Publications by authors named "Dhruv Kumar"

50 Publications

Computational study of novel inhibitory molecule, 1-(4-((2,3)-3-amino-2-hydroxy-4-phenylbutyl)piperazin-1-yl)-3-phenylurea, with high potential to competitively block ATP binding to the RNA dependent RNA polymerase of SARS-CoV-2 virus.

J Biomol Struct Dyn 2021 Jun 21:1-19. Epub 2021 Jun 21.

Laboratory for Translational Chemistry and Drug Discovery, Department of Chemistry, Hansraj College, University of Delhi, Delhi, India.

For coronaviruses, RNA-dependent RNA polymerase (RdRp) is an essential enzyme that catalyses the replication from RNA template and therefore remains an attractive therapeutic target for anti-COVID drug discovery. In the present study, we performed a comprehensive screening for 16,776 potential molecules from recently established drug libraries based on two important pharmacophores (3-amino-4-phenylbutan-2-ol and piperazine). Based on initial assessment, 4042 molecules were obtained suitable as drug candidates, which were following Lipinski's rule. Molecular docking implemented for the analysis of molecular interactions narrowed this number of compounds down to 19. Subsequent to screening filtering criteria and considering the critical parameters docking score and MM-GBSA binding free energy, 1-(4-((2,3)-3-amino-2-hydroxy-4-phenylbutyl)piperazin-1-yl)-3-phenylurea (compound ) was accomplished to score highest in comparison to the remaining 18 shortlisted drug candidates. Notably, compound displayed higher docking score (-8.069 kcal/mol) and MM-GBSA binding free energy (-49.56 kcal/mol) than the control drug, remdesivir triphosphate, the active form of remdesivir as well as adenosine triphosphate. Furthermore, a molecular dynamics simulation was carried out (100 ns), which substantiated the candidacy of compound as better inhibitor. Overall, our systematic study predicts the potential of compound to exhibit a more favourable specific activity than remdesivir triphosphate. Hence, we suggest compound 1 as a novel potential drug candidate, which should be considered for further exploration and validation of its potential against SARS-CoV-2 in wet lab experimental studies.Communicated by Ramasawamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2021.1940281DOI Listing
June 2021

Novel Antiplasmodial Compounds Leveraged with Multistage Potency against the Parasite : and Evaluations and Pharmacokinetic Studies.

J Med Chem 2021 Jun 14;64(12):8666-8683. Epub 2021 Jun 14.

Laboratory for Translational Chemistry and Drug Discovery, Department of Chemistry, Hansraj College University Enclave, University of Delhi, Delhi 110007, India.

Hydroxyethylamine (HEA)-based novel compounds were synthesized and their activity against 3D7 was assessed, identifying a few hits without any apparent toxicity. Hits and also exhibited activity against resistant field strains, RKL-9 and C580Y. A single dose, 50 mg/Kg, of hits administered to the rodent parasite ANKA exhibited up to 70% reduction in the parasite load. Compound tested in combination with artesunate produced an additional antiparasitic effect with a prolonged survival period. Additionally, compound showed 50% inhibition against hepatic infection at 1.56 ± 0.56 μM concentration. This compound also considerably delayed the progression of transmission stages, ookinete and oocyst. Furthermore, the toxicity of assessed in mice supported the normal liver and kidney functions. Altogether, HEA analogues (), particularly , are nontoxic multistage antiplasmodial agents with therapeutic and transmission-blocking efficacy, along with favorable preliminary pharmacokinetic properties.
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http://dx.doi.org/10.1021/acs.jmedchem.1c00659DOI Listing
June 2021

Role of monocarboxylate transporters in head and neck squamous cell carcinoma.

Life Sci 2021 Aug 5;279:119709. Epub 2021 Jun 5.

Amity Institute of Molecular Medicine & Stem Cell Research (AIMMSCR), Amity University Uttar Pradesh, Sec-125, Noida 201313, UP, India. Electronic address:

Head and Neck tumors are metabolically highly altered solid tumors. Head and Neck cancer cells may utilise different metabolic pathways for energy production. Whereas, glycolysis is the major source coupled with oxidative phosphorylation in a metabolic symbiosis manner that results in the proliferation and metastasis in Head and Neck Cancer. The monocarboxylate transporters (MCTs) constitute a family of 14 members among which MCT1-4 are responsible for transporting monocarboxylates such as l-lactate and pyruvate, and ketone bodies across the plasma membrane. Additionally, MCTs mediate absorption and distribution of monocarboxylates across the cell membrane. Head and Neck cancer cells are highly glycolytic in nature and generate significant amount of lactic acid in the extracellular environment. In such condition, MCTs play a critical role in the regulation of pH, and lactate shuttle maintenance. The intracellular lactate accumulation is harmful for the cells since it drastically lowers the intracellular pH. MCTs facilitate the export of lactate out of the cell. The lactate export mediated by MCTs is crucial for the cancer cells survival. Therefore, targeting MCTs is important and could be a potential therapeutic approach to control growth of the tumor.
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http://dx.doi.org/10.1016/j.lfs.2021.119709DOI Listing
August 2021

Identification and validation of potent Mycobacterial proteasome inhibitor from Enamine library.

J Biomol Struct Dyn 2021 May 6:1-11. Epub 2021 May 6.

Centre for Drug Design Discovery and Development (C4D), SRM University, Delhi NCR, Sonepat, India.

As a consequence of present status of tuberculosis (TB) it is the obligation to develop novel targets and potential drugs so that rate of drug resistant TB can be declined. Mycobacterium proteasome is considered to be significant target for the purpose of drug designing as it is responsible for resisting the effect of NO (nitric oxide) immune system defence mechanism against the bacterial cells. Small compounds library from Enamine database has already been tested using virtual screening and molecular docking studies. Further a reanalysis with two picked out significant compounds Z1020863610, Z106766984 was carried out using molecular dynamic simulation studies and in vitro validations ( susceptibility assay, enzyme inhibition assay and MTT assay). outcome that two inhibiters were interacting at the active site pocket of receptor with high stability, was found to be very consistent with results. So it was conferred that compounds (Z1020863610, Z106766984) are potential lead for future process of drug development ( testing and clinical trials).Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2021.1914173DOI Listing
May 2021

identification and validation of triarylchromones as potential inhibitor against main protease of severe acute respiratory syndrome coronavirus 2.

J Biomol Struct Dyn 2021 May 3:1-16. Epub 2021 May 3.

Amity Institute of Molecular Medicine and Stem Cell Research, Amity University Uttar Pradesh, Noida 201313, India.

The ongoing pandemic due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused COVID-19 has emerged as a severe threat to the life of human kind. The identification and designing of appropriate and reliable drug molecule for the treatment of COVID-19 patients is the pressing need of the present time. Among different drug targets, the main protease of SARS-CoV-2 is being considered as most effective target. In addition to the drug repurposing, different compounds of natural as well as synthetic origins are being investigated for their efficacy against different drug targets of SARS-CoV-2 virus. In that context, the chromone based natural flavonols have also exhibited significant antiviral properties against different targets of SARS-CoV-2. The studies presented here discloses the efficacy of triarylchromones (TAC) as potential inhibitor against main protease of SARS-CoV-2. The molecular docking and ADMET study performed using 14 arylchromones which could easily be accessed through simple synthetic protocols, revealed best binding affinities in case of TAC-3 (-11.2 kcal/mol), TAC-4 (-10.5 kcal/mol), TAC-6 (-11.2 kcal/mol), TAC-7 (-10.0 kcal/mol). Additional validation studies including molecular dynamics simulation and binding energy calculation using MMGBSA for protein ligand complex for 100 ns revealed the best binding interaction of TAC-3, TAC-4, TAC-6, TAC-7 against main protease of SARS-CoV-2. Moreover, the and preclinical validation of identified compounds will help us to understand the molecular mechanisms of regulation of TACs against SARS-CoV-2.Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2021.1918255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108196PMC
May 2021

Mutational heterogeneity in spike glycoproteins of severe acute respiratory syndrome coronavirus 2.

3 Biotech 2021 May 25;11(5):236. Epub 2021 Apr 25.

Amity Institute of Molecular Medicine & Stem Cell Research (AIMMSCR), Amity University Uttar Pradesh, Sec-125, Noida, 201313 India.

The novel coronavirus SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) has led to a global crisis by infecting millions of people across the globe eventually causing multiple deaths. The prominent player of the virus has been known as the spike protein which enters the host system and leads to the infection. The S2 subunit is the most essential in this process of infection as it helps the SARS-CoV-2 to infect the host by binding to the human angiotensin converting enzyme 2 (hACE2), with the help of the receptor binding domain found at the S2 subunit of the virus. Studies also hypothesize that the S glycoproteins present in the virus interacts with different hosts in different ways which might be due to the mutations taking place in the genome of the virus over time. This work aims to decipher the similarities and differences in the sequences of spike proteins from samples of SARS-CoV-2 acquired from different infected individuals in different countries with the help of in silico methods such as multiple sequence alignment and phylogenetic analysis. It also aims to understand the differential infection rates among the infected countries by studying the amino acid composition and interactions of the virus with the host.
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http://dx.doi.org/10.1007/s13205-021-02791-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070983PMC
May 2021

Oxidative Stress in Cancer Cell Metabolism.

Antioxidants (Basel) 2021 Apr 22;10(5). Epub 2021 Apr 22.

Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Amity University Uttar Pradesh, Sec 125, Noida 201303, India.

Reactive oxygen species (ROS) are important in regulating normal cellular processes whereas deregulated ROS leads to the development of a diseased state in humans including cancers. Several studies have been found to be marked with increased ROS production which activates pro-tumorigenic signaling, enhances cell survival and proliferation and drives DNA damage and genetic instability. However, higher ROS levels have been found to promote anti-tumorigenic signaling by initiating oxidative stress-induced tumor cell death. Tumor cells develop a mechanism where they adjust to the high ROS by expressing elevated levels of antioxidant proteins to detoxify them while maintaining pro-tumorigenic signaling and resistance to apoptosis. Therefore, ROS manipulation can be a potential target for cancer therapies as cancer cells present an altered redox balance in comparison to their normal counterparts. In this review, we aim to provide an overview of the generation and sources of ROS within tumor cells, ROS-associated signaling pathways, their regulation by antioxidant defense systems, as well as the effect of elevated ROS production in tumor progression. It will provide an insight into how pro- and anti-tumorigenic ROS signaling pathways could be manipulated during the treatment of cancer.
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http://dx.doi.org/10.3390/antiox10050642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143540PMC
April 2021

Assessment of arsenic exposure in the population of Sabalpur village of Saran District of Bihar with mitigation approach.

Environ Sci Pollut Res Int 2021 Apr 11. Epub 2021 Apr 11.

Mahavir Cancer Sansthan and Research Centre, Phulwarisharif, Patna, Bihar, 801505, India.

Arsenic poisoning through groundwater is the world's greatest normal groundwater catastrophe which got an immense effect on worldwide general wellbeing. India is confronting the outcomes of arsenic poisoning in the zone of Ganga Brahmaputra alluvial plains. In Bihar, out of 38 districts, 18 districts are exceptionally influenced with groundwater arsenic defilement. In the present study, we have assessed the current situation of arsenic exposure in Sabalpur village of Saran district of Bihar after reporting of breast, renal, skin and thyroid cancer cases from this village along with typical symptoms of arsenicosis. Such cancer patients were identified at our institute and were taken for the study. The present investigation deals with the quantification of arsenic in groundwater, hair and nail samples of subjects as well as the survey of entire village to know the overall health status of the village people. A total of n=128 household handpump water samples as well as n=128 human hair and nail samples were collected from over n=520 households. Using the graphite furnace atomic absorption spectrophotometer (GF-AAS), all the samples were analysed. The investigation resulted that the 61% of the analysed samples particularly the groundwater had the arsenic levels more than the permissible limit of WHO (> 10 μg/L) with 244.20 μg/L as the highest arsenic contamination in one of the handpump water sample. The exposure effect of hair sample was worst as 88% of all the collected samples were having high arsenic levels more than the permissible limit (> 0.2 mg/Kg). In case of nail samples, 92% of the samples were having high arsenic concentration more than the permissible limit (> 0.5 mg/Kg). The health survey study revealed high magnitude of disease burden in the exposed population with symptoms such as asthma, anaemia, hepatomegaly, diabetes, cardiac problem, skin fungal infections, breathlessness and mental disability. Few cancer cases of renal, skin, breast and cervix were also found among the exposed population of this village. The percentage of cancer cases in this village was 0.94% that was low, but it would be an aggravated situation in the near future if people will continue drinking arsenic-contaminated water. Therefore, a mitigation intervention was carried out in March 2020 by installing an arsenic filter plant. The health situation in the village in the present scenario is hope to improve in the coming years. However, motivation and awareness among the village population are still required.
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http://dx.doi.org/10.1007/s11356-021-13521-5DOI Listing
April 2021

Regulation of Glycolysis in Head and Neck Cancer.

Adv Exp Med Biol 2021 ;1280:219-230

Amity Institute of Molecular Medicine & Stem Cell Research, Amity University, Noida, Uttar Pradesh, India.

Head and neck squamous cell carcinoma (HNSCC) glycolysis is an important factor for the advancement of the disease and metastasis. Upregulation of glycolysis leads to decreased sensitivity to chemotherapy and radiation. HNSCC cells maintain constitutive glycolytic flux generating metabolic intermediates for the synthesis of amino acids, nucleotides, and fats for cell survival and disease progression. There are several pathways such as PI3K/Akt, EGFR, and JAK-STAT that contribute a major role in metabolic alteration in HNSCC. Recent studies have demonstrated that cancer-associated fibroblasts abundant in the HNSCC tumor microenvironment play a major role in HNSCC metabolic alteration via hepatocyte growth factor (HGF)/c-Met cross signaling. Despite therapeutic advancement, HNSCC lacks broad range of therapeutic interventions for the treatment of the disease. Thus, understanding the different key players involved in glucose metabolism and targeting them would lead to the development of novel drugs for the treatment of HNSCC.
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http://dx.doi.org/10.1007/978-3-030-51652-9_15DOI Listing
April 2021

In silico identification of potential inhibitor for TP53-induced glycolysis and apoptosis regulator in head and neck squamous cell carcinoma.

3 Biotech 2021 Mar 7;11(3):117. Epub 2021 Feb 7.

Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Amity University Uttar Pradesh, Sec-125, Noida, 201313 India.

Head and neck squamous cell carcinoma (HNSCC) is the six most common cancer globally and most common cancer in men in India. The metabolic regulation is highly altered and is considered as a hall mark of HNSCC. TP53-induced glycolysis and apoptosis regulator (TIGAR) plays very important role in the development and progression of HNSCC. The aim of our study is to identify a novel FDA approved anticancer inhibitor against mutated TP53-induced glycolysis and apoptosis regulator (TIGAR) through drug repurposing approach. A library of 105 FDA approved anticancer compounds were screened using molecular docking approach against TIGAR (PDB: 3DCY) both Wild-Type (WT) and mutated (Mut). Specific mutations in TIGAR were identified using cBioPortal, a cancer genomics database and mutated structure was modelled using SWISS-MODEL. Out of 510 sequenced cases/patients samples, 17(3%) patients showed alteration in TIGAR [TIGAR and TIGAR]. The virtual drug screening showed 45 drugs out of 105 high binding affinity with TIGAR, Trabectedin showed highest binding affinity with both TIGAR (- 13.3 kcal/mol) as well as TIGAR (- 13.8 kcal/mol). The molecular docking studies were validated using molecular dynamics simulation (MD Simulation) of protein-ligand complex of TIGAR and Trabectedin for 100 ns. The MD Simulation of Trabectedin complex showed more stable with TIGAR compared to TIGAR. Moreover, the string analysis revealed that metabolic-related genes, HK2, PFKFB1, PFKM, PFKP, PFKL, FBP1 are closely associated with TIGAR in HNSCC. Our findings suggest that Trabectedin can be proposed as an inhibitor for [TIGAR] which can be used to target metabolic signalings in HNSCC. However, further investigation and in vitro and in vivo validation our findings required to understand the molecular mechanisms of regulation of Trabectedin in HNSCC.
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http://dx.doi.org/10.1007/s13205-021-02665-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868312PMC
March 2021

Arsenic exposure in Indo Gangetic plains of Bihar causing increased cancer risk.

Sci Rep 2021 Jan 27;11(1):2376. Epub 2021 Jan 27.

Mahavir Cancer Sansthan and Research Centre, Patna, Bihar, 801505, India.

Reportedly, 300 million people worldwide are affected by the consumption of arsenic contaminated groundwater. India prominently figures amongst them and the state of Bihar has shown an upsurge in cases affected by arsenic poisoning. Escalated arsenic content in blood, leaves 1 in every 100 human being highly vulnerable to being affected by the disease. Uncontrolled intake may lead to skin, kidney, liver, bladder, or lung related cancer but even indirect forms of cancer are showing up on a regular basis with abnormal arsenic levels as the probable cause. But despite the apparent relation, the etiology has not been understood clearly. Blood samples of 2000 confirmed cancer patients were collected from pathology department of our institute. For cross-sectional design, 200 blood samples of subjects free from cancer from arsenic free pockets of Patna urban agglomeration, were collected. Blood arsenic levels in carcinoma patients as compared to sarcomas, lymphomas and leukemia were found to be higher. The geospatial map correlates the blood arsenic with cancer types and the demographic area of Gangetic plains. Most of the cancer patients with high blood arsenic concentration were from the districts near the river Ganges. The raised blood arsenic concentration in the 2000 cancer patients strongly correlates the relationship of arsenic with cancer especially the carcinoma type which is more vulnerable. The average arsenic concentration in blood of the cancer patients in the Gangetic plains denotes the significant role of arsenic which is present in endemic proportions. Thus, the study significantly correlates and advocates a strong relation of the deleterious element with the disease. It also underlines the need to address the problem by deciphering the root cause of the elevated cancer incidences in the Gangetic basin of Bihar and its association with arsenic poisoning.
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http://dx.doi.org/10.1038/s41598-021-81579-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841152PMC
January 2021

Viral pathogenesis of SARS-CoV-2 infection and male reproductive health.

Open Biol 2021 01 20;11(1):200347. Epub 2021 Jan 20.

Department of Animal Morphology, Physiology and Genetics, Faculty of AgriSciences, Mendel University in Brno, Brno, Czech Republic.

Coronavirus disease 2019 (COVID-19) has emerged as a new public health crisis, threatening almost all aspects of human life. Originating in bats, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is transmitted to humans through unknown intermediate hosts, where it is primarily known to cause pneumonia-like complications in the respiratory system. Organ-to-organ transmission has not been ruled out, thereby raising the possibility of the impact of SARS-CoV-2 infection on multiple organ systems. The male reproductive system has been hypothesized to be a potential target of SARS-CoV-2 infection, which is supported by some preliminary evidence. This may pose a global threat to male fertility potential, as men are more prone to SARS-CoV-2 infection than women, especially those of reproductive age. Preliminary reports have also indicated the possibility of sexual transmission of SARS-CoV-2. It may cause severe complications in infected couples. This review focuses on the pathophysiology of potential SARS-CoV-2 infection in the reproductive organs of males along with their invasion mechanisms. The risks of COVID-19 on male fertility as well as the differences in vulnerability to SARS-CoV-2 infection compared with females have also been highlighted.
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http://dx.doi.org/10.1098/rsob.200347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881178PMC
January 2021

Evidence of Coronavirus (CoV) Pathogenesis and Emerging Pathogen SARS-CoV-2 in the Nervous System: A Review on Neurological Impairments and Manifestations.

J Mol Neurosci 2021 Jan 19. Epub 2021 Jan 19.

Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute (HMRI), University of Newcastle, New Lambton Heights, Newcastle, NSW, 2305, Australia.

The coronavirus disease 2019 (COVID-19) pandemic is an issue of global significance that has taken the lives of many across the world. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus responsible for its pathogenesis. The pulmonary manifestations of COVID-19 have been well described in the literature. Initially, it was thought to be limited to the respiratory system; however, we now recognize that COVID-19 also affects several other organs, including the nervous system. Two similar human coronaviruses (CoV) that cause severe acute respiratory syndrome (SARS-CoV-1) and Middle East respiratory syndrome (MERS-CoV) are also known to cause disease in the nervous system. The neurological manifestations of SARS-CoV-2 infection are growing rapidly, as evidenced by several reports. There are several mechanisms responsible for such manifestations in the nervous system. For instance, post-infectious immune-mediated processes, direct virus infection of the central nervous system (CNS), and virus-induced hyperinflammatory and hypercoagulable states are commonly involved. Guillain-Barré syndrome (GBS) and its variants, dysfunction of taste and smell, and muscle injury are numerous examples of COVID-19 PNS (peripheral nervous system) disease. Likewise, hemorrhagic and ischemic stroke, encephalitis, meningitis, encephalopathy acute disseminated encephalomyelitis, endothelialitis, and venous sinus thrombosis are some instances of COVID-19 CNS disease. Due to multifactorial and complicated pathogenic mechanisms, COVID-19 poses a large-scale threat to the whole nervous system. A complete understanding of SARS-CoV-2 neurological impairments is still lacking, but our knowledge base is rapidly expanding. Therefore, we anticipate that this comprehensive review will provide valuable insights and facilitate the work of neuroscientists in unfolding different neurological dimensions of COVID-19 and other CoV associated abnormalities.
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http://dx.doi.org/10.1007/s12031-020-01767-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814864PMC
January 2021

Stem Cell Based Preclinical Drug Development and Toxicity Prediction.

Curr Pharm Des 2020 Oct 18. Epub 2020 Oct 18.

Amity Institute of Molecular Medicine & Stem Cell Research, Amity University, Noida, Uttar Pradesh. India.

Stem cell based toxicity prediction plays very important role in the development of drug. Unexpected adverse effects of the drugs during clinical trials are a major reason for termination or withdrawal of drugs. Methods for predicting toxicity employ in vitro as well as in vivo models, however, the major drawback seen in the data derived from these animal models is lack of extrapolation, owing to interspecies variations. Due to these limitations, researchers have been striving to develop more robust drug screening platforms based on stem cells. The application of stem cells based toxicity testing has opened up robust methods to study the impact of new chemical entities on not only specific cell types, but also organs. Pluripotent stem cells, as well as cells derived from them, can be evaluated for modulation of cell function in response to drugs. Moreover, the combination of state-of-the -art techniques such as tissue engineering and microfluidics to fabricate organ-on-a-chip, has led to assays which are amenable to high throughput screening to understand the adverse and toxic effects of chemicals and drugs. This review summarizes the important aspects of the establishment of the embryonic stem cell test (EST), use of stem cells, pluripotent, induced pluripotent stem cells and organoids for toxicity prediction and drug development.
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http://dx.doi.org/10.2174/1381612826666201019104712DOI Listing
October 2020

Development of potential proteasome inhibitors against .

J Biomol Struct Dyn 2020 Oct 19:1-15. Epub 2020 Oct 19.

Centre for Drug Design Discovery and Development (C4D), SRM University, Delhi, Haryana, India.

Tuberculosis (TB) has been recently declared as a health emergency because of sporadic increase in Multidrug-resistant Tuberculosis (MDR-TB) problem throughout the world. TB causing bacteria, has become resistant to the first line of treatment along with second line of treatment and drugs, which are accessible to us. Thus, there is an urgent need of identification of key targets and development of potential therapeutic approach(s), which can overcome the complications. In the present study, proteasome has been taken as a potential target as it is one of the key regulatory proteins in propagation. Further, a library of 400 compounds (small molecule) from Medicines for Malaria Venture (MMV) were screened against the target (proteasome) using molecular docking and simulation approach, and selected lead compounds were validated in model. In this study, we have identified two potent small molecules from the MMV Pathogen Box library, MMV019838 and MMV687146 with -9.8kcal/mol and -8.7kcal/mol binding energy respectively, which actively interact with the catalytic domain/active domain of proteasome and inhibit the growth in culture. Furthermore, the molecular docking and simulation study of MMV019838 and MMV687146 with proteasome show strong and stable interaction with compared to human proteasome and show no cytotoxicity effect. A better understanding of proteasome inhibition in in and model would eventually allow us to understand the molecular mechanism(s) and discover a novel and potent therapeutic agent against Tuberculosis. Active efflux of drugs mediated by efflux pumps that confer drug resistance is one of the mechanisms developed by bacteria to counter the adverse effects of antibiotics and chemicals. Efflux pump activity was tested for a specific compound MMV019838 which was showing good in silico results than MIC values.Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2020.1835722DOI Listing
October 2020

Human kidney stone matrix proteins alleviate hyperoxaluria induced renal stress by targeting cell-crystal interactions.

Life Sci 2020 Dec 28;262:118498. Epub 2020 Sep 28.

Amity Institute of Biotechnology (AIB), Amity University, Noida, Uttar Pradesh 201301, India. Electronic address:

Increased levels of urinary oxalate also known as hyperoxaluria, increase the likelihood of kidney stone formation through enhanced calcium oxalate (CaOx) crystallization. The management of lithiatic renal pathology requires investigations at the initial macromolecular stages. Hence, the current study was designed to unravel the protein make-up of human kidney stones and its impact on renal cells' altered proteome, induced as the consequence of CaOx injury. CaOx kidney stones were collected from patients; stones were pooled for entire cohort, followed by protein extraction. Immunocytochemistry, RT-PCR and flow-cytometric analysis revealed the promising antilithiatic activity of kidney stone matrix proteins. The iTRAQ analysis of renal cells showed up-regulation of 12 proteins and down-regulation of 41 proteins due to CaOx insult, however, this differential expression was normalized in the presence of kidney stone matrix proteins. Protein network analysis revealed involvement of up-regulated proteins in apoptosis, calcium-binding, inflammatory and stress response pathways. Moreover, seven novel antilithiatic proteins were identified from human kidney stones' matrix: Tenascin-X-isoform2, CCDC-144A, LIM domain kinase-1, Serine/Arginine receptor matrix protein-2, mitochondrial peptide methionine sulfoxide reductase, volume-regulated anion channel subunit-LRRC8A and BMPR2. In silico analysis concluded that these proteins exert antilithiatic potential through crystal binding, thereby inhibiting the crystal-cell interaction, a pre-requisite to initiate inflammatory response. Thus, the outcomes of this study provide insights into the molecular events of CaOx induced renal toxicity and subsequent progression into nephrolithiasis.
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http://dx.doi.org/10.1016/j.lfs.2020.118498DOI Listing
December 2020

Deciphering the SSR incidences across viral members of Coronaviridae family.

Chem Biol Interact 2020 Nov 21;331:109226. Epub 2020 Sep 21.

King Fahd Medical Research Center, King Abdulaziz University, P. O. Box 80216, Jeddah, 21589, Saudi Arabia; Enzymoics, Novel Global Community Educational Foundation, 7 Peterlee Place, Hebersham, NSW, 2770, Australia.

Presence of Simple Sequence Repeats (SSRs), both in genic and intergenic regions, have been widely studied in eukaryotes, prokaryotes, and viruses. In the current study, we undertook a survey to analyze the frequency and distribution of microsatellites or SSRs in multiple genomes of Coronaviridae members. We successfully identified 919 SSRs with length ≥12 bp across 55 reference genomes majority of which (838 SSRs) were found abundant in genic regions. The in-silico analysis further identified the preferential abundance of hexameric SSRs than any other size-based motif class. Our analysis shows that the genome size and GC content of the genome had a weak influence on SSR frequency and density. However, we find a positive correlation of SSRs GC content with genomic GC content. We also report relatively low abundances of all theoretically possible 501 repeat motif classes in all the genomes of Coronaviridae. The majority of SSRs were AT-rich. Overall, we see an underrepresentation of SSRs across the genomes of Coronaviridae. Besides, our integrative study highlights the presence of SSRs in ORF1ab (nsp3, nsp4, nsp5A_3CLpro and nsp5B_3CLpro, nsp6, nsp10, nsp12, nsp13, & nsp15 domains), S, ORF3a, ORF7a, N & 3' UTR regions of SARS-CoV-2 and harbours multiple mutations (3'UTR and ORF1ab SSRs serving as major mutational hotspots). This indicates the genic SSRs are under selection pressure against mutations that might alter the reading frame and at the same time responsible for rapid protein evolution. Our preliminary results indicate the significance of the limited repertoire of SSRs in the genomes of Coronaviridae.
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http://dx.doi.org/10.1016/j.cbi.2020.109226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505113PMC
November 2020

Structure-based drug repurposing for targeting Nsp9 replicase and spike proteins of severe acute respiratory syndrome coronavirus 2.

J Biomol Struct Dyn 2020 Aug 24:1-14. Epub 2020 Aug 24.

Amity Institute of Molecular Medicine & Stem Cell Research (AIMMSCR), Amity University Uttar Pradesh, Noida, India.

Drug re-purposing might be a fast and efficient way of drug development against the novel coronavirus disease 2019 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We applied a bioinformatics approach using molecular dynamics and docking to identify FDA-approved drugs that can be re-purposed to potentially inhibit the non-structural protein 9 (Nsp9) replicase and spike proteins in SARS-CoV-2. We performed virtual screening of FDA-approved compounds, including antiviral, anti-malarial, anti-parasitic, anti-fungal, anti-tuberculosis, and active phytochemicals against the Nsp9 replicase and spike proteins. Selected hit compounds were identified based on their highest binding energy and favorable absorption, distribution, metabolism and excretion (ADME) profile. Conivaptan, an arginine vasopressin antagonist drug exhibited the highest binding energy (-8.4 Kcal/mol) and maximum stability with the amino acid residues present at the active site of the Nsp9 replicase. Tegobuvir, a non-nucleoside inhibitor of the hepatitis C virus, also exhibited maximum stability along with the highest binding energy (-8.1 Kcal/mol) at the active site of the spike proteins. Molecular docking scores were further validated by molecular dynamics using Schrodinger, which supported the strong stability of ligands with the proteins at their active sites through water bridges, hydrophobic interactions, and H-bonding. Our findings suggest Conivaptan and Tegobuvir as potential therapeutic agents against SARS-CoV-2. Further and validation and evaluation are warranted to establish how these drug compounds target the Nsp9 replicase and spike proteins.
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http://dx.doi.org/10.1080/07391102.2020.1811773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484568PMC
August 2020

Metabolic regulation in HPV associated head and neck squamous cell carcinoma.

Life Sci 2020 Oct 11;258:118236. Epub 2020 Aug 11.

Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Amity University UttarPradesh, Sec 125, Noida 201303, India. Electronic address:

Cancer cells exhibit distinct energy metabolic pathways due to multiple oncogenic events. In normoxia condition, the anaerobic glycolysis (Warburg effect) is highly observed in head and neck squamous cell carcinoma (HNSCC). HNSCC is associated with smoking, chewing tobacco, consumption of alcohol or Human Papillomavirus (HPV) infection primarily HPV16. In recent years, the correlation of HPV with HNSCC has significantly expanded. Despite the recent advancement in therapeutic approaches, the rate of HPV infected HNSCC has significantly increased in the last few years, specifically, in lower middle-income countries. The oncoproteins of High-risk Human Papillomavirus (HR-HPV), E6 and E7, alter the metabolic phenotype in HNSCC, which is distinct from non-HPV associated HNSCC. These oncoproteins, modulate the cell cycle and metabolic signalling through interacting with tumor suppressor proteins, p53 and pRb. Since, metabolic alteration represents a major hallmark for tumorigenesis, HPV acts as a source of biomarker linked to cancer progression in HNSCC. The dependency of cancer cells to specific nutrients and alteration of various metabolic associated genes may provide a unique opportunity for pharmacological intervention in HPV infected HNSCC. In this review, we have discussed the molecular mechanism (s) and metabolic regulation in HNSCC depending on the HPV status. We have also discussed the possible potential therapeutic approaches for HPV associated HNSCC through targeting metabolic pathways.
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http://dx.doi.org/10.1016/j.lfs.2020.118236DOI Listing
October 2020

Molecular mechanisms of interplay between autophagy and metabolism in cancer.

Life Sci 2020 Oct 5;259:118184. Epub 2020 Aug 5.

Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Amity University Uttar Pradesh, Noida 201313, India. Electronic address:

Autophagy is an essential mechanism of cellular degradation, a way to protect the cells under stress conditions, such as deprivation of nutrients, growth factors and cellular damage. However, in normal physiology autophagy plays a significant role in cancer cells. Current research is in progress to understand how autophagy and cancer cells go hand in hand to support cancer cell progression. The important aspect in cancer and autophagy is the interdependence of autophagy in the survival and progression of cancer cells. Autophagy is known to be a major cause of chemotherapeutic resistance in various cancer cell types. Therefore, inhibition of autophagy as an effective therapeutic approach is being actively studied and tested in clinical studies. Multiple metabolic pathways are linked with autophagy that could potentially be a significant target for chemotherapeutic strategy. The comprehension of the interconnection of autophagy with cancer metabolism can pave a novel findings for effective combinatorial therapeutic strategies.
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http://dx.doi.org/10.1016/j.lfs.2020.118184DOI Listing
October 2020

Targeting Signalling Cross-Talk between Cancer Cells and Cancer Associate Fibroblast through Monocarboxylate Transporters in Head and Neck Cancer.

Anticancer Agents Med Chem 2020 Jul 21. Epub 2020 Jul 21.

Amity Institute of Molecular Medicine & Stem Cell Research (AIMMSCR), Amity University Uttar Pradesh, Sec-125, Noida-201313, (UP). India.

Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy affecting more than 600,000 cases worldwide annually, associated with poor prognosis and significant morbidity. HNSCC tumors are dysplastic with up to 80% fibroblasts. It has been reported that cancer associated fibroblasts (CAFs) facilitate HNSCC progression. Unlike normal cells, malignant cells often display increased glycolysis, even in the presence of oxygen; a phenomenon known as the Warburg effect. As a consequence, there is an increase in lactic acid (LA) production. Earlier, it has been reported that HNSCC tumors exhibit high LA levels that correlate with reduced survival. It has been reported that the activation of the receptor tyrosine kinase, c-MET, by CAF-secreted hepatocyte growth factor (HGF) is a major contributing event in the progression of HNSCC. In nasopharyngeal carcinoma, c-MET inhibition down regulates the TP53-induced glycolysis and apoptosis regulator (TIGAR) and NADPH production resulting in apoptosis. Previously, it was demonstrated that HNSCC tumor cells are highly glycolytic. Further, CAFs show a higher capacity to utilize LA as a carbon source to fuel mitochondrial respiration than HNSCC. Earlier, we have reported that in admixed cultures, both cell types increase expression of monocarboxylate transporters (MCTs) for a bidirectional LA transporter. Consequently, MCTs play important role in signalling cross-talk between cancer cells and cancer associate fibroblast in head and neck cancer, and targeting MCTs would lead to the development of potential therapeutic approach for head and neck cancer. In this review, we focus on the regulation of MCTs in head and neck cancer through signalling cross-talk between cancer cells and cancer associated fibroblasts, and targeting this signalling cross talk would lead to the development of potential therapeutic approach for head and neck cancer.
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http://dx.doi.org/10.2174/1871520620666200721135230DOI Listing
July 2020

Novel 3,4-diarylpyrazole as prospective anti-cancerous agents.

Heliyon 2020 Jul 14;6(7):e04397. Epub 2020 Jul 14.

Centre for Genetic Disorder, Banaras Hindu University, Varanasi, U.P., India.

Cancer is a leading cause of death globally. Despite therapeutic advancements the mortality rate of cancer is continuously increasing. Thus, it is important to identify and design potential therapeutic agents which can specifically bind with most common targets of cancer and inhibit tumor progression. The present work discloses the potential therapeutic application of the novel 3,4-diaryl 1-pyrazoles as prospective anti-cancerous agent. The molecular docking studies performed with 3,4-disubstituted pyrazoles as ligand with targets including DNA, BCL-2 and F1-ATP Synthase revealed strong binding affinity with DNA (-7.5 kcal/mol), BCL-2 (-8.1 kcal/mol) and F1-ATP Synthase (-7.2 kcal/mol). Furthermore, the finding was validated with the cytotoxicity assay with human breast cancer cell line (MDA-MB-231). MDA-MB-231 cells treated with 3,4-diarylpyrazole resulted in an increase in annexin-V positive cells, production of reactive oxygen species (ROS), dissipation of the mitochondrial membrane potential and activation of caspase-3. Taken together, this study demonstrate that a novel synthesized 3,4-diarylpyrazoles, showed strong binding affinity against DNA, anti-proliferative activity and executed apoptosis through ROS-dependent caspase-3-mediated mitochondrial intrinsic apoptotic pathway against MDA-MB-231 cells. These findings increase our understanding of the molecular mechanism (s) by which 3,4-diarylpyrazoles can exert their anticancer activity and may contribute towards development of novel therapeutic agent against breast cancer.
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http://dx.doi.org/10.1016/j.heliyon.2020.e04397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7364028PMC
July 2020

Discovery of New Hydroxyethylamine Analogs against 3CL Protein Target of SARS-CoV-2: Molecular Docking, Molecular Dynamics Simulation, and Structure-Activity Relationship Studies.

J Chem Inf Model 2020 12 18;60(12):5754-5770. Epub 2020 Jun 18.

Laboratory for Translational Chemistry and Drug Discovery, Hansraj College, University of Delhi, Delhi 110007, India.

The novel coronavirus, SARS-CoV-2, has caused a recent pandemic called COVID-19 and a severe health threat around the world. In the current situation, the virus is rapidly spreading worldwide, and the discovery of a vaccine and potential therapeutics are critically essential. The crystal structure for the main protease (M) of SARS-CoV-2, 3-chymotrypsin-like cysteine protease (3CL), was recently made available and is considerably similar to the previously reported SARS-CoV. Due to its essentiality in viral replication, it represents a potential drug target. Herein, a computer-aided drug design (CADD) approach was implemented for the initial screening of 13 approved antiviral drugs. Molecular docking of 13 antivirals against the 3-chymotrypsin-like cysteine protease (3CL) enzyme was accomplished, and indinavir was described as a lead drug with a docking score of -8.824 and a XP Gscore of -9.466 kcal/mol. Indinavir possesses an important pharmacophore, hydroxyethylamine (HEA), and thus, a new library of HEA compounds (>2500) was subjected to virtual screening that led to 25 hits with a docking score more than indinavir. Exclusively, compound with a docking score of -8.955 adhered to drug-like parameters, and the structure-activity relationship (SAR) analysis was demonstrated to highlight the importance of chemical scaffolds therein. Molecular dynamics (MD) simulation analysis performed at 100 ns supported the stability of within the binding pocket. Largely, our results supported that this novel compound binds with domains I and II, and the domain II-III linker of the 3CL protein, suggesting its suitability as a strong candidate for therapeutic discovery against COVID-19.
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http://dx.doi.org/10.1021/acs.jcim.0c00326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7304236PMC
December 2020

Specific targeting cancer cells with nanoparticles and drug delivery in cancer therapy.

Semin Cancer Biol 2021 Feb 9;69:166-177. Epub 2019 Nov 9.

Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Amity University Uttar Pradesh, Noida, 201313, India. Electronic address:

Nanotechnology has been the latest approach for diagnosis and treatment for cancer, which opens up a new alternative therapeutic drug delivery option to treat disease. Nanoparticles (NPs) display a broad role in cancer diagnosis and has various advantages over the other conventional chemotherapeutic drug delivery. NPs possess more specific and efficient drug delivery to the targeted tissue, cell, or organs and minimize the risk of side effects. NPs undergo passive and active mode of drug targets to tumor area with less elimination of the drug from the system. Size and surface characteristics of nanoparticles play a crucial role in modulating nanocarrier efficiency and the biodistribution of chemo drugs in the body. Several types of nanocarriers, such as polymers, dendrimers, liposome-based, and carbon-based, are studied widely in cancer therapy. Although FDA approved very few nanotechnology drugs for cancer therapy, a large number of studies are undergoing for the development of novel nanocarriers for potent cancer therapy. In this review, we discuss the details of the nano-based therapeutics and diagnostics strategies, and the potential use of nanomedicines in cancer therapy and cancer drug delivery.
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http://dx.doi.org/10.1016/j.semcancer.2019.11.002DOI Listing
February 2021

Investigation of Precise Molecular Mechanistic Action of Tobacco-Associated Carcinogen `NNK´ Induced Carcinogenesis: A System Biology Approach.

Genes (Basel) 2019 07 26;10(8). Epub 2019 Jul 26.

Department of Applied Physics, Aalto University, 00076 Espoo, Finland.

Cancer is the second deadliest disease listed by the WHO. One of the major causes of cancer disease is tobacco and consumption possibly due to its main component, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). A plethora of studies have been conducted in the past aiming to decipher the association of NNK with other diseases. However, it is strongly linked with cancer development. Despite these studies, a clear molecular mechanism and the impact of NNK on various system-level networks is not known. In the present study, system biology tools were employed to understand the key regulatory mechanisms and the perturbations that will happen in the cellular processes due to NNK. To investigate the system level influence of the carcinogen, NNK rewired protein-protein interaction network (PPIN) was generated from 544 reported proteins drawn out from 1317 articles retrieved from PubMed. The noise was removed from PPIN by the method of modulation. Gene ontology (GO) enrichment was performed on the seed proteins extracted from various modules to find the most affected pathways by the genes/proteins. For the modulation, Molecular COmplex DEtection (MCODE) was used to generate 19 modules containing 115 seed proteins. Further, scrutiny of the targeted biomolecules was done by the graph theory and molecular docking. GO enrichment analysis revealed that mostly cell cycle regulatory proteins were affected by NNK.
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http://dx.doi.org/10.3390/genes10080564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6723528PMC
July 2019

Effect of incorporation of montmorillonite on Xylan/Chitosan conjugate scaffold.

Colloids Surf B Biointerfaces 2019 Aug 16;180:75-82. Epub 2019 Apr 16.

Department of Polymer and Process Engineering, Indian Institute of Technology Roorkee, Saharanpur Campus, Saharanpur, India. Electronic address:

The present study reports the fabrication of Xylan/Chitosan/Montmorillonite (MMT) composite scaffold by freeze drying process with the aim of achieving improved properties for bone tissue engineering applications. The scaffolds were characterized using Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), Scanning electron microscopy (SEM) and mechanical testing. The fabricated scaffolds were found to be highly porous with variations in pore size (102 μm-290 μm) on varying the filler concentration. XRD study revealed complete exfoliation of MMT incorporated in polymer conjugates (Xylan/Chitosan) prepared by Maillard reaction. In-vitro bio-mineralization study revealed significant apatite deposition on polymer matrix. Scaffolds with 5% MMT concentration exhibited needle like morphology of deposited apatite which can further provide synergistic response in increasing the mechanical properties of scaffolds when placed in contact with body fluid. The average length and thickness of apatite needles were calculated to be 140 μm and 1.2 μm respectively. The deposited apatite crystals on scaffold with 2% MMT content demonstrated Ca/P ratio of 1.67, resembling that of natural bone apatite. Swelling and biodegradation behavior of scaffold were also studied with regard to hydrophilic and barrier effect of MMT on composites. MTT assay revealed non-cytotoxic nature of scaffold with good cell viability.
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http://dx.doi.org/10.1016/j.colsurfb.2019.04.032DOI Listing
August 2019

Potent Antitumor Effects of a Combination of Three Nutraceutical Compounds.

Sci Rep 2018 08 15;8(1):12163. Epub 2018 Aug 15.

Department of Otolaryngology, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS, 66160, USA.

Head and neck squamous cell carcinoma (HNSCC) is associated with low survival, and the current aggressive therapies result in high morbidity. Nutraceuticals are dietary compounds with few side effects. However, limited antitumor efficacy has restricted their application for cancer therapy. Here, we examine combining nutraceuticals, establishing a combination therapy that is more potent than any singular component, and delineate the mechanism of action. Three formulations were tested: GZ17-S (combined plant extracts from Arum palaestinum, Peganum harmala and Curcuma longa); GZ17-05.00 (16 synthetic components of GZ17-S); and GZ17-6.02 (3 synthetic components of GZ17S; curcumin, harmine and isovanillin). We tested the formulations on HNSCC proliferation, migration, invasion, angiogenesis, macrophage viability and infiltration into the tumor and tumor apoptosis. GZ17-6.02, the most effective formulation, significantly reduced in vitro assessments of HNSCC progression. When combined with cisplatin, GZ17-6.02 enhanced anti-proliferative effects. Molecular signaling cascades inhibited by GZ17-6.02 include EGFR, ERK1/2, and AKT, and molecular docking analyses demonstrate GZ17-6.02 components bind at distinct binding sites. GZ17-6.02 significantly inhibited growth of HNSCC cell line, patient-derived xenografts, and murine syngeneic tumors in vivo (P < 0.001). We demonstrate GZ17-6.02 as a highly effective plant extract combination and pave the way for future clinical application in HNSCC.
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http://dx.doi.org/10.1038/s41598-018-29683-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6093880PMC
August 2018

Cancer-Associated Fibroblasts Drive Glycolysis in a Targetable Signaling Loop Implicated in Head and Neck Squamous Cell Carcinoma Progression.

Cancer Res 2018 07 16;78(14):3769-3782. Epub 2018 May 16.

Department of Otolaryngology, University of Kansas Medical Center, Kansas City, Kansas.

Despite aggressive therapies, head and neck squamous cell carcinoma (HNSCC) is associated with a less than 50% 5-year survival rate. Late-stage HNSCC frequently consists of up to 80% cancer-associated fibroblasts (CAF). We previously reported that CAF-secreted HGF facilitates HNSCC progression; however, very little is known about the role of CAFs in HNSCC metabolism. Here, we demonstrate that CAF-secreted HGF increases extracellular lactate levels in HNSCC via upregulation of glycolysis. CAF-secreted HGF induced basic FGF (bFGF) secretion from HNSCC. CAFs were more efficient than HNSCC in using lactate as a carbon source. HNSCC-secreted bFGF increased mitochondrial oxidative phosphorylation and HGF secretion from CAFs. Combined inhibition of c-Met and FGFR significantly inhibited CAF-induced HNSCC growth and ( < 0.001). Our cumulative findings underscore reciprocal signaling between CAF and HNSCC involving bFGF and HGF. This contributes to metabolic symbiosis and a targetable therapeutic axis involving c-Met and FGFR. HNSCC cancer cells and CAFs have a metabolic relationship where CAFs secrete HGF to induce a glycolytic switch in HNSCC cells and HNSCC cells secrete bFGF to promote lactate consumption by CAFs. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-1076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6050074PMC
July 2018

Development and Characterization of an In Vitro Model for Radiation-Induced Fibrosis.

Radiat Res 2018 03 19;189(3):326-336. Epub 2018 Jan 19.

Department of a   Otolaryngology, University of Kansas Medical Center and University of Kansas Cancer Center, Kansas City, Kansas.

Radiation-induced fibrosis (RIF) is a major side effect of radiotherapy in cancer patients with no effective therapeutic options. RIF involves excess deposition and aberrant remodeling of the extracellular matrix (ECM) leading to stiffness in tissues and organ failure. Development of preclinical models of RIF is crucial to elucidate the molecular mechanisms regulating fibrosis and to develop therapeutic approaches. In addition to radiation, the main molecular perpetrators of fibrotic reactions are cytokines, including transforming growth factor-β (TGF-β). We hypothesized that human oral fibroblasts would develop an in vitro fibrotic reaction in response to radiation and TGF-β. We demonstrate here that fibroblasts exposed to radiation followed by TGF-β exhibit a fibrotic phenotype with increased collagen deposition, cell proliferation, migration and invasion. In this in vitro model of RIF (RIF), the early biological processes involved in fibrosis are demonstrated, along with increased levels of several molecules including collagen 1α1, collagen XIα1, integrin-α2 and cyclin D1 mRNA in irradiated cells. A clinically relevant antifibrotic agent, pentoxifylline, and a curcumin analogue both mitigated collagen deposition in irradiated fibroblast cultures. In summary, we have established an in vitro model for RIF that facilitates the elucidation of molecular mechanisms in radiation-induced fibrosis and the development of effective therapeutic approaches.
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http://dx.doi.org/10.1667/RR14926.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837959PMC
March 2018

Plantar Fibromatosis: Pathophysiology, Surgical and Nonsurgical Therapies: An Evidence-Based Review.

Foot Ankle Spec 2018 Apr 9;11(2):168-176. Epub 2018 Jan 9.

Division of Podiatric Surgery, Center for Wound Healing, MedStar Georgetown University Hospital, Washington, DC (PC).

Plantar fibromatosis (morbus Ledderhose), an extra-abdominal desmoid tumor of the plantar foot, is a rare benign hyperproliferative disorder of the plantar fascia with an unknown etiology. The main clinical characteristics include slow growing nodules on the medial and central bands of the plantar fascia, which may become painful and negatively affect ambulation. Most established conservative therapies today target symptomatic relief. As symptoms progress, therapies such as injections, shockwave ablation, radiation, and/or surgery may be required. This review aims to provide insight into the pathophysiology of this condition in addition to detailing current and investigational therapies for this disorder. Many therapies have been proven in similar conditions, which could lead to promising treatment options for plantar fibromatosis.

Levels Of Evidence: Level V: Expert opinion.
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http://dx.doi.org/10.1177/1938640017751184DOI Listing
April 2018