| 1. |
- Kar, Rohan, et al.
(författare)
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The FBXW7-NOTCH interactome : A ubiquitin proteasomal system-induced crosstalk modulating oncogenic transformation in human tissues
- 2021
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Ingår i: Cancer Reports. - : John Wiley & Sons. - 2573-8348. ; 4:4
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Forskningsöversikt (refereegranskat)abstract
- Background Ubiquitin ligases or E3 ligases are well programmed to regulate molecular interactions that operate at a post-translational level. Skp, Cullin, F-box containing complex (or SCF complex) is a multidomain E3 ligase known to mediate the degradation of a wide range of proteins through the proteasomal pathway. The three-dimensional domain architecture of SCF family proteins suggests that it operates through a novel and adaptable "super-enzymatic" process that might respond to targeted therapeutic modalities in cancer. Recent findings Several F-box containing proteins have been characterized either as tumor suppressors (FBXW8, FBXL3, FBXW8, FBXL3, FBXO1, FBXO4, and FBXO18) or as oncogenes (FBXO5, FBXO9, and SKP2). Besides, F-box members like beta TrcP1 and beta TrcP2, the ones with context-dependent functionality, have also been studied and reported. FBXW7 is a well-studied F-box protein and is a tumor suppressor. FBXW7 regulates the activity of a range of substrates, such as c-Myc, cyclin E, mTOR, c-Jun, NOTCH, myeloid cell leukemia sequence-1 (MCL1), AURKA, NOTCH through the well-known ubiquitin-proteasome system (UPS)-mediated degradation pathway. NOTCH signaling is a primitive pathway that plays a crucial role in maintaining normal tissue homeostasis. FBXW7 regulates NOTCH protein activity by controlling its half-life, thereby maintaining optimum protein levels in tissue. However, aberrations in the FBXW7 or NOTCH expression levels can lead to poor prognosis and detrimental outcomes in patients. Therefore, the FBXW7-NOTCH axis has been a subject of intense study and research over the years, especially around the interactome's role in driving cancer development and progression. Several studies have reported the effect of FBXW7 and NOTCH mutations on normal tissue behavior. The current review attempts to critically analyze these mutations prognostic value in a wide range of tumors. Furthermore, the review summarizes the recent findings pertaining to the FBXW7 and NOTCH interactome and its involvement in phosphorylation-related events, cell cycle, proliferation, apoptosis, and metastasis. Conclusion The review concludes by positioning FBXW7 as an effective diagnostic marker in tumors and by listing out recent advancements made in cancer therapeutics in identifying protocols targeting the FBXW7-NOTCH aberrations in tumors.
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| 2. |
- Allam, Venkata Sita Rama Raju, et al.
(författare)
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Nutraceuticals and mitochondrial oxidative stress : bridging the gap in the management of bronchial asthma
- 2022
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Ingår i: Environmental Science and Pollution Research. - : Springer Nature. - 0944-1344 .- 1614-7499. ; 29:42, s. 62733-62754
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Forskningsöversikt (refereegranskat)abstract
- Asthma is a chronic inflammatory disease primarily characterized by inflammation and reversible bronchoconstriction. It is currently one of the leading causes of morbidity and mortality in the world. Oxidative stress further complicates the pathology of the disease. The current treatment strategies for asthma mainly involve the use of anti-inflammatory agents and bronchodilators. However, long-term usage of such medications is associated with severe adverse effects and complications. Hence, there is an urgent need to develop newer, novel, and safe treatment modalities for the management of asthma. This has therefore prompted further investigations and detailed research to identify and develop novel therapeutic interventions from potent untapped resources. This review focuses on the significance of oxidative stressors that are primarily derived from both mitochondrial and non-mitochondrial sources in initiating the clinical features of asthma. The review also discusses the biological scavenging system of the body and factors that may lead to its malfunction which could result in altered states. Furthermore, the review provides a detailed insight into the therapeutic role of nutraceuticals as an effective strategy to attenuate the deleterious effects of oxidative stress and may be used in the mitigation of the cardinal features of bronchial asthma.
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| 3. |
- Mehta, Meenu, et al.
(författare)
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Recent trends of NFkB decoy oligodeoxynucleotide-based nanotherapeutics in lung diseases
- 2021
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Ingår i: Journal of Controlled Release. - : Elsevier. - 0168-3659 .- 1873-4995. ; 337, s. 629-644
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Forskningsöversikt (refereegranskat)abstract
- Nuclear factor Kappa B (NFicB) is a unique protein complex that plays a major role in lung inflammation and respi-ratory dysfunction. The NFicB signaling pathway, therefore becomes an avenue for the development of potential pharmacological interventions, especially in situations where chronic inflammation is often constitutively active and plays a key role in the pathogenesis and progression of the disease. NFicB decoy oligodeoxynucleotides (ODNs) are double-stranded and carry NFicB binding sequences. They prevent the formation of NFicB-mediated inflammatory cytokines and thus have been employed in the treatment of a variety of chronic inflammatory diseases. However, the systemic administration of naked decoy ODNs restricts their therapeutic effectiveness because of their poor pharmacokinetic profile, instability, degradation by cellular enzymes and their low cellular uptake. Both structural modification and nanotechnology have shown promising results in enhancing the pharmacokinetic profiles of potent therapeutic substances and have also shown great potential in the treatment of respiratory diseases such as asthma, chronic obstructive pulmonary disease and cystic fibrosis. In this review, we examine the contribution of NFicB activation in respiratory diseases and recent advancements in the thera-peutic use of decoy ODNs. In addition, we also highlight the limitations and challenges in use of decoy ODNs as therapeutic molecules, cellular uptake of decoy ODNs, and the current need for novel delivery systems to provide efficient delivery of decoy ODNs. Furthermore, this review provides a common platform for discussion on the existence of decoy ODNs, as well as outlining perspectives on the latest generation of delivery systems that encapsulate decoy ODNs and target NFxB in respiratory diseases.
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| 4. |
- Paudel, Keshav Raj, et al.
(författare)
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Recent Advances in Chronotherapy Targeting Respiratory Diseases
- 2021
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Ingår i: Pharmaceutics. - : MDPI. - 1999-4923. ; 13:12
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Forskningsöversikt (refereegranskat)abstract
- Respiratory diseases contribute to a significant percentage of mortality and morbidity worldwide. The circadian rhythm is a natural biological process where our bodily functions align with the 24 h oscillation (sleep-wake cycle) process and are controlled by the circadian clock protein/gene. Disruption of the circadian rhythm could alter normal lung function. Chronotherapy is a type of therapy provided at specific time intervals based on an individual's circadian rhythm. This would allow the drug to show optimum action, and thereby modulate its pharmacokinetics to lessen unwanted or unintended effects. In this review, we deliberated on the recent advances employed in chrono-targeted therapeutics for chronic respiratory diseases.
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| 5. |
- Chan, Yinghan, et al.
(författare)
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Nutraceuticals : unlocking newer paradigms in the mitigation of inflammatory lung diseases
- 2023
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Ingår i: Critical reviews in food science and nutrition. - : Taylor & Francis. - 1040-8398 .- 1549-7852. ; 63:19, s. 3302-3332
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Forskningsöversikt (refereegranskat)abstract
- Persistent respiratory tract inflammation contributes to the pathogenesis of various chronic respiratory diseases, such as asthma, chronic obstructive pulmonary disease, and pulmonary fibrosis. These inflammatory respiratory diseases have been a major public health concern as they are the leading causes of worldwide mortality and morbidity, resulting in heavy burden on socioeconomic growth throughout these years. Although various therapeutic agents are currently available, the clinical applications of these agents are found to be futile due to their adverse effects, and most patients remained poorly controlled with a low quality of life. These drawbacks have necessitated the development of novel, alternative therapeutic agents that can effectively improve therapeutic outcomes. Recently, nutraceuticals such as probiotics, vitamins, and phytochemicals have gained increasing attention due to their nutritional properties and therapeutic potential in modulating the pathological mechanisms underlying inflammatory respiratory diseases, which could ultimately result in improved disease control and overall health outcomes. As such, nutraceuticals have been held in high regard as the possible alternatives to address the limitations of conventional therapeutics, where intensive research are being performed to identify novel nutraceuticals that can positively impact various inflammatory respiratory diseases. This review provides an insight into the utilization of nutraceuticals with respect to their molecular mechanisms targeting multiple signaling pathways involved in the pathogenesis of inflammatory respiratory diseases.
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| 6. |
- Patel, Vyoma K., et al.
(författare)
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Tackling the cytokine storm using advanced drug delivery in allergic airway disease
- 2023
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Ingår i: Journal of Drug Delivery Science and Technology. - : Elsevier. - 1773-2247. ; 82
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Forskningsöversikt (refereegranskat)abstract
- Asthma is one of the leading causes of mortality worldwide presenting a huge socio-economic burden with rising morbidity and mortality rates. It is a chronic inflammatory airway disease that is eminent with multiple epidemiological and pathophysiological features such as over production of pro-inflammatory cytokines that triggers an uncontrolled aberrant inflammatory response known as 'cytokine storm'. This phenomenon interferes with the signalling and production of cytokines over time leading to the progression of disease and the development of complications that lead to fatal consequences in many individuals. Targeting this overproduction and signalling of cytokines may prove a promising approach to develop novel cytokine specific therapies in the treatment of asthma. This review discusses on the various pharmacological strategies, recent advancements in drug delivery systems and significant findings from clinical trials that may have a potential to outweigh the limitations of the current therapies in the treatment of asthma.
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| 7. |
- Tarai, Madhumita, et al.
(författare)
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Eigenvalue-eigenvector decomposition (EED) analysis of dissimilarity and covariance matrix obtained from total synchronous fluorescence spectral (TSFS) data sets of herbal preparations : optimizing the classification approach
- 2017
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Ingår i: Spectrochimica Acta Part A - Molecular and Biomolecular Spectroscopy. - : Elsevier. - 1386-1425 .- 1873-3557. ; 184, s. 128-133
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Tidskriftsartikel (refereegranskat)abstract
- The present work compares the dissimilarity and covariance baseckinsupervised chemometric classification approaches by, taking the total synchronous fluorescence spectroscopy data sets acquired for the cumin and non cumin based herbal preparations. The conventional decomposition method involves eigenvalue-eigenvector analysis of the covariance of the data set and finds the factors that can explain the overall major sources of variation present in the data set. The conventional approach does this irrespective of the fact that the samples belong to intrinsically different groups and hence leads to poor class separation. The present work shows that classification of such samples can be optimized by performing the eigenvalue-eigenvector decomposition on the pair-wise dissimilarity matrix.
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| 8. |
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| 9. |
- Gupta, Abhishek Kumar, et al.
(författare)
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EFFECTS OF THE SWIRL FIELD ON THE STRUCTURE, PLANNER DROP SIZING AND LARGE-SCALE INSTABILITIES OF FLOW-BLURRING SPRAY
- 2023
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Ingår i: Proceedings of ASME 2023 Gas Turbine India Conference, GTINDIA 2023. - 9780791887721
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Konferensbidrag (refereegranskat)abstract
- Effective atomisation is a governing parameter in a liquidbased gas turbine. Incorporating the swirling air with the spray influences the spray structure, drop dispersion, and large-scale unsteadiness. Therefore, reliable measurement of drop sizes, spray structure, and large-scale instabilities are necessary for the detailed analysis of the complex interaction of the spray droplets in the swirl airfield. We aim to investigate the spray structure, drop sizing, and large-scale unsteadiness of a flow-blurring (FB) spray under swirl airfield conditions. In previous studies, the drop size distribution in FB sprays in a stagnant medium has been characterized based on the point measurement tool, namely Phase Doppler Particle Analyzer (PDPA). However, the PDPA measurement is time-consuming, suffers issues related to multiple scattering in the dense region of the spray, and provides only the time-averaged statistics. Herein, we characterize FB spray under the influence of an external swirling air stream using structured laser illumination planar imaging (SLIPI) technique. The SLIPI technique eliminates unwanted optical signals due to the multiple scattering and provides shot-to-shot variations of the drop size mapping and spray structure. A lab-scale experimental setup consisting of a centrally mounted FB atomiser with co-annular swirl air passage is operated at a fixed air-liquid mass ratio but with different swirl velocities. Following 1p-SLIPI technique, simultaneous Mie and LIF signals are recorded using two cameras, which are eventually used to obtain two-dimensional droplet Sauter mean diameter (SMD) contours. The calibration constant for the LIF/Mie ratio is deduced using PDPA measurements. The ensemble of instantaneous images is utilized for the proper orthogonal decomposition (POD) analysis to investigate the spatio-temporal features of the large-scale structure. The role of the swirling air on the different types of large-scale instabilities is explained based on the POD modes and energy contributions by the individual modes.
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| 10. |
- Kumar, Keshav, et al.
(författare)
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Chromatographic analysis of peptidoglycan samples with the aid of a chemometric technique : introducing a novel analytical procedure to classify bacterial cell wall collection
- 2019
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Ingår i: Analytical Methods. - : Royal Society of Chemistry (RSC). - 1759-9660 .- 1759-9679. ; 11:12, s. 1671-1679
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Tidskriftsartikel (refereegranskat)abstract
- The technical development of liquid chromatography has provided the necessary sensitivity to characterise peptidoglycan samples. However, the analysis of large numbers of complex chromatographic data sets without the aid of a proper chemometric technique is a laborious task, carrying a high risk of losing important biochemical information. The present work describes the development of a simple analytical procedure using self-organising map (SOM) analysis to analyse the large number of complex chromatographic data sets from bacterial peptidoglycan samples. SOM analysis essentially maps the samples to a hexagonal sheet based on their compositional similarity, and thus provides an approach to classify the bacterial cell wall collection in an unsupervised manner. The utility of the proposed approach was successfully validated by analysing peptidoglycan samples belonging to the Alphaproteobacterium class. The classification results achieved with SOM analysis were found to correlate well with their relative similarity in peptidoglycan compositions. In summary, the SOM analysis-based analytical procedure is shown to be useful towards automatising the analyses of chromatographic data sets of peptidoglycan samples from bacterial collections.
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| 11. |
- Kumar, Keshav, et al.
(författare)
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Constraint randomised non-negative factor analysis (CRNNFA) : an alternate chemometrics approach for analysing the biochemical data sets
- 2017
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Ingår i: The Analyst. - : ROYAL SOC CHEMISTRY. - 0003-2654 .- 1364-5528. ; 142:11, s. 1916-1928
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Tidskriftsartikel (refereegranskat)abstract
- The present work introduces an alternate chemometrics approach constraint randomised non-negative factor analysis (CRNNFA) for analysing the bioanalytical data sets. The CRNNFA algorithm provides the outputs that are easy to interpret and correlate with the real chromatograms. The CRNNFA algorithm achieves termination when the iteration limit is reached circumventing the premature convergence. Theoretical and computational aspects of the proposed method are also described. The analytical and computational potential of CRNNFA are successfully tested by analysing the complex chromatograms of the peptidoglycan samples belonging to the Alphaproteobacterium members. The obtained results clearly show that CRNNFA can easily trace the compositional variability of the peptidoglycan samples. In summary, the proposed method in general can be a potential alternate approach for analysing the data sets obtained from different analytical and clinical fields.
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| 12. |
- Kumar, Keshav
(författare)
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Discrete wavelet assisted correlation optimised warping of chromatograms : optimizing the computational time for correcting the drifts in peak positions
- 2017
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Ingår i: Analytical Methods. - : Royal Society of Chemistry (RSC). - 1759-9660 .- 1759-9679. ; 9:13, s. 2049-2058
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Tidskriftsartikel (refereegranskat)abstract
- Correlation optimised warping (COW) has been the most favourite chromatographic peak alignment approach in recent years. After optimization of the two parameters, slack and segment length, COW works well in aligning the chromatograms. However, one of the serious disadvantages of COW is that it is computationally time consuming. Often several segment lengths and slack parameters need to be tested to find the optimum combination for achieving the alignment that makes the whole analysis take several hours. In the present work, it has been shown that with the application of wavelet analysis prior to alignment it is possible to provide the necessary computational economy to the COW algorithm.
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| 13. |
- Kumar, Keshav, et al.
(författare)
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Integrating network analysis with chromatography : introducing a novel chemometry-chromatography based analytical procedure to classify the bacterial cell wall collection
- 2018
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Ingår i: Analytical Methods. - : Royal Society of Chemistry. - 1759-9660 .- 1759-9679. ; 10:10, s. 1172-1180
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Tidskriftsartikel (refereegranskat)abstract
- The present work integrates network analysis with chromatography and proposes a novel analytical procedure to classify the bacterial cell wall collection. The network analysis model can capture the heterogeneity present in the datasets and hence can provide unsupervised classification. The proposed approach is successfully applied for classifying the peptidoglycan samples of certain bacterial collections belonging to the class of Alphaproteobacteria. The obtained classification results are found to correlate well with their relative similarity in the peptidoglycan compositions. In summary, the proposed network analysis approach can be helpful in automatizing the bacterial cell wall analysis. The proposed approach can be useful to accelerate the research related to understanding the morphology of bacterial cell walls, host-pathogen interaction and development of effective antibiotics.
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| 14. |
- Kumar, Keshav, et al.
(författare)
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PG-metrics : a chemometric-based approach for classifying bacterial peptidoglycan data sets and uncovering their subjacent chemical variability
- 2017
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Ingår i: PLOS ONE. - : Public library science. - 1932-6203. ; 12:10
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Tidskriftsartikel (refereegranskat)abstract
- Bacteria cells are protected from osmotic and environmental stresses by an exoskeleton-like polymeric structure called peptidoglycan ( PG) or murein sacculus. This structure is fundamental for bacteria's viability and thus, the mechanisms underlying cell wall assembly and how it is modulated serve as targets for many of our most successful antibiotics. Therefore, it is now more important than ever to understand the genetics and structural chemistry of the bacterial cell walls in order to find new and effective methods of blocking it for the treatment of disease. In the last decades, liquid chromatography and mass spectrometry have been demonstrated to provide the required resolution and sensitivity to characterize the fine chemical structure of PG. However, the large volume of data sets that can be produced by these instruments today are difficult to handle without a proper data analysis work-flow. Here, we present PG-metrics, a chemometric based pipeline that allows fast and easy classification of bacteria according to their muropeptide chromatographic profiles and identification of the subjacent PG chemical variability between e.g. bacterial species, growth conditions and, mutant libraries. The pipeline is successfully validated here using PG samples from different bacterial species and mutants in cell wall proteins. The obtained results clearly demonstrated that PG-metrics pipeline is a valuable bioanalytical tool that can lead us to cell wall classification and biomarker discovery.
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| 15. |
- Kumar, Keshav, et al.
(författare)
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Principal coordinate analysis assisted chromatographic analysis of bacterial cell wall collection : a robust classification approach
- 2018
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Ingår i: Analytical Biochemistry. - : Elsevier. - 0003-2697 .- 1096-0309. ; 550, s. 8-14
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Tidskriftsartikel (refereegranskat)abstract
- In the present work, Principal coordinate analysis (PCoA) is introduced to develop a robust model to classify the chromatographic data sets of peptidoglycan sample. PcoA captures the heterogeneity present in the data sets by using the dissimilarity matrix as input. Thus, in principle, it can even capture the subtle differences in the bacterial peptidoglycan composition and can provide a more robust and fast approach for classifying the bacterial collection and identifying the novel cell wall targets for further biological and clinical studies. The utility of the proposed approach is successfully demonstrated by analysing the two different kind of bacterial collections. The first set comprised of peptidoglycan sample belonging to different subclasses of Alphaproteobacteria. Whereas, the second set that is relatively more intricate for the chemometric analysis consist of different wild type Vibrio Cholerae and its mutants having subtle differences in their peptidoglycan composition. The present work clearly proposes a useful approach that can classify the chromatographic data sets of chromatographic peptidoglycan samples having subtle differences. Furthermore, present work clearly suggest that PCoA can be a method of choice in any data analysis workflow.
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| 16. |
- Kumar, Keshav
(författare)
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Random Initialisation of the Spectral Variables : an Alternate Approach for Initiating Multivariate Curve Resolution Alternating Least Square (MCR-ALS) Analysis
- 2017
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Ingår i: Journal of Fluorescence. - : Springer. - 1053-0509 .- 1573-4994. ; 27:6, s. 1957-1968
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Tidskriftsartikel (refereegranskat)abstract
- Multivariate curve resolution alternating least square (MCR-ALS) analysis is the most commonly used curve resolution technique. The MCR-ALS model is fitted using the alternate least square (ALS) algorithm that needs initialisation of either contribution profiles or spectral profiles of each of the factor. The contribution profiles can be initialised using the evolve factor analysis; however, in principle, this approach requires that data must belong to the sequential process. The initialisation of the spectral profiles are usually carried out using the pure variable approach such as SIMPLISMA algorithm, this approach demands that each factor must have the pure variables in the data sets. Despite these limitations, the existing approaches have been quite a successful for initiating the MCR-ALS analysis. However, the present work proposes an alternate approach for the initialisation of the spectral variables by generating the random variables in the limits spanned by the maxima and minima of each spectral variable of the data set. The proposed approach does not require that there must be pure variables for each component of the multicomponent system or the concentration direction must follow the sequential process. The proposed approach is successfully validated using the excitation-emission matrix fluorescence data sets acquired for certain fluorophores with significant spectral overlap. The calculated contribution and spectral profiles of these fluorophores are found to correlate well with the experimental results. In summary, the present work proposes an alternate way to initiate the MCR-ALS analysis.
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| 17. |
- Paudel, Keshav Raj, et al.
(författare)
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In vitro anti-cancer activity of a polyherbal preparation, VEDICINALS®9, against A549 human lung adenocarcinoma cells
- 2023
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Ingår i: Pathology, Research and Practice. - : Elsevier. - 0344-0338 .- 1618-0631. ; 250
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Tidskriftsartikel (refereegranskat)abstract
- PurposeNon-small cell lung cancer (NSCLC) is among the leading causes of morbidity and mortality worldwide. Despite the availability of several treatment options, the five-year survival rate of NSCLC is extremely low (<20%). This underlines the necessity of more effective therapeutic alternatives. In this context, plant-derived extracts and bioactive molecules extracted from plants, known collectively as phytoceuticals, represent an extremely variegated source of bioactive compounds with potent anticancer potential. In the present study, we tested the in vitro anticancer activity of a polyherbal preparation, VEDICINALS®9, containing nine different bioactive principles extracted by medicinal plants.MethodsThe anticancer activity of VEDICINALS®9 was investigated by measuring its impact on A549 human NSCLC cell proliferation (MTT assay and trypan blue staining), migration (wound healing assay and transwell chamber assay) and by measuring the impact on the expression of cancer-related proteins (Human XL Oncology Protein Array).ResultsWe show that VEDICINALS®9 at a concentration of 0.2% v/v has potent anticancer effect, significantly inhibiting A549 cell proliferation and migration. Mechanistically, this was achieved by downregulating the expression of proteins involved in cancer cell proliferation (Axl, FGF basic, enolase 2, progranulin, survivin) and migration (Dkk-1, cathepsins B and D, BCL-x, amphiregulin, CapG, u-plasminogen activator). Furthermore, treatment with VEDICINALS®9 resulted in increased expression of the oncosuppressor protein p53 and of the angiogenesis inhibitor endostatin.ConclusionsTaken together, our results provide proof of principle of the potent anticancer activity of the polyherbal preparation VEDICINALS®9, highlighting its enormous potential as an alternative or adjuvant therapy for lung cancer.
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| 18. |
- Shastri, Madhur D., et al.
(författare)
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Interleukin-13 : A pivotal target against influenza-induced exacerbation of chronic lung diseases
- 2021
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Ingår i: Life Sciences. - : Elsevier. - 0024-3205 .- 1879-0631. ; 283
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Tidskriftsartikel (refereegranskat)abstract
- Non-communicable, chronic respiratory diseases (CRDs) affect millions of individuals worldwide. The course of these CRDs (asthma, chronic obstructive pulmonary disease, and cystic fibrosis) are often punctuated by microbial infections that may result in hospitalization and are associated with increased risk of morbidity and mortality, as well as reduced quality of life. Interleukin-13 (IL-13) is a key protein that regulates airway inflammation and mucus hypersecretion. There has been much interest in IL-13 from the last two decades. This cytokine is believed to play a decisive role in the exacerbation of inflammation during the course of viral infections, especially, in those with pre-existing CRDs. Here, we discuss the common viral infections in CRDs, as well as the potential role that IL-13 plays in the virus-induced disease pathogenesis of CRDs. We also discuss, in detail, the immune-modulation potential of IL-13 that could be translated to in-depth studies to develop IL-13based therapeutic entities.
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