165 results on '"Neeraj Chauhan"'
Search Results
2. The Candida auris Hog1 MAP kinase is essential for the colonization of murine skin and intradermal persistence
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Raju Shivarathri, Manju Chauhan, Abhishek Datta, Diprasom Das, Adela Karuli, Ariel Aptekmann, Sabrina Jenull, Karl Kuchler, Shankar Thangamani, Anuradha Chowdhary, Jigar V. Desai, and Neeraj Chauhan
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Candida auris ,HOG1 ,MAP kinase ,skin colonization ,intradermal infection ,biofilm ,Microbiology ,QR1-502 - Abstract
ABSTRACT Candida auris, a multidrug-resistant human fungal pathogen, was first identified in 2009 in Japan. Since then, systemic C. auris infections have now been reported in more than 50 countries, with mortality rates of 30%–60%. A major contributing factor to its high inter- and intrahospital clonal transmission is that C. auris, unlike most Candida species, displays unique skin tropism and can stay on human skin for a prolonged period. However, the molecular mechanisms responsible for C. auris skin colonization, intradermal persistence, and systemic virulence are poorly understood. Here, we report that C. auris Hog1 mitogen-activated protein kinase is essential for efficient skin colonization, intradermal persistence as well as systemic virulence. RNA-seq analysis of wild-type parental and hog1Δ mutant strains revealed marked downregulation of genes involved in processes such as cell adhesion, cell wall rearrangement, and pathogenesis in hog1Δ mutant compared to the wild-type parent. Consistent with these data, we found a prominent role for Hog1 in maintaining cell wall architecture, as the hog1Δ mutant demonstrated a significant increase in cell-surface β-glucan exposure and a concomitant reduction in chitin content. Additionally, we observed that Hog1 was required for biofilm formation in vitro and fungal survival when challenged with primary murine macrophages and neutrophils ex vivo. Collectively, these findings have important implications for understanding the C. auris skin adherence mechanisms and penetration of skin epithelial layers preceding bloodstream infections.IMPORTANCECandida auris is a World Health Organization fungal priority pathogen and an urgent public health threat recognized by the Centers for Disease Control and Prevention. C. auris has a unique ability to colonize human skin. It also persists on abiotic surfaces in healthcare environments for an extended period of time. These attributes facilitate the inter- and intrahospital clonal transmission of C. auris. Therefore, understanding C. auris skin colonization mechanisms is critical for infection control, especially in hospitals and nursing homes. However, despite its profound clinical relevance, the molecular and genetic basis of C. auris skin colonization mechanisms are poorly understood. Herein, we present data on the identification of the Hog1 MAP kinase as a key regulator of C. auris skin colonization. These findings lay the foundation for further characterization of unique mechanisms that promote fungal persistence on human skin.
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- 2024
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3. Prevalence of musculoskeletal pain in dentists; A systematic review and meta-analysis
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Nikhil Chandrakant Thorat, S Sahana, Neeraj Chauhan, Tarun Pratap Singh, and Anshika Khare
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back pain ,dental practitioners ,musculoskeletal disorders ,musculoskeletal pain ,neck pain ,shoulder pain ,wrist pain ,Surgery ,RD1-811 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Musculoskeletal disorders (MSDs) are the most common occupational illnesses in the world. Dental professionals are more prone to injuries and pain in their muscles, tendons, nerves, and joints, which are known as MSDs. Prolonged static postures, repeated actions, workplace designs, poor alignment, genetic predisposition, mental stress, physical conditioning, age, and nonwork activities are all factors that might contribute to musculoskeletal pain (MSP). This systematic review and meta-analysis was based on Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines, and the articles were retrieved from the search engines such as PubMed, Google Scholar, and Web of Science after fulfilling the eligibility criteria. After screening, a final of ten articles were included in the final analysis. This systematic and meta-analysis follows the PRISMA checklist. Medcalc software was used in order to find the significance of the prevalence of lower back pain, followed by neck pain, upper back pain, shoulder pain, and hand and wrist pain in dental practitioners. Significant differences were considered at P < 0.05. A total of ten studies were included, of which six studies met the criteria for the meta-analysis. The prevalence rates of musculoskeletal diseases were high. The lower back was the region most affected (47.753%, 95% confidence interval [CI]: 45.007–50.509), followed by the upper back body region (44.167%, 95% CI: 41.300–47.063%), neck pain (41.633%, 95% CI: 39.066%–44.234%), shoulder pain (33.608%, 95% CI: 31.222%–36.058% and 18.656%), and hand/wrist pain (95% CI: 16.359%–21.128%). Work-related MSP is the major health problem among dental professionals. Working posture of dental professionals is important and has been identified as a major risk factor for the development of work-related MSDs. A proper ergonomic design and posture can reduce the MSP. Therefore, further research is needed on possible ergonomics needed for preventing MSDs.
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- 2022
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4. Milk exosomes: Nature's abundant nanoplatform for theranostic applications
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Benilde Adriano, Nycol M. Cotto, Neeraj Chauhan, Meena Jaggi, Subhash C. Chauhan, and Murali M. Yallapu
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Milk exosomes ,Extracellular vesicles ,Drug delivery ,Imaging agents ,Theranostic applications ,Materials of engineering and construction. Mechanics of materials ,TA401-492 ,Biology (General) ,QH301-705.5 - Abstract
Exosomes are a unique subpopulation of naturally occurring extracellular vesicles which are smaller intracellular membrane nanoparticle vesicles. Exosomes have proven to be excellent nanocarriers for carrying lipids, proteins, mRNAs, non-coding RNAs, and DNAs, and disseminating long-distance intercellular communications in various biological processes. Among various cell-line or biological fluid derived exosomes, milk exosomes are abundant in nature and exhibit many nanocarrier characteristics favorable for theranostic applications. To be an effective delivery carrier for their clinical translation, exosomes must inbuilt loading, release, targeting, and imaging/tracking characteristics. Considering the unmet gaps of milk exosomes in theranostic technology it is essential to focus the current review on drug delivery and imaging applications. This review delineates the efficiency of exosomes to load therapeutic or imaging agents and their successful delivery approaches. It is emphasized on possible modifications of exosomes towards increasing the stability and delivery of agents. This article also summarizes the specific applications and the process of developing milk exosomes as a future pharmaceutical drug delivery vehicle.
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- 2021
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5. Transcriptomics and Phenotyping Define Genetic Signatures Associated with Echinocandin Resistance in Candida auris
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Sabrina Jenull, Raju Shivarathri, Irina Tsymala, Philipp Penninger, Phan-Canh Trinh, Filomena Nogueira, Manju Chauhan, Ashutosh Singh, Andriy Petryshyn, Anton Stoiber, Anuradha Chowdhary, Neeraj Chauhan, and Karl Kuchler
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Candida auris ,antifungal resistance ,phenotypic variation ,transcriptomics ,Microbiology ,QR1-502 - Abstract
ABSTRACT Candida auris emerged as a human fungal pathogen only during the past decade. Remarkably, C. auris displays high degrees of genomic diversity and phenotypic plasticity, with four major clades causing hospital outbreaks with high mortality and morbidity rates. C. auris can show clinical resistance to all classes of antifungal drugs, including echinocandins that are usually recommended as first-line therapies for invasive candidiasis. Here, we exploit transcriptomics coupled with phenotypic profiling to characterize a set of clinical C. auris isolates displaying pronounced echinocandin resistance (ECN-R). A hot spot mutation in the echinocandin FKS1 target gene is present in all resistant isolates. Moreover, ECN-R strains share a core signature set of 362 genes differentially expressed in ECN-R isolates. Among others, mitochondrial gene expression and genes affecting cell wall function appear to be the most prominent, with the latter correlating well with enhanced adhesive traits, increased cell wall mannan content, and altered sensitivity to cell wall stress of ECN-R isolates. Moreover, ECN-R phenotypic signatures were also linked to pathogen recognition and interaction with immune cells. Hence, transcriptomics paired with phenotyping is a suitable tool to predict resistance and fitness traits as well as treatment outcomes in pathogen populations with complex phenotypic diversity. IMPORTANCE The surge in antimicrobial drug resistance in some bacterial and fungal pathogens constitutes a significant challenge to health care facilities. The emerging human fungal pathogen Candida auris has been particularly concerning, as isolates can display pan-antifungal resistance traits against all drugs, including echinocandins. However, the mechanisms underlying this phenotypic diversity remain poorly understood. We identify transcriptomic signatures in C. auris isolates resistant to otherwise fungicidal echinocandins. We identify a set of differentially expressed genes shared by resistant strains compared to unrelated susceptible isolates. Moreover, phenotyping demonstrates that resistant strains show distinct behaviors, with implications for host-pathogen interactions. Hence, this work provides a solid basis to identify the mechanistic links between antifungal multidrug resistance and fitness costs that affect the interaction of C. auris with host immune defenses.
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- 2022
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6. Pluronic Polymer-Based Ormeloxifene Nanoformulations Induce Superior Anticancer Effects in Pancreatic Cancer Cells
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Neeraj Chauhan, Amber Kruse, Hilary Newby, Meena Jaggi, Murali M. Yallapu, and Subhash C. Chauhan
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Chemistry ,QD1-999 - Published
- 2020
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7. Therapeutic efficacy of a novel βIII/βIV-tubulin inhibitor (VERU-111) in pancreatic cancer
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Vivek K. Kashyap, Qinghui Wang, Saini Setua, Prashanth K. B. Nagesh, Neeraj Chauhan, Sonam Kumari, Pallabita Chowdhury, Duane D. Miller, Murali M. Yallapu, Wei Li, Meena Jaggi, Bilal Bin Hafeez, and Subhash C. Chauhan
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VERU-111 ,Pancreatic cancer ,β –tubulins ,miR-200c ,βIII/βIV-tubulin inhibitor ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background The management of pancreatic cancer (PanCa) is exceptionally difficult due to poor response to available therapeutic modalities. Tubulins play a major role in cell dynamics, thus are important molecular targets for cancer therapy. Among various tubulins, βIII and βIV-tubulin isoforms have been primarily implicated in PanCa progression, metastasis and chemo-resistance. However, specific inhibitors of these isoforms that have potent anti-cancer activity with low toxicity are not readily available. Methods We determined anti-cancer molecular mechanisms and therapeutic efficacy of a novel small molecule inhibitor (VERU-111) using in vitro (MTS, wound healing, Boyden chamber and real-time xCELLigence assays) and in vivo (xenograft studies) models of PanCa. The effects of VERU-111 treatment on the expression of β-tubulin isoforms, apoptosis, cancer markers and microRNAs were determined by Western blot, immunohistochemistry (IHC), confocal microscopy, qRT-PCR and in situ hybridization (ISH) analyses. Results We have identified a novel small molecule inhibitor (VERU-111), which preferentially represses clinically important, βIII and βIV tubulin isoforms via restoring the expression of miR-200c. As a result, VERU-111 efficiently inhibited tumorigenic and metastatic characteristics of PanCa cells. VERU-111 arrested the cell cycle in the G2/M phase and induced apoptosis in PanCa cell lines via modulation of cell cycle regulatory (Cdc2, Cdc25c, and Cyclin B1) and apoptosis - associated (Bax, Bad, Bcl-2, and Bcl-xl) proteins. VERU-111 treatment also inhibited tumor growth (P
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- 2019
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8. Transcriptome Signatures Predict Phenotypic Variations of Candida auris
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Sabrina Jenull, Michael Tscherner, Nataliya Kashko, Raju Shivarathri, Anton Stoiber, Manju Chauhan, Andriy Petryshyn, Neeraj Chauhan, and Karl Kuchler
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Candida auris ,transcriptional profiling ,phenotypic variation ,antifungal multidrug resistance ,RNA-seq ,Microbiology ,QR1-502 - Abstract
Health care facilities are facing serious threats by the recently emerging human fungal pathogen Candida auris owing to its pronounced antifungal multidrug resistance and poor diagnostic tools. Distinct C. auris clades evolved seemingly simultaneously at independent geographical locations and display both genetic and phenotypic diversity. Although comparative genomics and phenotypic profiling studies are increasing, we still lack mechanistic knowledge about the C. auris species diversification and clinical heterogeneity. Since gene expression variability impacts phenotypic plasticity, we aimed to characterize transcriptomic signatures of C. auris patient isolates with distinct antifungal susceptibility profiles in this study. First, we employed an antifungal susceptibility screening of clinical C. auris isolates to identify divergent intra-clade responses to antifungal treatments. Interestingly, comparative transcriptional profiling reveals large gene expression differences between clade I isolates and one clade II strain, irrespective of their antifungal susceptibilities. However, comparisons at the clade levels demonstrate that minor changes in gene expression suffice to drive divergent drug responses. Finally, we functionally validate transcriptional signatures reflecting phenotypic divergence of clinical isolates. Thus, our results suggest that large-scale transcriptional profiling allows for predicting phenotypic diversities of patient isolates, which may help choosing suitable antifungal therapies of multidrug-resistant C. auris.
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- 2021
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9. Inositol Phosphoryl Transferase, Ipt1, Is a Critical Determinant of Azole Resistance and Virulence Phenotypes in Candida glabrata
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Garima Shahi, Mohit Kumar, Nitesh Kumar Khandelwal, Atanu Banerjee, Parijat Sarkar, Sonam Kumari, Brooke D. Esquivel, Neeraj Chauhan, Amitabha Chattopadhyay, Theodore C. White, Naseem A. Gaur, Ashutosh Singh, and Rajendra Prasad
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Candida glabrata ,sphingolipids ,inositolphosphorylceramide ,lipidomics ,drug resistance ,virulence ,Biology (General) ,QH301-705.5 - Abstract
In this study, we have specifically blocked a key step of sphingolipid (SL) biosynthesis in Candida glabrata by disruption of the orthologs of ScIpt1 and ScSkn1. Based on their close homology with S. cerevisiae counterparts, the proteins are predicted to catalyze the addition of a phosphorylinositol group onto mannosyl inositolphosphoryl ceramide (MIPC) to form mannosyl diinositolphosphoryl ceramide (M(IP)2C), which accounts for the majority of complex SL structures in S. cerevisiae membranes. High throughput lipidome analysis confirmed the accumulation of MIPC structures in ΔCgipt1 and ΔCgskn1 cells, albeit to lesser extent in the latter. Noticeably, ΔCgipt1 cells showed an increased susceptibility to azoles; however, ΔCgskn1 cells showed no significant changes in the drug susceptibility profiles. Interestingly, the azole susceptible phenotype of ΔCgipt1 cells seems to be independent of the ergosterol content. ΔCgipt1 cells displayed altered lipid homeostasis, increased membrane fluidity as well as high diffusion of radiolabeled fluconazole (3H-FLC), which could together influence the azole susceptibility of C. glabrata. Furthermore, in vivo experiments also confirmed compromised virulence of the ΔCgipt1 strain. Contrarily, specific functions of CgSkn1 remain unclear.
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- 2022
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10. The Two-Component Response Regulator Ssk1 and the Mitogen-Activated Protein Kinase Hog1 Control Antifungal Drug Resistance and Cell Wall Architecture of Candida auris
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Raju Shivarathri, Sabrina Jenull, Anton Stoiber, Manju Chauhan, Rounik Mazumdar, Ashutosh Singh, Filomena Nogueira, Karl Kuchler, Anuradha Chowdhary, and Neeraj Chauhan
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Candida auris ,SSK1 ,HOG1 ,multidrug resistance ,cell wall ,MAPK signaling ,Microbiology ,QR1-502 - Abstract
ABSTRACT Candida auris is an emerging multidrug-resistant human fungal pathogen refractory to treatment by several classes of antifungal drugs. Unlike other Candida species, C. auris can adhere to human skin for prolonged periods of time, allowing for efficient skin-to-skin transmission in the hospital environments. However, molecular mechanisms underlying pronounced multidrug resistance and adhesion traits are poorly understood. Two-component signal transduction and mitogen-activated protein (MAP) kinase signaling are important regulators of adherence, antifungal drug resistance, and virulence. Here, we report that genetic removal of SSK1 encoding a response regulator and the mitogen-associated protein kinase HOG1 restores the susceptibility to both amphotericin B (AMB) and caspofungin (CAS) in C. auris clinical strains. The loss of SSK1 and HOG1 alters membrane lipid permeability, cell wall mannan content, and hyperresistance to cell wall-perturbing agents. Interestingly, our data reveal variable functions of SSK1 and HOG1 in different C. auris clinical isolates, suggesting a pronounced genetic plasticity affecting cell wall function, stress adaptation, and multidrug resistance. Taken together, our data suggest that targeting two-component signal transduction systems could be suitable for restoring C. auris susceptibility to antifungal drugs. IMPORTANCE Candida auris is an emerging multidrug-resistant (MDR) fungal pathogen that presents a serious global threat to human health. The Centers for Disease Control and Prevention (CDC) have classified C. auris as an urgent threat to public health for the next decade due to its major clinical and economic impact and the lack of effective antifungal drugs and because of future projections concerning new C. auris infections. Importantly, the Global Antimicrobial Resistance Surveillance System (GLASS) has highlighted the need for more robust and efficacious global surveillance schemes enabling the identification and monitoring of antifungal resistance in Candida infections. Despite the clinical relevance of C. auris infections, our overall understanding of its pathophysiology and virulence, its response to human immune surveillance, and the molecular basis of multiple antifungal resistance remains in its infancy. Here, we show a marked phenotypic plasticity of C. auris clinical isolates. Further, we demonstrate critical roles of stress response mechanisms in regulating multidrug resistance and show that cell wall architecture and composition are key elements that determine antifungal drug susceptibilities. Our data promise new therapeutic options to treat drug-refractory C. auris infections.
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- 2020
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11. Identification of Genomewide Alternative Splicing Events in Sequential, Isogenic Clinical Isolates of Candida albicans Reveals a Novel Mechanism of Drug Resistance and Tolerance to Cellular Stresses
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Suraya Muzafar, Ravi Datta Sharma, Abdul Haseeb Shah, Naseem A. Gaur, Ujjaini Dasgupta, Neeraj Chauhan, and Rajendra Prasad
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Candida albicans ,alternative splicing ,SOD3 ,amphotericin B ,menadione ,Microbiology ,QR1-502 - Abstract
ABSTRACT Alternative splicing (AS)—a process by which a single gene gives rise to different protein isoforms in eukaryotes—has been implicated in many basic cellular processes, but little is known about its role in drug resistance and fungal pathogenesis. The most common human fungal pathogen, Candida albicans, has introns in 4 to 6% of its genes, the functions of which remain largely unknown. Here, we report AS regulating drug resistance in C. albicans. Comparative RNA-sequencing of two different sets of sequential, isogenic azole-sensitive and -resistant isolates of C. albicans revealed differential expression of splice isoforms of 14 genes. One of these was the superoxide dismutase gene SOD3, which contains a single intron. The sod3Δ/Δ mutant was susceptible to the antifungals amphotericin B (AMB) and menadione (MND). While AMB susceptibility was rescued by overexpression of both the spliced and unspliced SOD3 isoforms, only the spliced isoform could overcome MND susceptibility, demonstrating the functional relevance of this splicing in developing drug resistance. Furthermore, unlike AMB, MND inhibits SOD3 splicing and acts as a splicing inhibitor. Consistent with these observations, MND exposure resulted in increased levels of unspliced SOD3 isoform that are unable to scavenge reactive oxygen species (ROS), resulting in increased drug susceptibility. Collectively, these observations suggest that AS is a novel mechanism for stress adaptation and overcoming drug susceptibility in C. albicans. IMPORTANCE The emergence of resistance in Candida albicans, an opportunistic pathogen, against the commonly used antifungals is becoming a major obstacle in its treatment. The necessity to identify new drug targets demands fundamental insights into the mechanisms used by this organism to develop drug resistance. C. albicans has introns in 4 to 6% of its genes, the functions of which remain largely unknown. Using the RNA-sequencing data from isogenic pairs of azole-sensitive and -resistant isolates of C. albicans, here, we show how C. albicans uses modulations in mRNA splicing to overcome antifungal drug stress.
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- 2020
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12. Oral hygiene and periodontal status in the primitive hidden tribe of Patalkot, a tribal area in Central India
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Arpan Shrivastav, Rajkumar Maurya, Chandresh Shukla, Trilok Sahu, Neeraj Chauhan, Antriksh Azad, and Ashutosh Dubey
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Community Periodontal Index ,loss of attachment ,Oral Hygiene Index-simplified ,periodontal status ,tribals ,Dentistry ,RK1-715 - Abstract
Introduction: Very little is known about the hard to reach tribal communities in India and one such community is a primitive hidden and isolated tribe group of Bharia people in Patalkot. Their health problems need special attention as they have very limited access to health care. The aim of this study is to assess the oral hygiene and periodontal status in the primitive tribe group of Bharias in Patalkot, Madhya Pradesh, India. Materials and Methods: A descriptive cross-sectional study was undertaken with sample size of 462 patients. The sample was selected using simple random technique. A predefined pro forma was used to record information about oral hygiene practices and tobacco-related habits. Oral Hygiene Index-simplified (OHI-S), Community Periodontal Index (CPI), and loss of attachment (LOA) were used to assess oral hygiene and periodontal status, respectively. Results: The prevalence of periodontal disease based on CPI scores showed that 35.4 % had periodontal pocket > 6mm. It was also found that 27.9% people had attachment loss of 6-8mm. Mean Debris Index-simplified, Calculus Index-simplified, and OHI-S for the participants were 1.59 ± 0.73, 0.99 ± 0.70, and 2.56 ± 1.36, respectively. Poor oral hygiene status was found in 36.3% of Bharias. Conclusion: Higher prevalence of periodontal diseases and poor oral hygiene status in Bharia people can be attributed mainly to their difficult terrain, isolation, very low literacy level, socioeconomic status, and cultural practices.
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- 2018
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13. Bay Leaf Extract-Based Near-Infrared Fluorescent Probe for Tissue and Cellular Imaging
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Benilde Adriano, Nycol M. Cotto, Neeraj Chauhan, Vinita Karumuru, Meena Jaggi, Subhash C. Chauhan, and Murali M. Yallapu
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near-infrared imaging ,chlorophyll ,dietary leaf ,cancer ,nanoparticles ,Photography ,TR1-1050 ,Computer applications to medicine. Medical informatics ,R858-859.7 ,Electronic computers. Computer science ,QA75.5-76.95 - Abstract
The development of fluorescence dyes for near-infrared (NIR) fluorescence imaging has been a significant interest for deep tissue imaging. Among many imaging fluoroprobes, indocyanine green (ICG) and its analogues have been used in oncology and other medical applications. However, these imaging agents still experience poor imaging capabilities due to low tumor targetability, photostability, and sensitivity in the biological milieu. Thus, developing a biocompatible NIR imaging dye from natural resources holds the potential of facilitating cancer cell/tissue imaging. Chlorophyll (Chl) has been demonstrated to be a potential candidate for imaging purposes due to its natural NIR absorption qualities and its wide availability in plants and green vegetables. Therefore, it was our aim to assess the fluorescence characteristics of twelve dietary leaves as well as the fluorescence of their Chl extractions. Bay leaf extract, a high-fluorescence agent that showed the highest levels of fluorescence, was further evaluated for its tissue contrast and cellular imaging properties. Overall, this study confirms bay-leaf-associated dye as a NIR fluorescence imaging agent that may have important implications for cellular imaging and image-guided cancer surgery.
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- 2021
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14. The Candida albicans HIR histone chaperone regulates the yeast-to-hyphae transition by controlling the sensitivity to morphogenesis signals
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Sabrina Jenull, Michael Tscherner, Megha Gulati, Clarissa J. Nobile, Neeraj Chauhan, and Karl Kuchler
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Medicine ,Science - Abstract
Abstract Morphological plasticity such as the yeast-to-hyphae transition is a key virulence factor of the human fungal pathogen Candida albicans. Hyphal formation is controlled by a multilayer regulatory network composed of environmental sensing, signaling, transcriptional modulators as well as chromatin modifications. Here, we demonstrate a novel role for the replication-independent HIR histone chaperone complex in fungal morphogenesis. HIR operates as a crucial modulator of hyphal development, since genetic ablation of the HIR complex subunit Hir1 decreases sensitivity to morphogenetic stimuli. Strikingly, HIR1-deficient cells display altered transcriptional amplitudes upon hyphal initiation, suggesting that Hir1 affects transcription by establishing transcriptional thresholds required for driving morphogenetic cell-fate decisions. Furthermore, ectopic expression of the transcription factor Ume6, which facilitates hyphal maintenance, rescues filamentation defects of hir1Δ/Δ cells, suggesting that Hir1 impacts the early phase of hyphal initiation. Hence, chromatin chaperone-mediated fine-tuning of transcription is crucial for driving morphogenetic conversions in the fungal pathogen C. albicans.
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- 2017
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15. miR-205: A Potential Biomedicine for Cancer Therapy
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Neeraj Chauhan, Anupam Dhasmana, Meena Jaggi, Subhash C. Chauhan, and Murali M. Yallapu
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miRNAs ,miR-205 ,cancer ,tumor suppressor ,nanoformulation ,targeted delivery ,Cytology ,QH573-671 - Abstract
microRNAs (miRNAs) are a class of small non-coding RNAs that regulate the expression of their target mRNAs post transcriptionally. miRNAs are known to regulate not just a gene but the whole gene network (signaling pathways). Accumulating evidence(s) suggests that miRNAs can work either as oncogenes or tumor suppressors, but some miRNAs have a dual nature since they can act as both. miRNA 205 (miR-205) is one such highly conserved miRNA that can act as both, oncomiRNA and tumor suppressor. However, most reports confirm its emerging role as a tumor suppressor in many cancers. This review focuses on the downregulated expression of miR-205 and discusses its dysregulation in breast, prostate, skin, liver, gliomas, pancreatic, colorectal and renal cancers. This review also confers its role in tumor initiation, progression, cell proliferation, epithelial to mesenchymal transition, and tumor metastasis. Restoration of miR-205 makes cells more sensitive to drug treatments and mitigates drug resistance. Additionally, the importance of miR-205 in chemosensitization and its utilization as potential biomedicine and nanotherapy is described. Together, this review research article sheds a light on its application as a diagnostic and therapeutic marker, and as a biomedicine in cancer.
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- 2020
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16. Novel Mechanistic Insight into the Anticancer Activity of Cucurbitacin D against Pancreatic Cancer (Cuc D Attenuates Pancreatic Cancer)
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Mohammed Sikander, Shabnam Malik, Sheema Khan, Sonam Kumari, Neeraj Chauhan, Parvez Khan, Fathi T. Halaweish, Bhavin Chauhan, Murali M. Yallapu, Meena Jaggi, and Subhash C. Chauhan
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pancreatic cancer ,cucurbitacin d ,mucin ,mir-145 and muc13 ,Cytology ,QH573-671 - Abstract
Pancreatic cancer (PanCa) is one of the leading causes of death from cancer in the United States. The current standard treatment for pancreatic cancer is gemcitabine, but its success is poor due to the emergence of drug resistance. Natural products have been widely investigated as potential candidates in cancer therapies, and cucurbitacin D (Cuc D) has shown excellent anticancer properties in various models. However, there is no report on the therapeutic effect of Cuc D in PanCa. In the present study, we investigated the effects of the Cuc D on PanCa cells in vitro and in vivo. Cuc D inhibited the viability of PanCa cells in a dose and time dependent manner, as evident by MTS assays. Furthermore, Cuc D treatment suppressed the colony formation, arrest cell cycle, and decreased the invasion and migration of PanCa cells. Notably, our findings suggest that mucin 13 (MUC13) is down-regulated upon Cuc D treatment, as demonstrated by Western blot and qPCR analyses. Furthermore, we report that the treatment with Cuc D restores miR-145 expression in PanCa cells/tissues. Cuc D treatment suppresses the proliferation of gemcitabine resistant PanCa cells and inhibits RRM1/2 expression. Treatment with Cuc D effectively inhibited the growth of xenograft tumors. Taken together, Cuc D could be utilized as a novel therapeutic agents for the treatment/sensitization of PanCa.
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- 2019
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17. Fungal KATs/KDACs: A New Highway to Better Antifungal Drugs?
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Karl Kuchler, Sabrina Jenull, Raju Shivarathri, and Neeraj Chauhan
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Immunologic diseases. Allergy ,RC581-607 ,Biology (General) ,QH301-705.5 - Published
- 2016
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18. The Candida albicans Histone Acetyltransferase Hat1 Regulates Stress Resistance and Virulence via Distinct Chromatin Assembly Pathways.
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Michael Tscherner, Florian Zwolanek, Sabrina Jenull, Fritz J Sedlazeck, Andriy Petryshyn, Ingrid E Frohner, John Mavrianos, Neeraj Chauhan, Arndt von Haeseler, and Karl Kuchler
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Immunologic diseases. Allergy ,RC581-607 ,Biology (General) ,QH301-705.5 - Abstract
Human fungal pathogens like Candida albicans respond to host immune surveillance by rapidly adapting their transcriptional programs. Chromatin assembly factors are involved in the regulation of stress genes by modulating the histone density at these loci. Here, we report a novel role for the chromatin assembly-associated histone acetyltransferase complex NuB4 in regulating oxidative stress resistance, antifungal drug tolerance and virulence in C. albicans. Strikingly, depletion of the NuB4 catalytic subunit, the histone acetyltransferase Hat1, markedly increases resistance to oxidative stress and tolerance to azole antifungals. Hydrogen peroxide resistance in cells lacking Hat1 results from higher induction rates of oxidative stress gene expression, accompanied by reduced histone density as well as subsequent increased RNA polymerase recruitment. Furthermore, hat1Δ/Δ cells, despite showing growth defects in vitro, display reduced susceptibility to reactive oxygen-mediated killing by innate immune cells. Thus, clearance from infected mice is delayed although cells lacking Hat1 are severely compromised in killing the host. Interestingly, increased oxidative stress resistance and azole tolerance are phenocopied by the loss of histone chaperone complexes CAF-1 and HIR, respectively, suggesting a central role for NuB4 in the delivery of histones destined for chromatin assembly via distinct pathways. Remarkably, the oxidative stress phenotype of hat1Δ/Δ cells is a species-specific trait only found in C. albicans and members of the CTG clade. The reduced azole susceptibility appears to be conserved in a wider range of fungi. Thus, our work demonstrates how highly conserved chromatin assembly pathways can acquire new functions in pathogenic fungi during coevolution with the host.
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- 2015
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19. A case for two-component signaling systems as antifungal drug targets.
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Erika Shor and Neeraj Chauhan
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Immunologic diseases. Allergy ,RC581-607 ,Biology (General) ,QH301-705.5 - Published
- 2015
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20. Indocyanine Green-based Glow Nanoparticles Probe for Cancer Imaging
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Neeraj Chauhan, Marco Cabrera, Pallabita Chowdhury, Prashanth K.B. Nagesh, Anupam Dhasmana, null Pranav, Meena Jaggi, Subhash C. Chauhan, and Murali M. Yallapu
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Biomedical Engineering ,Medicine (miscellaneous) ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,Biotechnology - Published
- 2023
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21. Current status of biopsy markers for the breast in clinical settings
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Elian A. Martin, Neeraj Chauhan, Vijian Dhevan, Elias George, Partha Laskar, Meena Jaggi, Subhash C. Chauhan, and Murali M. Yallapu
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Biomedical Engineering ,Surgery ,General Medicine - Abstract
A breast biopsy marker is a very small object that is introduced into the breast to serve as a tissue marker. The placement of a breast marker following a biopsy or to mark an abnormality in the breast has become standard practice in the clinical setting. Breast biopsy markers offer a wide range of benefits which includes the prevention of re-biopsy of a benign tumor, differentiating multiple lesions within the breast, evaluation of the extent of a tumor, and increased precision during surgery.This review article presents a range of breast biopsy markers used in clinical practice. First, an overview of the necessity of breast markers in healthy breast management. Second, it summarizes the diversity in composition, shape, unique properties and features, and bio-absorbable carriers of breast biopsy markers. Finally, it also discusses the possible use of clinically approved breast biopsy markers in various scenarios and their implications.This review serves as a guide in the selection of an appropriate breast marker. We believe that some of the common drawbacks associated with current breast biopsy markers can be overcome by developing novel polymer-metal and composite-based breast biopsy markers.
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- 2022
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22. Figure S3 from Ormeloxifene Suppresses Prostate Tumor Growth and Metastatic Phenotypes via Inhibition of Oncogenic β-catenin Signaling and EMT Progression
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Meena Jaggi, Subhash C. Chauhan, Murali M. Yallapu, Man M. Singh, Nadeem Zafar, Fathi T. Halaweish, Manish K. Tripathi, Andrew E. Massey, Shabnam Malik, Neeraj Chauhan, Zubair Bin Hafeez, Vivek K. Kashyap, Mohammed Sikander, Aditya Ganju, and Bilal Bin Hafeez
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Effect of ORM on cell cycle analysis and β-catenin localization. A. Histogram (i) and table (ii) represent the cell cycle distribution in DU145 cells. B. Confocal images of β-catenin, DAPI and merged images of control (i) and ORM treated (ii) PC3 cells.
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- 2023
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23. Supplementary Figure 1 from Novel Curcumin-Loaded Magnetic Nanoparticles for Pancreatic Cancer Treatment
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Subhash C. Chauhan, Meena Jaggi, Susan E. Puumala, Brij K. Gupta, Neeraj Chauhan, Vasudha Sundram, Sheema Khan, Mara C. Ebeling, and Murali M. Yallapu
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PDF file - 126K, MNP-CUR nanoparticles efficiently internalize in cancer cells.
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- 2023
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24. Data from Ormeloxifene Suppresses Prostate Tumor Growth and Metastatic Phenotypes via Inhibition of Oncogenic β-catenin Signaling and EMT Progression
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Meena Jaggi, Subhash C. Chauhan, Murali M. Yallapu, Man M. Singh, Nadeem Zafar, Fathi T. Halaweish, Manish K. Tripathi, Andrew E. Massey, Shabnam Malik, Neeraj Chauhan, Zubair Bin Hafeez, Vivek K. Kashyap, Mohammed Sikander, Aditya Ganju, and Bilal Bin Hafeez
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Ormeloxifene is a clinically approved selective estrogen receptor modulator, which has also shown excellent anticancer activity, thus it can be an ideal repurposing pharmacophore. Herein, we report therapeutic effects of ormeloxifene on prostate cancer and elucidate a novel molecular mechanism of its anticancer activity. Ormeloxifene treatment inhibited epithelial-to-mesenchymal transition (EMT) process as evident by repression of N-cadherin, Slug, Snail, vimentin, MMPs (MMP2 and MMP3), β-catenin/TCF-4 transcriptional activity, and induced the expression of pGSK3β. In molecular docking analysis, ormeloxifene showed proficient docking with β-catenin and GSK3β. In addition, ormeloxifene induced apoptosis, inhibited growth and metastatic potential of prostate cancer cells and arrested cell cycle in G0–G1 phase via modulation of cell-cycle regulatory proteins (inhibition of Mcl-1, cyclin D1, and CDK4 and induction of p21 and p27). In functional assays, ormeloxifene remarkably reduced tumorigenic, migratory, and invasive potential of prostate cancer cells. In addition, ormeloxifene treatment significantly (P < 0.01) regressed the prostate tumor growth in the xenograft mouse model while administered through intraperitoneal route (250 μg/mouse, three times a week). These molecular effects of ormeloxifene were also observed in excised tumor tissues as shown by immunohistochemistry analysis. Our results, for the first time, demonstrate repurposing potential of ormeloxifene as an anticancer drug for the treatment of advanced stage metastatic prostate cancer through a novel molecular mechanism involving β-catenin and EMT pathway. Mol Cancer Ther; 16(10); 2267–80. ©2017 AACR.
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- 2023
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25. A Review on Herbal Extracts in Dentistry: Current Scenario and Future Trends
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Dr. Shital Gandhalikar, Dr. Neeraj Chauhan, Dr. Abhishek Gupta, Dr. Junaid Kapadia, Dr. Manoj Jain, and Dr. Arshdeep Kaur
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Background: A global review on oral health by the World Health Organization (WHO) emphasized that despite great improvements in the oral health of populations in several countries, global problems still persist. Dental caries and periodontal disease have historically been considered the most important global oral health burdens. This is particularly so among underprivileged groups in both developing and developed countries. The application of natural products for the control of oral diseases is considered as an interesting alternative to synthetic antimicrobials due to their lower negative impact, and for the effort to overcome primary or secondary resistance to the drug during therapy. Objective: To review the current evidence on the antimicrobial efficacy of plant extracts on dental caries and plaque microorganisms. Materials and Methods: A literature search was made for 6 months in PubMed, PubMed Central, MEDLINE, LILACS/BBO, Cochrane database of systematic reviews, SCIENCE DIRECT, and Google scholar databases. The results from the relevant published literatures are discussed. Summary and Conclusion: The extracts of Azadirachta Indica, Ocimum sanctum, Murraya koenigii L., Acacia nilotica, Eucalyptus camaldulensis, Hibiscus sabdariffa, Mangifera indica, Psidium guajava, Rosa indica, and Aloe barbadensis The current evidence is on individual plant extracts against bacteria involved in either caries or periodontitis. The research assessing the antimicrobial efficacy of a combination of these plant extracts against dental caries and periodontal pathogens is the need of the hour, and such research will aid in the development of a novel, innovative method that can simultaneously inhibit two of the most common dental diseases of mankind, besides slowing the development of drug resistance.
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- 2022
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26. Study of Naturally Occurring Radioactive Material Present in Deep Soil of the Malwa Region of Punjab State of India Using Low Level Background Gamma-Ray Spectrometry
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Alok Srivastava, Vikash Chahar, Neeraj Chauhan, Dominik Krupp, and Ulrich W. Scherer
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Radiation ,Health, Toxicology and Mutagenesis ,Public Health, Environmental and Occupational Health ,Radiology, Nuclear Medicine and imaging - Abstract
Background: Epidemiological observations such as mental retardation, physical deformities, etc., in children besides different types of cancer in the adult population of the Malwa region have been reported. The present study is designed to get insight into the role of naturally occurring radioactive material (NORM) in causing detrimental health effects observed in the general population of this region.Materials and Methods: Deep soil samples were collected from different locations in the Malwa region. Their activity concentrations were determined using low-level background gammaray spectrometry. High efficiency and high purity germanium detector capped in a lead-shielded chamber having a resolution of 1.8 keV at 1,173 keV and 2.0 keV at the 1,332 keV line of 60Co was used in the present work. Data were evaluated with Genie-2000 software.Results and Discussion: Mean activity concentrations of 238U, 232Th, and 40K in deep soil were found to be 101.3 Bq/kg, 65.8 Bq/kg, and 688.6 Bq/kg, respectively. The mean activity concentration of 238U was found to be three and half times higher than the global average prescribed by the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR). It was further observed that the activity concentration of 232Th and 40K has a magnitude that is nearly one and half times higher than the global average prescribed by UNSCEAR. In addition, the radioisotope 137Cs which is likely to have its origin in radiation fallout was also observed. It is postulated that the NORM present in high quantity in deep soil somehow get mobilized into the water aquifers used by the general population and thereby causing harmful health problems.Conclusion: It can be stated that the present work has been able to demonstrate the use of low background gamma-ray spectrometry to understand the role of NORM in causing health-related effects in a general population of the Malwa region of Punjab, India.
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- 2022
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27. In Situ Nanoparticle Self-Assembly for Combination Delivery of Therapeutics to Non-Small Cell Lung Cancer
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Elham Hatami, Prashanth K. B. Nagesh, Neeraj Chauhan, Meena Jaggi, Subhash C. Chauhan, and Murali M. Yallapu
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Biomaterials ,Biochemistry (medical) ,Biomedical Engineering ,General Chemistry - Published
- 2022
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28. Supplementary Figure S4 from Ormeloxifene Suppresses Desmoplasia and Enhances Sensitivity of Gemcitabine in Pancreatic Cancer
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Subhash C. Chauhan, Meena Jaggi, Man Mohan Singh, Nadeem Zafar, Haotian Zhao, Stephen W. Behrman, Murali M. Yallapu, Aditya Ganju, Rishi K. Gara, Paul A. Thompson, Neeraj Chauhan, Mara C. Ebeling, and Sheema Khan
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Supplementary Figure S4. Schematic representation of the treatment regime of xenograft mice.
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- 2023
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29. Data from Ormeloxifene Suppresses Desmoplasia and Enhances Sensitivity of Gemcitabine in Pancreatic Cancer
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Subhash C. Chauhan, Meena Jaggi, Man Mohan Singh, Nadeem Zafar, Haotian Zhao, Stephen W. Behrman, Murali M. Yallapu, Aditya Ganju, Rishi K. Gara, Paul A. Thompson, Neeraj Chauhan, Mara C. Ebeling, and Sheema Khan
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The management of pancreatic ductal adenocarcinoma (PDAC) is extremely poor due to lack of an efficient therapy and development of chemoresistance to the current standard therapy, gemcitabine. Recent studies implicate the intimate reciprocal interactions between epithelia and underlying stroma due to paracrine Sonic hedgehog (SHH) signaling in producing desmoplasia and chemoresistance in PDAC. Herein, we report for the first time that a nonsteroidal drug, ormeloxifene, has potent anticancer properties and depletes tumor-associated stromal tissue by inhibiting the SHH signaling pathway in PDAC. We found that ormeloxifene inhibited cell proliferation and induced death in PDAC cells, which provoked us to investigate the combinatorial effects of ormeloxifene with gemcitabine at the molecular level. Ormeloxifene caused potent inhibition of the SHH signaling pathway via downregulation of SHH and its related important downstream targets such as Gli-1, SMO, PTCH1/2, NF-κB, p-AKT, and cyclin D1. Ormeloxifene potentiated the antitumorigenic effect of gemcitabine by 75% in PDAC xenograft mice. Furthermore, ormeloxifene depleted tumor-associated stroma in xenograft tumor tissues by inhibiting the SHH cellular signaling pathway and mouse/human collagen I expression. Xenograft tumors treated with ormeloxifene in combination with gemcitabine restored the tumor-suppressor miR-132 and inhibited stromal cell infiltration into the tumor tissues. In addition, invasiveness of tumor cells cocultivated with TGFβ-stimulated human pancreatic stromal cells was effectively inhibited by ormeloxifene treatment alone or in combination with gemcitabine. We propose that ormeloxifene has high therapeutic index and in a combination therapy with gemcitabine, it possesses great promise as a treatment of choice for PDAC/pancreatic cancer. Cancer Res; 75(11); 2292–304. ©2015 AACR.
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- 2023
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30. Supplementary Figure Legends from Ormeloxifene Suppresses Desmoplasia and Enhances Sensitivity of Gemcitabine in Pancreatic Cancer
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Subhash C. Chauhan, Meena Jaggi, Man Mohan Singh, Nadeem Zafar, Haotian Zhao, Stephen W. Behrman, Murali M. Yallapu, Aditya Ganju, Rishi K. Gara, Paul A. Thompson, Neeraj Chauhan, Mara C. Ebeling, and Sheema Khan
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Legends for Supplementary Figures S1-S4.
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- 2023
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31. P021 Comparative transcriptomic analysis of environmental Candida auris showing variable azole susceptibility
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Kusum Jain, Raju Shivarathri, Ashutosh Singh, Neeraj Chauhan, and Anuradha Chowdhary
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Infectious Diseases ,General Medicine - Abstract
Poster session 1, September 21, 2022, 12:30 PM - 1:30 PM Objective Candida auris is a multidrug-resistant pathogen that presents a serious global threat to human health. The U.S. Centers for Disease Control and Prevention has classified C. auris as an urgent threat to public health due to its clinical and economic impact and future projections of new infections over the next 10 years. Candida auris infections are difficult to treat since many isolates display high levels of resistance to fluconazole and exhibit variable resistance to amphotericin B and echinocandins. In this study, we performed comparative transcriptomics to understand the molecular mechanisms associated with azole-resistance in C. auris environmental isolates. Material and Methods Two sets of environmental isolates including azole-resistant (n = 2) and azole susceptible (n = 1) isolates were used for RNA-Seq analysis. Pair-wise comparisons in edgeR were used for comparing the number of differentially expressed genes (DEGs) between the azole susceptible and resistant isolates. GO term enrichment analysis was performed using the ‘enrichGO’ function from the cluster Profiler package. Only GO categories with a q-value Results Our data show significant enrichment of ergosterol biosynthesis genes, drug transport, MAPK pathway as well as chromatin remodeling genes in azole-resistant strains compared to susceptible isolates. A total of 468 and 564 differentially expressed genes were identified in two azole-resistant isolates compared with the susceptible strain. A large number of multidrug transporter genes (CDR1, MDR1, HGT2, HGT7, HGT13, HGT17, and NGT1) were differentially expressed between the two sets of strains. Interestingly, the overexpression of ERG11 (azole target gene), and CDR1 (drug transporter) genes was observed in resistant isolates as compared with susceptible strain. Furthermore, resistant strain has two copies of ERG11 while susceptible isolate has single copy of ERG11. Notably, 8/21 genes involved in the ergosterol biosynthesis pathway were found to be induced in azole resistant isolates. These include HMG1, ERG1, ERG2, ERG3, ERG6, ERG10, ERG13, and ERG25. Furthermore, other multidrug transporters MDR1 and SNQ2 responsible for azole resistance in other Candida species like C. glabrata also showed significant expression changes between the two sets of isolates. Furthermore, HGT7 (glucose transporter) and NGT1, (N-acetyl glucosamine transporter) genes associated with azole and polyene resistance were found to be upregulated in the resistant isolate as compared with susceptible strain. Additionally, a Glycophosphatidylinositol (GPI)-anchored protein unique for C. auris, PGA7 was found to be overexpressed in resistant isolate. Importantly, we also identified several secreted aspartic proteases (SAP3, SAP5, SAP8, and SAP9) to be downregulated between the two sets. Conclusion The present study identifies several gene families that are differentially expressed in azole resistant vs susceptible C. auris strains. These findings suggest that azole-resistance in C. auris environmental isolates is influenced by changes in cell wall, lipid, and ergosterol biosynthesis. Overall, these data provide a framework for the mechanistic understanding of azole resistance mechanisms in C. auris environmental isolates.
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- 2022
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32. P008 Molecular mechanisms associated with fluconazole resistance and genetic diversity in clinical Candida krusei isolates from North India
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Kusum Jain, Raju Shivarathri, Gulnaz Bashir, Neeraj Chauhan, and Anuradha Chowdhary
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Infectious Diseases ,General Medicine - Abstract
Poster session 1, September 21, 2022, 12:30 PM - 1:30 PM Objectives Candida krusei accounts for 2.8% of invasive candidiasis worldwide. Fluconazole resistance and its underlying mechanism in clinical isolates of C. krusei (n = 137) collected from eight hospitals in India were investigated. Also, genetic diversity of C. krusei strains among different hospitals was studied through short tandem repeat (STR) genotyping. Material and Method All the isolates were identified by MALDI-TOF MS. Antifungal susceptibility test was done by using broth microdilution method (CLSI-M27). To evaluate the genetic relatedness among the strains, STR typing was done by using 9 STR markers. To understand the fluconazole-resistant mechanisms in C. krusei, known fluconazole resistance mechanisms such as alterations in target enzyme ERG11 and drug transporters ABC1, and ABC2 were investigated in 35 C. krusei isolates [18 fluconazole-susceptible (FLU-S), and 17 fluconazole-susceptible dose-dependent (FLU-SDD)]. Furthermore, transcriptomics of one FLU-SDD (MIC 32 mg/L) and one FLU-S (MIC 4 mg/l) isolate was performed. Results Majority (77%) of C. krusei isolates were from bloodstream infections. Notably, 70% of candidemia cases occurred in neonatal intensive care units (NICUs). Remarkably, 81% (n = 110) were detected as fluconazole-SDD (MIC 16-32 mg/l), and the remaining 19% were FLU-S (MIC ≤ 8 mg/l). Marked genetic diversity with 51 diverse STR types was noticed among the 106 isolates. Interestingly, two ongoing candidemia outbreaks were observed in two geographically separated hospitals both representing NICU isolates. In addition, a large cluster containing isolates from six different hospitals was observed. ERG11 mutation analysis revealed that it did not harbor any mutation contributing to the flu-resistance. Overexpression of the ABC1 gene in 11 FLU-SDD isolates out of 17 as compared to FLU-S isolates was noted. However, no alteration was observed in the expression of ERG11 and ABC2 in both groups. Transcriptomics analysis revealed a significant number of differentially regulated genes were distributed in various gene-ontology terms including transport (10 genes), mitogen-activated protein kinase (MAPK) signaling (8 genes, MSG5, PTP3, STE50, BNR1, OPY2, STE5, SKN7, and RLM1), ergosterol biosynthesis (3 genes, ERG24, ERG25, and ERG26) and transcription factors (7 genes). In addition to the up-regulation of ergosterol pathway genes, overexpression of key transcriptional regulator of ergosterol biosynthesis genes UPC2 was observed in FLU-SDD isolates as compared with susceptible. Additionally, FLU-SDD isolate showed 2-fold increased expression of PDR12, plasma membrane ATP-binding cassette (ABC) transporter. Next, ICL1 (Isocitrate Lyase), a major glyoxylate-synthesizing enzyme was found to be 5-fold down-regulated in FLU SDD isolate compared to susceptible. The loss of ICL1 alters the expression of the FKS1, ERG11, and CDR2 genes in C. albicans. Taken together, the increased expression of PDR12 and altered MAPK singling network may partially account for the FLU resistance in C. krusei FLU-SDD isolate. Conclusion Candida krusei isolates among different hospitals showed large genetic diversity (54 different genotypes). Also, the presence of C. krusei clonal strains in six different hospitals suggests possible introduction from a widespread environmental source and human-to-human transmission. In comparison to other Candida species, the resistant mechanism in C. krusei seems to be more complex. Therefore, an in-depth study of other resistance mechanism pathways in C. krusei is further warranted.
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- 2022
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33. A Proteomic Approach for the Quantification of Posttranslational Protein Lysine Acetylation in Candida albicans
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Raju, Shivarathri, Manju, Chauhan, Rounik, Mazumdar, Phan Canh, Trinh, Wolfgang, Reiter, Markus, Hartl, Karl, Kuchler, and Neeraj, Chauhan
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Histones ,Proteomics ,Lysine ,Candida albicans ,Humans ,Acetylation ,Protein Processing, Post-Translational - Abstract
Candida albicans is a normal component of the human microflora that colonizes mucosal/epithelial surfaces and the gastrointestinal tract as a commensal organism. However, in an immunocompromised host, it can cause life-threatening infections of high mortality and morbidity. Virulence as well as antifungal drug resistance of C. albicans is often regulated by posttranslational modifications (PTM) of proteins via lysine acetylation by lysine acetyltransferases. Here, we report an experimental approach using tandem mass tag (TMT) labeling for the detection and quantification of lysine acetylation of histone and nonhistone proteins in C. albicans.
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- 2022
34. Abstract 823: Piperlongumine nanoformulation enhances gemcitabine therapeutic response in pancreatic cancer
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Vivek Kumar Kashyap, Neeraj Chauhan, Mohammed Sikander, FNU Pranav, Rahul Tiwari, Bilal B. Hafeez, Murali M. Yallapu, Meena Jaggi, and Subhash C. Chauhan
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Cancer Research ,Oncology - Abstract
Pancreatic cancer (PanCa) is characterized by lack of early diagnosis, poor response to available therapeutic modalities and chemoresistance. Gemcitabine (GEM) is currently considered most effective therapy for PanCa; however, it shows only a marginal survival benefit of 6 months. This poor drug response has been attributed to desmoplasia, causes suboptimal drug delivery, alters tumor microenvironment (TME), which includes tumor surrounding blood vessels, fibroblasts, immune cells, extracellular matrix, and other signaling molecules and induces chemo-resistance in tumors. To overcome these existing issues associated with chemotherapy, identification and development of novel therapeutic modalities are a pressing need. Piperlongumine (PL) is a natural alkaloid isolated from the long pepper, Piper longum L., and has shown substantial cancer-preventive and therapeutic efficacy against a variety of cancers. However, delivering its effective concentration in pancreatic tumors has been challenging. We have recently engineered a multi-layered Pluronic F127 and polyvinyl alcohol stabilized and poly-L-lysine coated piperlongumine loaded poly(lactic-co-glycolic acid) nanoparticle formulation (PLGA-PL), which effectively inhibits the growth of PanCa cells. In this study, we demonstrate that PLGA-PL effectively sensitize tumor cells to GEM via decreased desmoplasia, altered TME, SHH/CXCL12/CXCR4 and immune surveillance. Our finding show that PLGA-PL synergizes with GEM in inhibiting PanCa cell (HPAF-II and Panc-1) growth, migration, and invasion compared to free PL. Mechanistically, PLGA-PL targets the TME via inhibition of sonic hedgehog (SHH) pathway and oncogenic CXCR4/CXCL12 signaling axis that inhibits bidirectional tumor-stromal cells interaction. We have also found that PLGA-PL alone and in combination with GEM targets cancer stem cells by inhibiting pluripotency maintaining stemness factors (Nanog, Sox2, c-Myc, CD133, and Oct-4) as determined by qRT-PCR, Western blotting, and immunofluorescence analysis, and further confirmed by restricting tumor sphere formation. Furthermore, PLGA-PL also effectively targets tumor-associated macrophages (TAM) by repolarizing M2 into M1 phenotype via inhibiting expression of M2 markers and an increase in M1 markers in mouse macrophage cell line RAW264.7. M2 polarization of RAW264.7 cells were induced by culture with IL-4 (20 ng/mL) in presence of PLGA-PL or vehicle control. In additions, PLGA-PL effectively increases phagocytic capacity in murine macrophages as determined by phagocytosis assay (Vybrant Phagocytosis Assay Kit). In conclusion, we observed that PLGA-PL effectively targets TME, facilitates GEM uptake by inhibiting the activation of CXCR4/CXCL12/SHH signaling, and reprograming the tumor immune surveillance. This study suggests that PLGA-PL has great potential for future clinical use in management of PanCa. Citation Format: Vivek Kumar Kashyap, Neeraj Chauhan, Mohammed Sikander, FNU Pranav, Rahul Tiwari, Bilal B. Hafeez, Murali M. Yallapu, Meena Jaggi, Subhash C. Chauhan. Piperlongumine nanoformulation enhances gemcitabine therapeutic response in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 823.
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- 2023
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35. Abstract 826: Illuminating cancer cells with a novel nano fluorescent NIR probe for bioimaging
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Neeraj Chauhan, Marco Cabrera, Pallabita Chowdhury, Prashanth K. Nagesh, Anupam Dhasmana, Meena Jaggi, Subhash C. Chauhan, and Murali M. Yallapu
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Cancer Research ,Oncology - Abstract
Background: Adequate bioimaging is crucial in cancer management in many ways including screening, detection, characterization, staging and grading, therapy response, surgical guidance, and margins assessment. Indocyanine green (ICG) is one of the FDA-approved near infra-red fluorescent (NIRF) probe for cancer imaging and image-guided surgery in clinical setting. However, limitations of ICG includes poor photostability, high concentration toxicity, short circulation time, and poor cancer cell specificity. To overcome these hurdles, we engineered a nanoconstruct composed of poly(vinyl pyrrolidone) (PVP)-indocyanine green that is cloaked self-assembled with tannic acid (termed as ICG-Glow NPs) for the cancer cells/tissues specific targeting. Methods: Pursuing the novel nanotherapy approach, our lab has developed PVP-TA based ICG (PVT-ICG) fluorescent nanoparticles via self-assembly process. Our optimized PVT-ICG nanoformulation was further characterized for its physicochemical properties. An IVIS imaging system was further used to measure NIR fluorescence of novel PVT-ICG. Moreover, Human cancer (Breast, Pancreatic, Liver and Prostate) tissue microarrays (TMAs) were histochemically stained to assess cancer cell targeting/specificity of PVT-ICG. Results: PVT-ICG indicated particle size and surface charge ideal for cancer cell/tissue delivery. PVT-ICG, further, demonstrated improved photostability and fluorescent intensity. Additionally, TMA studies exhibited enhanced internalization and cancer targeting/specificity of PVT-ICG nanoparticles compared to free ICG dye in all cancers. Conclusion: Collectively, our findings suggest that this NIR fluorescent probe PVT-ICG has great potential for becoming a novel and safe imaging modality for various types of cancer cells and tumors which can result in early cancer diagnosis leading to improved disease management. Citation Format: Neeraj Chauhan, Marco Cabrera, Pallabita Chowdhury, Prashanth K. Nagesh, Anupam Dhasmana, Meena Jaggi, Subhash C. Chauhan, Murali M. Yallapu. Illuminating cancer cells with a novel nano fluorescent NIR probe for bioimaging [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 826.
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- 2023
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36. Comparative Transcriptomics Reveal Possible Mechanisms of Amphotericin B Resistance in Candida auris
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Raju Shivarathri, Sabrina Jenull, Manju Chauhan, Ashutosh Singh, Rounik Mazumdar, Anuradha Chowdhary, Karl Kuchler, and Neeraj Chauhan
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Pharmacology ,Antifungal Agents ,Candidiasis ,Microbial Sensitivity Tests ,Candida auris ,Lipids ,Infectious Diseases ,Mechanisms of Resistance ,Drug Resistance, Fungal ,Amphotericin B ,Humans ,Pharmacology (medical) ,Transcriptome ,Candida - Abstract
Candida auris is an emerging multidrug-resistant human fungal pathogen often refractory to treatment by all classes of antifungal drugs. Amphotericin B (AmB) is a fungicidal drug that, despite its toxic side effects, remains a drug of choice for the treatment of drug-resistant fungal infections, including those caused by C. auris. However, the molecular mechanisms underlying AmB resistance are poorly understood. In this study, we present data that suggests membrane lipid alterations and chromatin modifications are critical processes that may contribute to or cause adaptive AmB resistance in clinical C. auris isolates. To determine the plausible cause of increased AmB resistance, we performed RNA-seq of AmB-resistant and sensitive C. auris isolates. Remarkably, AmB-resistant strains show a pronounced enrichment of genes involved in lipid and ergosterol biosynthesis, adhesion, drug transport as well as chromatin remodeling. The transcriptomics data confirm increased adhesion and reduced lipid membrane permeability of AmB-resistant strains compared to the sensitive isolates. The AmB-resistant strains also display hyper-resistance to cell wall perturbing agents, including Congo red, calcofluor white and caffeine. Additionally, we noticed an increased phosphorylation of Mkc1 cell integrity MAP kinase upon AmB treatment. Collectively, these data identify differences in the transcriptional landscapes of AmB-resistant versus AmB-sensitive isolates and provide a framework for the mechanistic understanding of AmB resistance in C. auris.
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- 2022
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37. COVID-19: fighting the invisible enemy with microRNAs
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Subhash C. Chauhan, Neeraj Chauhan, Meena Jaggi, and Murali M. Yallapu
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0301 basic medicine ,Microbiology (medical) ,2019-20 coronavirus outbreak ,Coronavirus disease 2019 (COVID-19) ,viruses ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,030106 microbiology ,Genome, Viral ,Disease ,medicine.disease_cause ,Microbiology ,Viral infection ,Article ,Betacoronavirus ,03 medical and health sciences ,0302 clinical medicine ,Virology ,microRNA ,Humans ,Medicine ,030212 general & internal medicine ,Coronavirus ,SARS-CoV-2 ,business.industry ,COVID-19 ,virus diseases ,MicroRNAs ,Nanomedicine ,Infectious Diseases ,business - Abstract
INTRODUCTION: The novel coronavirus (CoV) disease 2019 (COVID-19) is a viral infection that causes Severe Acute Respiratory Syndrome. It is believed that early reports of COVID-19 cases were noticed in December 2019 and soon after became a global public health emergency. It is advised that COVID-19 transmits through human to human contact and in most cases it remains asymptomatic. Several approaches are being utilized to control the outbreak of this fatal viral disease. microRNAs (miRNAs) are known signature therapeutic tool for the viral diseases; they are small non-coding RNAs that target the mRNAs to inhibit their post-transcriptional expression, therefore, impeding their functions, thus can serve as watchdogs or micromanagers in the cells. AREAS COVERED: This review work delineated COVID-19 and its association with SARS-CoV and MERS-CoV, the possible role of miRNAs in the pathogenesis of COVID-19, and therapeutic potential of microRNAs and their effective delivery to treat COVID 19. EXPERT OPINION: This review highlighted the importance of various miRNAs and their potential role in fighting with this pandemic as therapeutic molecules utilizing nanotechnology.
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- 2020
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38. Pluronic Polymer-Based Ormeloxifene Nanoformulations Induce Superior Anticancer Effects in Pancreatic Cancer Cells
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Hilary Newby, Subhash C. Chauhan, Amber Kruse, Meena Jaggi, Murali M. Yallapu, and Neeraj Chauhan
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0303 health sciences ,Biocompatible polymers ,Cell growth ,business.industry ,General Chemical Engineering ,Cancer ,General Chemistry ,Poloxamer ,Pharmacology ,medicine.disease ,Article ,3. Good health ,Chemistry ,03 medical and health sciences ,0302 clinical medicine ,Selective estrogen receptor modulator ,030220 oncology & carcinogenesis ,Pancreatic cancer ,medicine ,Cytotoxicity ,business ,Ormeloxifene ,QD1-999 ,030304 developmental biology ,medicine.drug - Abstract
Utilization of safe cytotoxic agents with precise anticancer activity is considered as the prime focus of cancer therapeutics research. A greater incentive for such agents arises from the molecules/drugs that are already being used for other indications. Ormeloxifene (ORM) is a nonsteroidal, nonhormonal selective estrogen receptor modulator (SERM), which has been in human use for contraception purposes. Although in the recent past, many reports have suggested its emerging role as an anticancer agent, no significant attention was paid toward generating simple and safe nanoformulation(s) for improved therapeutic activity and tumor cell-specific delivery. Our aim is to develop nanoformulation(s) of ormeloxifene to improve its targeted delivery in tumor cells. We developed ormeloxifene nanoformulation(s) by utilizing various biocompatible polymers. The optimized formulations with pluronic polymers F127 and F68 show improved nanoparticle characteristics. These formulations show enhanced cellular uptake that allows ormeloxifene's intracellular availability. We further evaluated its improved anticancer activity by performing cell proliferation, flow cytometry, and immunoblotting assays. Overall, this study confirms possible novel nanoformulation(s) of ormeloxifene to be evolved as a new therapeutic modality for cancer treatment.
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- 2020
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39. Therapeutic Effects of Ormeloxifene in Cervical Cancer Carcinogenesis
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Neeraj Chauhan
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Cervical cancer ,Oncology ,medicine.medical_specialty ,business.industry ,Internal medicine ,Therapeutic effect ,Medicine ,business ,medicine.disease ,Carcinogenesis ,medicine.disease_cause ,Ormeloxifene ,medicine.drug - Abstract
Cervical cancer (CxCa) remains the fourth leading cause of cancer related deaths among women worldwide. Cervical cancer is mainly (~ 99.7%) derived from high risk Human papillomavirus (HR HPV). HPV E6/E7 are the two main oncoproteins that interfere with p53 and pRb (retinoblastoma) cell cycle regulatory proteins and hinder their efficacy of controlling cell growth. Additionally, PI3K-Akt is a cell survival pathway that is aberrantly expressed in cervical cancer cells. This pathway has a profound role in inhibiting mitochondrial intrinsic apoptotic signaling pathway. Advanced stage cervical cancer is difficult to treat and patients diagnosed with metastatic disease have a poor survival rate. Therefore, there is an urgent need to develop newer treatment modalities. Ormeloxifene (ORM) is a non-hormonal, anti-estrogen, oral contraceptive for human use. Growing evidences also suggest that ormeloxifene has anti-cancerous properties in a variety of cancers. Developing nanoformulation of drugs has received much attention lately as nanoparticles have site specific targeted drug delivery. Nanoparticles have a specific size range that makes them capable of being entrapped and accumulated at the tumor site due to its leaky vasculature. As a result of it, drug is released from the particle core at a sustained rate; therefore, nanoparticulates offer enhanced bioavailability and better therapeutic efficacy. Considering these benefits, we engineered ormeloxifene loaded PLGA based novel nanoformulation (PLGA-ORM). In this work we validated anti-cancer properties of free ORM and its PLGA based nanoformulation. Our set of data showed that ormeloxifene significantly decreased the cellular proliferation and clonogenic potential of cervical cancer cells. Ormeloxifene also reduced the cellular motility and induced the apoptosis via targeting PI3K-Akt signaling in these cells. Furthermore, ormeloxifene modulated the HPV induced oncogenesis in Caski cells. Ormeloxifene also showed additive inhibitory effects on cellular proliferation and growth when used with radiation. Moreover, our novel PLGA-ORM had a particle size range of 100 – 280 nm and also exhibited excellent encapsulation of ormeloxifene in to PLGA core. PLGA-ORM was labeled with Coumarin 6 (green fluorescent) dye for its uptake studies, where PLGA-ORM internalized in cervical cancer cells in dose, time and energy dependent manner via endocytosis pathway. PLGA-ORM showed improved anti-proliferative/growth properties than free ormeloxifene in cervical cancer cells. When utilized in animals (an orthotopic mouse model) both ormeloxifene and PLGA-ORM showed great anti-tumorous properties, however PLGA-ORM had improved inhibitory effects on tumor growth than free ormeloxifene. To conclude, ormeloxifene and its nanoformulation have the potential to be a novel treatment modality for cervical cancer which can reduce the overall disease burden and improve patients’ life expectancy.
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- 2022
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40. A Proteomic Approach for the Quantification of Posttranslational Protein Lysine Acetylation in Candida albicans
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Raju Shivarathri, Manju Chauhan, Rounik Mazumdar, Phan Canh Trinh, Wolfgang Reiter, Markus Hartl, Karl Kuchler, and Neeraj Chauhan
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- 2022
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41. Soft Computing Applications in Solving Real Life Problems
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Lalan Kumar, Sandeep Srivastava, Roopali Gupta, Ankur Sharma, and Neeraj Chauhan
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History ,Polymers and Plastics ,Business and International Management ,Industrial and Manufacturing Engineering - Published
- 2022
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42. Complex sphingolipids: Vital determinants of drug susceptibility, membrane integrity and pathogenesis of Candida glabrata
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Garima Shahi, Mohit Kumar, Nitesh Kumar Khandelwal, Parijat Sarkar, Sonam Kumari, Neeraj Chauhan, Amitabha Chattopadhyay, Naseem A. Gaur, and Rajendra Prasad
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General Materials Science - Abstract
Complex Sphingolipids (SLs) are unique to fungi, which apart from being novel drug targets, also appear to act as molecular signals, in diverse biological processes. In this study, we have specifically blocked the key synthesis step of SLs metabolism by disruption of the uncharacterized CgIPT1 gene, which based on homology with other Candida spp., predicted to mediate the conversion of MIPC to M(IP)2C. We followed fusion based PCR homologous recombination method for IPT1 deletion by using dominant markerNAT1. The knockout was selected on a nourseothricin drug plate and confirmed by gene specific PCR and by checking M(IP)2C levels. We observed that the specific accumulation of MIPC or lack of M(IP)2C in C. glabrata displayed increased susceptibility to both imidazole’s (ketoconazole, miconazole and clotrimazole) and triazoles (fluconazole, itraconazole and posaconazole). RNA Sequencing of Cgipt1Δcells revealed no major impact on of expression levels of common MDR determinants albeit a distinct imbalances in expression of lipid homeostasis genes was evident. The Fluorescence Recovery after Photobleaching (FRAP) experiments confirmed that plasma membrane in Cgipt1Δ cells display a reduction in micro-viscosity leading to increase in drug diffusion and susceptibility of Cgipt1Δcells. Interestingly, the Cgipt1Δ also exhibit attenuated virulence in a murine model. Together, our data confirms the relevance of M(IP)2C in governing drug susceptibility and virulence in C. glabrata.
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- 2021
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43. Identification of genome-wide alternative splicing events in sequential, isogenic clinical isolates of Candida albicans reveals a mechanism important for drug resistance and tolerance to cellular stress
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Suraya Muzafar, Neeraj Chauhan, Ravi Datta Sharma, and Rajendra Prasad
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General Materials Science - Abstract
Alternative gene splicing (AS) is a process by which a single gene can give rise to different protein isoforms, generating proteome diversity. Despite recent advances in our understanding of AS in basic cellular processes, the role of AS in drug resistance and fungal pathogenesis is poorly understood. In Candida albicans, approximately 6% of the genes contain introns. Considering this low and random distribution of introns, we focused our study on alternative splicing (AS) and its impact on the development of drug resistance, an area largely unexplored in this yeast. We performed comparative RNA sequencing of sequential isogenic azole sensitive and resistant isolates of C. albicans. The analysis revealed differential expression of splice junctions/isoforms in 14 genes, between the drug sensitive and resistant isolates. Furthermore, C. albicans WT cells exposed to antifungal drugs, heat stress or metal deficiency also showed differential expression of isoforms for the genes undergoing AS. In this study we present data on the effect of AS on the function of SOD3. The C. albicans SOD3 has a single intron and is important for the removal of superoxide radicals. The overexpression of the two isoforms of SOD3 in its null background highlighted importance of spliced isoform in complementing the susceptibility to menadione. However, the two isoforms did not differ in rescuing the susceptibility of sod3Δ/Δto Amphotericin B. Collectively, these data suggest that AS may be a novel mechanism in C. albicans for stress adaptation and overcoming drug resistance.
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- 2021
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44. Intron distribution and emerging role of alternative splicing in fungi
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Suraya Muzafar, Ravi Datta Sharma, Neeraj Chauhan, and Rajendra Prasad
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Future studies ,Alternative splicing ,Intron ,Fungi ,Computational biology ,Biology ,Microbiology ,Genome ,Protein subcellular localization prediction ,Introns ,Alternative Splicing ,Proteome ,RNA splicing ,Genetics ,RNA Precursors ,Spliceosomes ,Minireview ,Molecular Biology ,Gene - Abstract
Spliceosomal introns are noncoding sequences that are spliced from pre-mRNA. They are ubiquitous in eukaryotic genomes, although the average number of introns per gene varies considerably between different eukaryotic species. Fungi are diverse in terms of intron numbers ranging from 4% to 99% genes with introns. Alternative splicing is one of the most common modes of posttranscriptional regulation in eukaryotes, giving rise to multiple transcripts from a single pre-mRNA and is widespread in metazoans and drives extensive proteome diversity. Earlier, alternative splicing was considered to be rare in fungi, but recently, increasing numbers of studies have revealed that alternative splicing is also widespread in fungi and has been implicated in the regulation of fungal growth and development, protein localization and the improvement of survivability, likely underlying their unique capacity to adapt to changing environmental conditions. However, the role of alternative splicing in pathogenicity and development of drug resistance is only recently gaining attention. In this review, we describe the intronic landscape in fungi. We also present in detail the newly discovered functions of alternative splicing in various cellular processes and outline areas particularly in pathogenesis and clinical drug resistance for future studies that could lead to the development of much needed new therapeutics.
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- 2021
45. Abstract B035: Targeting ribosome biogenesis addition is a novel strategy for pancreatic cancer therapy
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Mudassier Ahmad, Carlos Perez, Andrew Massey, Vivek Kashyap, Neeraj Chauhan, Haider Ahsan, Jasmine Jasmine, Manish Tripathi, Subhash Chauhan, and Bilal Hafeez
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Cancer Research ,Oncology - Abstract
Pancreatic cancer (PanCa) is the third leading cause of cancer-related deaths in the United States with limited therapeutic options available. Gemcitabine (GEM), a deoxycytidine nucleoside analog is currently considered the most effective therapy for PanCa; however, it shows only a marginal survival benefit of 6 months. PanCa cells are addicted to ribosome biogenesis (RiBi) which supports their high rate of growth and proliferation. Therefore, strategically targeting the process of RiBi could be one of the ideal strategies for the prevention and treatment of PanCa. In this study, we for the first-time report that RPA194, a catalytic subunit of RNA Pol I is differentially expressed in normal pancreatic ductal epithelial (NPDE) and cancer cells. We also observed differential expression of RPA194 in various grades of pancreatic tumor tissues and its level was increased in high-grade pancreatic tumor tissues. We tested our hypothesis that targeting RPA194 with a non-toxic pharmacological inhibitor (BMH-21) will inhibit the growth of advanced PanCa. We observed that BMH-21 inhibits the growth and induced apoptosis of PanCa cells in a dose-dependent manner and this inhibition was correlated with the expression of RPA194. We observed proteasomal mediated degradation of RPA194 in PanCa cells. BMH-21 treatment inhibited RPA194 occupancy on rDNA but did not affect other nucleolar proteins (UBF, fibrillarin, nucleolin, and nucleophosmin). Two times the effective concentration of BMH-21 (5 µM) did not show any cytotoxic effect in NPDE cells. However, BMH-21 degraded RPA 194 protein in these cells in a similar manner as in PanCa cells. Therefore, we speculate that other proteins are involved in the selective toxicity of BMH-21 in PanCa cells. These findings were translated to in vivo model systems. We observed that BMH-21 significantly (P Citation Format: Mudassier Ahmad, Carlos Perez, Andrew Massey, Vivek Kashyap, Neeraj Chauhan, Haider Ahsan, Jasmine Jasmine, Manish Tripathi, Subhash Chauhan, Bilal Hafeez. Targeting ribosome biogenesis addition is a novel strategy for pancreatic cancer therapy [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B035.
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- 2022
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46. microRNA-205 in prostate cancer: Overview to clinical translation
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Neeraj, Chauhan, Anjali, Manojkumar, Meena, Jaggi, Subhash C, Chauhan, and Murali M, Yallapu
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Male ,MicroRNAs ,Cancer Research ,Oncology ,Genetics ,Humans ,Prostatic Neoplasms ,Apoptosis - Abstract
Prostate cancer (PrCa) is the most common type of cancer among men in the United States. The metastatic and advanced PrCa develops drug resistance to current regimens which accounts for the poor management. microRNAs (miRNAs) have been well-documented for their diagnostic, prognostic, and therapeutic roles in various human cancers. Recent literature confirmed that microRNA-205 (miR-205) has been established as one of the tumor suppressors in PrCa. miR-205 regulates number of cellular functions, such as proliferation, invasion, migration/metastasis, and apoptosis. It is also evident that miR-205 can serve as a key biomarker in diagnostic, prognostic, and therapy of PrCa. Therefore, in this review, we will provide an overview of tumor suppressive role of miR-205 in PrCa. This work also outlines miR-205's specific role in targeted mechanisms for chemosensitization and radiosensitization in PrCa. A facile approach of delivery paths for successful clinical translation is documented. Together, all these studies provide a novel insight of miR-205 as an adjuvant agent for reducing the widening gaps in clinical outcome of PrCa patients.
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- 2022
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47. Structural and functional characterization of Rv0792c from Mycobacterium tuberculosis: identifying small molecule inhibitors against GntR protein
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Eshan Khan, Amit Kumar, Ramandeep Singh, Tarun Kumar Sharma, Arun Sharma, Tannu Priya Gosain, Ashish Ganguly, Prashant Singh, Kanika Dhiman, Anjali Anand, Deepak Sharma, and Neeraj Chauhan
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Mycobacterium tuberculosis ,biology ,Chemistry ,Aptamer ,Gene expression ,Virulence ,biology.organism_classification ,Gene ,Transcription factor ,Small molecule ,Systematic evolution of ligands by exponential enrichment ,Cell biology - Abstract
In order to adapt in host tissues, microbial pathogens regulate their gene expression through an array of transcription factors. Here, we have functionally characterized Rv0792c, a GntR homolog from M. tuberculosis. In comparison to the parental strain, ΔRv0792c mutant strain of M. tuberculosis was compromised for survival upon exposure to oxidative stress, cell wall agents and infection in guinea pigs. RNA-seq analysis revealed that Rv0792c regulates the expression of genes that are involved in stress adaptation and virulence of M. tuberculosis. Solution small angle X-ray scattering (SAXS) data steered model building confirmed that the C-terminal region plays a pivotal role in dimer formation. Systematic evolution of ligands by exponential enrichment resulted in identification of ssDNA aptamers that can be used as a tool to identify small molecule inhibitors targeting Rv0792c. Using SELEX and SAXS data based modelling, we identified residues essential for the DNA binding activity of Rv0792c and I-OMe-Tyrphostin as an inhibitor of Rv0792c aptamer binding activity. Taken together, we provide a detailed shape-function characterization of GntR family of transcription factors from M. tuberculosis. To the best of our knowledge, this is the first study that has resulted in the identification of small molecule inhibitors against GntR family of transcription factors from bacterial pathogens.
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- 2021
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48. Ormeloxifene nanotherapy for cervical cancer treatment
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Murali M. Yallapu, Diane M. Maher, Subhash C. Chauhan, Meena Jaggi, Bilal Bin Hafeez, Man Mohan Singh, Hassan Mandil, and Neeraj Chauhan
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Drug ,medicine.medical_treatment ,media_common.quotation_subject ,Biophysics ,Pharmaceutical Science ,Bioengineering ,02 engineering and technology ,010402 general chemistry ,01 natural sciences ,Biomaterials ,Drug Discovery ,medicine ,Ormeloxifene ,Clonogenic assay ,media_common ,Cervical cancer ,Chemotherapy ,business.industry ,Organic Chemistry ,Cancer ,General Medicine ,021001 nanoscience & nanotechnology ,medicine.disease ,3. Good health ,0104 chemical sciences ,Targeted drug delivery ,Selective estrogen receptor modulator ,Cancer research ,0210 nano-technology ,business ,medicine.drug - Abstract
Background Cervical cancer (CxCa) ranks as the fourth most prevalent women-related cancer worldwide. Therefore, there is a crucial need to develop newer treatment modalities. Ormeloxifene (ORM) is a non-steroidal, selective estrogen receptor modulator (SERM) that is used as an oral contraceptive in humans. Recent investigations suggest that ORM exhibits potent anti-cancer activity against various types of cancers. Nanoparticulates offer targeted delivery of anti-cancer drugs with minimal toxicity and promise newer approaches for cancer diagnosis and treatment. Therefore, the nanotherapy approach is superior compared to traditional chemotherapy, which is not site-specific and is often associated with various side effects. Methods Pursuing this novel nanotherapy approach, our lab has recently developed ORM-loaded poly [lactic-co-glycolic acid] (PLGA), an FDA-approved biodegradable polymer, nanoparticles to achieve targeted drug delivery and improved bioavailability. Our optimized PLGA-ORM nanoformulation showed improved internalization in both dose- and energy-dependent manners, through endocytosis-mediated pathways in both Caski and SiHa cell lines. Additionally, we employed MTS and colony forming assays to determine the short- and long-term effects of PLGA-ORM on these cells. Results Our results showed that this formulation demonstrated improved inhibition of cellular proliferation and clonogenic potential compared to free ORM. Furthermore, the PLGA-ORM nanoformulation exhibited superior anti-tumor activities in an orthotopic cervical cancer mouse model than free ORM. Conclusion Collectively, our findings suggest that our novel nanoformulation has great potential for repurposing the drug and becoming a novel modality for CxCa management.
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- 2019
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49. A triphenylethylene nonsteroidal SERM attenuates cervical cancer growth
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Murali M. Yallapu, Diane M. Maher, Bilal Bin Hafeez, Meena Jaggi, Neeraj Chauhan, Man Singh, and Subhash C. Chauhan
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0301 basic medicine ,Cyclin E ,Carcinogenesis ,Papillomavirus E7 Proteins ,Mice, Nude ,Uterine Cervical Neoplasms ,lcsh:Medicine ,Antineoplastic Agents ,Apoptosis ,HPV vaccines ,Article ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,Chemotherapy ,Animals ,Humans ,Medicine ,Benzopyrans ,Ormeloxifene ,lcsh:Science ,PI3K/AKT/mTOR pathway ,Membrane Potential, Mitochondrial ,Cervical cancer ,Multidisciplinary ,business.industry ,lcsh:R ,Drug Repositioning ,Cell cycle ,medicine.disease ,G1 Phase Cell Cycle Checkpoints ,Xenograft Model Antitumor Assays ,3. Good health ,030104 developmental biology ,Selective estrogen receptor modulator ,Cancer research ,Female ,lcsh:Q ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Selective estrogen receptor modulator drug molecules of triphenylethylene family have gained considerable attention as anti-cancer agents. Despite recent advances in screening and development of HPV vaccines, cervical cancer remains one of the deadliest malignancies as advanced stage metastatic disease is mostly untreatable, thus warrants newer therapeutic strategies. Ormeloxifene (ORM) is a well-known SERM of triphenylethylene family that has been approved for human use, thus represents an ideal molecule for repurposing. In this study, we for the first time have demonstrated the anti-cancerous properties of ormeloxifene in cervical cancer. Ormeloxifene efficiently attenuated tumorigenic and metastatic properties of cervical cancer cells via arresting cell cycle at G1-S transition, inducing apoptosis, decreasing PI3K and Akt phosphorylation, mitochondrial membrane potential, and modulating G1-S transition related proteins (p21, cyclin E and Cdk2). Moreover, ORM repressed the expression of HPV E6/ E7 oncoproteins and restored the expression of their downstream target tumor suppressor proteins (p53, Rb and PTPN 13). As a result, ormeloxifene induces radio-sensitization in cervical cancer cells and caused potent tumor growth inhibition in orthotopic mouse model. Taken together, ormeloxifene represents an alternative therapeutic modality for cervical cancer which may have rapid clinical translation as it is already proven safe for human use.
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- 2019
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50. Identification and characterization of drought responsive miRNAs in a drought tolerant upland rice cultivar KMJ 1-12-3
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Sagarika Mishra, Tilak Chandra, Shaifaly Parmar, Birendra Prasad Shaw, Smita Sahoo, Sanjib Kumar Panda, Neeraj Chauhan, Pravin Nilawe, and Jay Prakash Awasthi
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0106 biological sciences ,0301 basic medicine ,Physiology ,Drought tolerance ,RNA-dependent RNA polymerase ,Plant Science ,Biology ,Upland rice ,01 natural sciences ,03 medical and health sciences ,Gene Expression Regulation, Plant ,Genetics ,MYB ,Transcription factor ,MADS-box ,Plant Proteins ,Oryza sativa ,Reverse Transcriptase Polymerase Chain Reaction ,fungi ,Reproducibility of Results ,food and beverages ,Oryza ,Equilibrative nucleoside transporter ,Ethylenes ,Blotting, Northern ,Droughts ,MicroRNAs ,030104 developmental biology ,Transcription Factors ,010606 plant biology & botany - Abstract
Shortfall of rain that creates drought like situation in non-irrigated agriculture system often limits rice production, necessitating introduction of drought tolerance trait into the cultivar of interest. The mechanism governing drought tolerance is, however, largely unknown, particularly the involvement of miRNAs, the master regulators of biochemical events. In this regard, response study on a drought tolerant rice variety KMJ 1-12-3 to 20% PEG (osmolality- 315 mOsm/kg) as drought stress revealed significant changes in abundance of several conserved miRNAs targeting transcription factors like homeodomain-leucine zipper, MADS box family protein, C2H2 zinc finger protein and Myb, well known for their importance in drought tolerance in plants. The response study also revealed significant PEG-induced decrease in abundance of the miRNAs targeting cyclin A, cyclin-dependent kinase, guanine nucleotide exchange factor, GTPase-activating protein, 1-aminocyclopropane-1-carboxylic acid oxidase and indole-3-acetic beta-glucosyl transferase indicating miRNA-regulated role of the cell cycle regulators, G-protein signalling and the plant hormones ethylene and IAA in drought tolerance in plants. The study confirmed the existence of four novel miRNAs, including osa-miR12470, osa-miR12471, osa-miR12472 and osa-miR12473, and the targets of three of them could be successfully validated. The PEG-induced decrease in abundance of the novel miRNAs osa-miR12470 and osa-miR12473 targeting RNA dependent RNA polymerase and equilibrative nucleoside transporter, respectively suggested an overall increase in both degradation and synthesis of nucleic acids in plants challenged with drought stress. The drought-responsive miRNAs identified in the study may be proved useful in introducing the trait in the rice cultivars of choice by manipulation of their cellular abundance.
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- 2019
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