation of glutamine-derived aspartate in S2−013.MUC1 cells.

Gastroenterology, 2021

BACKGROUND & AIMS: SIRT5 plays pleiotropic roles via posttranslational modifications, serving as ... more BACKGROUND & AIMS: SIRT5 plays pleiotropic roles via posttranslational modifications, serving as a tumor suppressor, or an oncogene, in different tumors. However, the role SIRT5 plays in the initiation and progression of pancreatic ductal adenocarcinoma (PDAC) remains unknown. METHODS: Published datasets and tissue arrays with SIRT5 staining were used to investigate the clinical relevance of SIRT5 in PDAC. Furthermore, to define the role of SIRT5 in the carcinogenesis of PDAC, we generated autochthonous mouse models with conditional Sirt5 knockout. Moreover, to examine the mechanistic role of SIRT5 in PDAC carcinogenesis, SIRT5 was knocked down in PDAC cell lines and organoids, followed by metabolomics and proteomics studies. A novel SIRT5 activator was used for therapeutic studies in organoids and patient-derived xenografts. RESULTS: SIRT5 expression negatively regulated tumor cell proliferation and correlated with a favorable prognosis in patients with PDAC. Genetic ablation of Sirt5 in PDAC mouse models promoted acinar-to-ductal metaplasia, precursor lesions, and pancreatic tumorigenesis, resulting in poor survival. Mechanistically, SIRT5 loss enhanced glutamine and glutathione metabolism via acetylation-mediated activation of GOT1. A selective SIRT5 activator, MC3138, phenocopied the effects of

Immuno

Interceding nutrients have been acquiring increased attention and prominence in the field of heal... more Interceding nutrients have been acquiring increased attention and prominence in the field of healing and deterrence of various disorders. In this light, the present article encompasses several facets of ketogenic diet as an immunomodulator with respect to its expansive clinical applications. Accordingly, several scientific records, models, and case histories, including viral infections, cancer, chronic diseases, e.g., cardiovascular diseases, epilepsy, as well as numerous other neuro-disorders, are assembled, revealing a profound influence of KD in favor of improvement in the patient’s condition. We accentuate possible manifold mechanisms of KD that require further exploration.

Introduction Fractures of the talus are usually highenergy injuries and relatively uncommon accou... more Introduction Fractures of the talus are usually highenergy injuries and relatively uncommon accounting for 0.1% to 0.85% of all fractures [1]. More than 50% of all fractures involve the talar neck [2], and up to 25% of fractures involve the body of the talus [3]. Fractures involving the body of the talus are associated with complications such as ankle and subtalar osteoarthrosis and osteonecrosis. The combination of talar body fracture in the sagittal and coronal plane is an unusual pattern of injury and rarely reported in the literature [4-10]. Severity of injury, preservation of remaining precarious blood supply during surgery, quality of reduction and fixation and time of surgery since trauma predicts surgical outcome of such fracture. Medial malleolus fracture with intact deltoid ligament may preserve some amount of blood supply to talar body, also it provides natural window to exposure the Talus. Case Report An 18-year-old boy met with an accident by falling from ladder from he...

At present almost all the pectinolytic enzymes used for industrial applications are produced by f... more At present almost all the pectinolytic enzymes used for industrial applications are produced by fungi. There are a few reports of pectinase production by bacterial strains. Therefore, in the present study, seventy-four bacterial strains, isolated from soil and rotten vegetable samples, were screened for polygalacturonase production. The strain PG-31, which gave maximum activity, was identified as Bacillus sphaericus (MTCC 7542). Maximal quantities of polygalacturonase were produced when a 16-hours-old inoculum was used at 7.5% (v/v) in production medium and incubated in shaking conditions (160 rpm) for 72 hours. The optimal temperature and pH for bacterial growth and polygalacturonase production were found to be 30 • C and 6.8, respectively. Maximum enzyme production resulted when citrus pectin was used as the carbon source at a concentration of 1.25% (w/v), whereas other carbon sources led to a decrease (30%-70%) in enzyme production. Casein hydrolysate and yeast extract used toget...

Animal Models in Cancer Drug Discovery, 2019

Cachexia is a complex metabolic disorder associated with several chronic diseases, including canc... more Cachexia is a complex metabolic disorder associated with several chronic diseases, including cancer. Cachexia-associated complications, including muscle wasting, fat depletion, immobility, severe impairment of respiratory muscles, and cardiopulmonary failure, contribute to significant mortality in cancer patients. Currently, there is no FDA (Food and Drug Administration)-approved treatment for cachexia. The key factor for the lack of anticachectic therapy is the complexity of this disease and its variable nature. The clinical end points of cachexia are poorly defined, and a scarcity of information exists regarding the exact underlying molecular mechanisms of cancer-associated cachexia. The use of improved, physiologically relevant models of cancer-induced cachexia will improve our understanding of underlying molecular mechanism of cancer-induced cachexia and provide a platform to evaluate novel therapeutic agents. The focus of the current chapter is to provide updated information ab...

Oncotarget, Jan 16, 2015

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in t... more Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in the US. Cancer-associated cachexia is present in up to 80% of PDAC patients and is associated with aggressive disease and poor prognosis. In the present studies we evaluated an anti-cancer natural product silibinin for its effectiveness in targeting pancreatic cancer aggressiveness and the cachectic properties of pancreatic cancer cells and tumors. Our results demonstrate that silibinin inhibits pancreatic cancer cell growth in a dose-dependent manner and reduces glycolytic activity of cancer cells. Our LC-MS/MS based metabolomics data demonstrates that silibinin treatment induces global metabolic reprogramming in pancreatic cancer cells. Silibinin treatment diminishes c-MYC expression, a key regulator of cancer metabolism. Furthermore, we observed reduced STAT3 signaling in silibinin-treated cancer cells. Overexpression of constitutively active STAT3 was sufficient to substantially rever...

Oncotarget, Jan 3, 2015

MUC16, a transmembrane mucin, facilitates pancreatic adenocarcinoma progression and metastasis. I... more MUC16, a transmembrane mucin, facilitates pancreatic adenocarcinoma progression and metastasis. In the current studies, we observed that MUC16 knockdown pancreatic cancer cells exhibit reduced glucose uptake and lactate secretion along with reduced migration and invasion potential, which can be restored by supplementing the culture media with lactate, an end product of aerobic glycolysis. MUC16 knockdown leads to inhibition of mTOR activity and reduced expression of its downstream target c-MYC, a key player in cellular growth, proliferation and metabolism. Ectopic expression of c-MYC in MUC16 knockdown pancreatic cancer cells restores the altered cellular physiology. Our LC-MS/MS based metabolomics studies indicate global metabolic alterations in MUC16 knockdown pancreatic cancer cells, as compared to the controls. Specifically, glycolytic and nucleotide metabolite pools were significantly decreased. We observed similar metabolic alterations that correlated with MUC16 expression in ...