Publications by authors named "Mamunur Rashid"

103 Publications

Isoformononetin, a dietary isoflavone protects against streptozotocin induced rat model of neuroinflammation through inhibition of NLRP3/ASC/IL-1 axis activation.

Life Sci 2021 Sep 28;286:119989. Epub 2021 Sep 28.

Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India. Electronic address:

Aims: Isoformononetin (IFN), a methoxyl isoflavone present in most of human dietary supplements. However, being a highly potent antioxidant and anti-inflammatory molecule, its activity against neuronal oxidative stress and neuroinflammation has not been explored till now. The present study was inquested to assess the antioxidant, anti-apoptotic and anti-inflammatory activity of IFN against streptozotocin induced neuroinflammation in different brain regions of rat.

Main Methods: Four groups of animals were subjected to treatment as control, toxic control (STZ; single intracerebrovascular injection), third group (STZ + IFN; 20 mg/kg p.o.), fourth group (IFN) for 14 days. The different brain regions of rats were evaluated for inflammatory, apoptotic and biochemical antioxidant markers. The brain tissues were further assessed for gene expression, immunohistochemical and western blotting examination for localization of inflammasome cascade expression that plays a pivotal role in neuroinflammation.

Key Findings: The modulation in oxidant/antioxidant status after exposure of STZ was significantly balanced after administration of IFN to rats. Further, IFN was also found to be an apoptotic agent as it modulates the apoptotic gene (Bax) and anti-apoptotic gene (BcL) expression. IFN significantly curtailed the augmented protein expression of NLRP3, NLRP2, ASC, NFκBP65, IL-1β and caspase-1 due to STZ administration in cortex and hippocampus rat brain regions.

Significance: The aforementioned results proclaim the neuroprotective functioning of IFN against STZ induced inflammation. IFN significantly prevents the neuroinflammation by decreasing the generation of ROS that reduces the activation of NLRP3/ASC/IL-1 axis thereby exerting neuroprotection as evidenced in rat model of STZ induced neuroninflammation.
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http://dx.doi.org/10.1016/j.lfs.2021.119989DOI Listing
September 2021

Antiproliferative and antioxidant potentials of bioactive edible vegetable fraction of Roxb. in cancer cell line.

Food Sci Nutr 2021 Jul 1;9(7):3777-3805. Epub 2021 Jun 1.

Department of Pharmacy University of Rajshahi Rajshahi Bangladesh.

In the present study, the aerial parts of underwent investigation of their in vitro antioxidant and free radical-scavenging activities in cell-free conditions, their phytoconstituents using gas chromatography-mass spectrometry (GC-MS), and their cytotoxic activity in HeLa cells. was extracted with 80% methanol and successively fractionated with solvents to yield petroleum ether (PEF), chloroform (CHF), ethyl acetate (EAF), and aqueous (AQF) fractions. GC-MS analysis revealed that CHF contained ten phytoconstituents, including different forms of octadecanoic acid methyl esters. The total antioxidant and ferric-reducing antioxidant capacities of the extracts and the standard catechin (CA) were as follows: CA >CHF >PEF >CME (crude methanolic extract) >EAF >AQF, and CA >CHF >EAF >PEF >AQF >CME, respectively. CHF showed the highest DPPH-free radical-scavenging activity, with a median inhibitory concentration of 10.5 ± 0.28 µg/ml, which was slightly higher than that of the standard butylated hydroxytoluene (12.0 ± 0.09 µg/ml). In the hydroxyl radical-scavenging assay, CHF showed identical scavenging activity (9.25 ± 0.73 µg/ml) when compared to CA (10.50 ± 1.06 µg/ml). Moreover, CHF showed strong cytotoxic activity (19.95 ± 1.18 µg/ml) in HeLa cells, which was alike to that of the standards vincristine sulfate and 5-fluorouracil (15.84 ± 1.64 µg/ml and 12.59 ± 1.75 µg/ml, respectively). The in silico study revealed that identified compounds were significantly linked to the targets of various cancer cells and oxidative enzymes. However, online prediction by SwissADME, admetSAR, and PASS showed that it has drug-like, nontoxic, and potential pharmacological actions.
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http://dx.doi.org/10.1002/fsn3.2343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8269638PMC
July 2021

Structural Violence and Health-Related Outcomes in Europe: A Descriptive Systematic Review.

Int J Environ Res Public Health 2021 06 30;18(13). Epub 2021 Jun 30.

Department of Health Sciences, Mid-Sweden University, Holmgatan 10, SE-85170 Sundsvall, Sweden.

In recent years, there has been a revival of the term "structural violence (SV)" which was coined by Johan Galtung in the 1960s in the context of Peace Studies. "Structural violence" refers to social structures-economic, legal, political, religious, and cultural-that prevent individuals, groups and societies from reaching their full potential. In the European context, very few studies have investigated health and well-being using an SV perspective. Therefore, this paper sought to systematically and descriptively review studies that used an SV framework to examine health-related outcomes across European countries. The review included two studies each from Spain and France, one each from the UK, Ukraine and Russia, and another study including the three countries Sweden, Portugal and Germany. With the exception of one mixed-method study, the studies used a qualitative design. Furthermore, the eight studies in the review used different conceptualizations of SV, which indicates the complexity of using SV as a concept in public health in the European context. Future research that attempts to identify and standardize measures of SV is needed; the knowledge gained is hoped to inform appropriate interventions aiming to reduce the effects of SV on population health.
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http://dx.doi.org/10.3390/ijerph18136998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8296855PMC
June 2021

Unfolding the apoptotic mechanism of antioxidant enriched-leaves of Tabebuia pallida (lindl.) miers in EAC cells and mouse model.

J Ethnopharmacol 2021 Oct 10;278:114297. Epub 2021 Jun 10.

Department of Pharmacy, University of Rajshahi, Rajshahi, 6205, Bangladesh. Electronic address:

Ethnopharmacological Relevance: Tabebuia pallida (Lindl.) Miers (T. pallida) is a well-known native Caribbean medicinal plant. The leaves and barks of T. pallida are used as traditional medicine in the form of herbal or medicinal tea to manage cancer, fever, and pain. Moreover, extracts from the leaves of T. pallida showed anticancer activity. However, the chemical profile and mechanism of anticancer activity of T. pallida leaves (TPL), stem bark (TPSB), root bark (TPRB) and flowers (TPF) remain unexplored.

Aim Of The Study: The present study was designed to explore the regulation of apoptosis by T. pallida using Ehrlich Ascites Carcinoma (EAC) cultured cells and an EAC mouse model. LC-ESI-MS/MS was used for compositional analysis of T. pallida extracts.

Materials And Methods: Dried and powdered TPL, TPSB, TPRB and TPF were extracted with 80% methanol. Using cultured EAC cells and EAC-bearing mice with and without these extracts, anticancer activities were studied by assessing cytotoxicity and tumor cell growth inhibition, changes in life span of mice, and hematological and biochemical parameters. Apoptosis was analyzed by microscopy and expression of selected apoptosis-related genes (Bcl-2, Bcl-xL, NFκ-B, PARP-1, p53, Bax, caspase-3 and -8) using RT-PCR. LC-ESI-MS analysis was performed to identify the major compounds from active extracts. Computer aided analyses was undertaken to sort out the best-fit phytoconstituent of total ten isolated compounds of this plant for antioxidant and anticancer activity.

Results: In EAC mice compared with untreated controls, the TPL extract exhibited the highest cancer cell toxicity with significant tumor cell growth inhibition (p < 0.001), reduced ascites by body weight (p < 0.01), increased the life span (p < 0.001), normalized blood parameters (RBC/WBC counts), and increased the levels of superoxide dismutase and catalase. TPL-treated EAC cells showed increased apoptotic characteristics of membrane blebbing, chromatin condensation and nuclear fragmentation, and caspase-3 activation, compared with untreated EAC cells. Moreover, annexin V-FITC and propidium iodide signals were greatly enhanced in response to TPL treatment, indicating apoptosis induction. Pro- and anti-apoptotic signaling after TPL treatment demonstrated up-regulated p53, Bax and PARP-1, and down-regulated NFκ-B, Bcl-2 and Bcl-xL expression, suggesting that TPL shifts the balance of pro- and anti-apoptotic genes towards cell death. LC-ESI-MS data of TPL showed a mixture of glycosides, lapachol, and quercetin antioxidant and its derivatives that were significantly linked to cancer cell targets. The compound, pelargonidin-3-O-glucoside was found to be most effective in computer aided models.

Conclusions: In conclusion, the TPL extract of T. pallida possesses significant anticancer activity. The tumor suppressive mechanism is due to apoptosis induced by activation of antioxidant enzymes and caspases and mediated by a change in the balance of pro- and anti-apoptotic genes that promotes cell death.
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http://dx.doi.org/10.1016/j.jep.2021.114297DOI Listing
October 2021

A real-time approach of diagnosing rice leaf disease using deep learning-based faster R-CNN framework.

PeerJ Comput Sci 2021 7;7:e432. Epub 2021 Apr 7.

Innovative Manufacturing, Mechatronics and Sports Laboratory, Faculty of Manufacturing and Mechatronic Engineering Technology, Universiti Malaysia Pahang, Pekan, Pahang, Malaysia.

The rice leaves related diseases often pose threats to the sustainable production of rice affecting many farmers around the world. Early diagnosis and appropriate remedy of the rice leaf infection is crucial in facilitating healthy growth of the rice plants to ensure adequate supply and food security to the rapidly increasing population. Therefore, machine-driven disease diagnosis systems could mitigate the limitations of the conventional methods for leaf disease diagnosis techniques that is often time-consuming, inaccurate, and expensive. Nowadays, computer-assisted rice leaf disease diagnosis systems are becoming very popular. However, several limitations ranging from strong image backgrounds, vague symptoms' edge, dissimilarity in the image capturing weather, lack of real field rice leaf image data, variation in symptoms from the same infection, multiple infections producing similar symptoms, and lack of efficient real-time system mar the efficacy of the system and its usage. To mitigate the aforesaid problems, a faster region-based convolutional neural network (Faster R-CNN) was employed for the real-time detection of rice leaf diseases in the present research. The Faster R-CNN algorithm introduces advanced RPN architecture that addresses the object location very precisely to generate candidate regions. The robustness of the Faster R-CNN model is enhanced by training the model with publicly available online and own real-field rice leaf datasets. The proposed deep-learning-based approach was observed to be effective in the automatic diagnosis of three discriminative rice leaf diseases including rice blast, brown spot, and hispa with an accuracy of 98.09%, 98.85%, and 99.17% respectively. Moreover, the model was able to identify a healthy rice leaf with an accuracy of 99.25%. The results obtained herein demonstrated that the Faster R-CNN model offers a high-performing rice leaf infection identification system that could diagnose the most common rice diseases more precisely in real-time.
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http://dx.doi.org/10.7717/peerj-cs.432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049121PMC
April 2021

The classification of EEG-based winking signals: a transfer learning and random forest pipeline.

PeerJ 2021 31;9:e11182. Epub 2021 Mar 31.

Innovative Manufacturing, Mechatronics and Sports Laboratory, Faculty of Manufacturing and Mechatronics Engineering Technology, Universiti Malaysia Pahang, Pekan, Pahang Darul Makmur, Malaysia.

Brain Computer-Interface (BCI) technology plays a considerable role in the control of rehabilitation or peripheral devices for stroke patients. This is particularly due to their inability to control such devices from their inherent physical limitations after such an attack. More often than not, the control of such devices exploits electroencephalogram (EEG) signals. Nonetheless, it is worth noting that the extraction of the features and the classification of the signals is non-trivial for a successful BCI system. The use of Transfer Learning (TL) has been demonstrated to be a powerful tool in the extraction of essential features. However, the employment of such a method towards BCI applications, particularly in regard to EEG signals, are somewhat limited. The present study aims to evaluate the effectiveness of different TL models in extracting features for the classification of wink-based EEG signals. The extracted features are classified by means of fine-tuned Random Forest (RF) classifier. The raw EEG signals are transformed into a scalogram image via Continuous Wavelet Transform (CWT) before it was fed into the TL models, namely InceptionV3, Inception ResNetV2, Xception and MobileNet. The dataset was divided into training, validation, and test datasets, respectively, via a stratified ratio of 60:20:20. The hyperparameters of the RF models were optimised through the grid search approach, in which the five-fold cross-validation technique was adopted. The optimised RF classifier performance was compared with the conventional TL-based CNN classifier performance. It was demonstrated from the study that the best TL model identified is the Inception ResNetV2 along with an optimised RF pipeline, as it was able to yield a classification accuracy of 100% on both the training and validation dataset. Therefore, it could be established from the study that a comparable classification efficacy is attainable via the Inception ResNetV2 with an optimised RF pipeline. It is envisaged that the implementation of the proposed architecture to a BCI system would potentially facilitate post-stroke patients to lead a better life quality.
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http://dx.doi.org/10.7717/peerj.11182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019310PMC
March 2021

The classification of motor imagery response: an accuracy enhancement through the ensemble of random subspace k-NN.

PeerJ Comput Sci 2021 2;7:e374. Epub 2021 Mar 2.

Innovative Manufacturing, Mechatronics and Sports Laboratory, Faculty of Manufacturing and Mechatronic Engineering Technology, Universiti Malaysia Pahang, Pekan, Pahang, Malaysia.

Brain-computer interface (BCI) is a viable alternative communication strategy for patients of neurological disorders as it facilitates the translation of human intent into device commands. The performance of BCIs primarily depends on the efficacy of the feature extraction and feature selection techniques, as well as the classification algorithms employed. More often than not, high dimensional feature set contains redundant features that may degrade a given classifier's performance. In the present investigation, an ensemble learning-based classification algorithm, namely random subspace -nearest neighbour (-NN) has been proposed to classify the motor imagery (MI) data. The common spatial pattern (CSP) has been applied to extract the features from the MI response, and the effectiveness of random forest (RF)-based feature selection algorithm has also been investigated. In order to evaluate the efficacy of the proposed method, an experimental study has been implemented using four publicly available MI dataset (BCI Competition III dataset 1 (data-1), dataset IIIA (data-2), dataset IVA (data-3) and BCI Competition IV dataset II (data-4)). It was shown that the ensemble-based random subspace -NN approach achieved the superior classification accuracy (CA) of 99.21%, 93.19%, 93.57% and 90.32% for data-1, data-2, data-3 and data-4, respectively against other models evaluated, namely linear discriminant analysis, support vector machine, random forest, Naïve Bayes and the conventional -NN. In comparison with other classification approaches reported in the recent studies, the proposed method enhanced the accuracy by 2.09% for data-1, 1.29% for data-2, 4.95% for data-3 and 5.71% for data-4, respectively. Moreover, it is worth highlighting that the RF feature selection technique employed in the present study was able to significantly reduce the feature dimension without compromising the overall CA. The outcome from the present study implies that the proposed method may significantly enhance the accuracy of MI data classification.
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http://dx.doi.org/10.7717/peerj-cs.374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7959631PMC
March 2021

Do work ability and life satisfaction matter for return to work? Predictive ability of the work ability index and life satisfaction questionnaire among women with long-term musculoskeletal pain.

BMC Public Health 2021 03 24;21(1):584. Epub 2021 Mar 24.

Department of Caring Sciences, Faculty of Health and Occupational Studies, University of Gävle, Gävle, Sweden.

Background: Impaired work ability and reduced life satisfaction due to long-term musculoskeletal pain, particularly in neck, shoulders and back, are considered occupational health problems that can result in workers taking sick leave. The aim of the study was to determine whether work ability and life satisfaction predict return to work (RTW) among women with long-term neck/shoulder and/or back pain, and to assess the ability of the Work Ability Index (WAI) and the Life Satisfaction Questionnaire (LiSat-11) to discriminate between those who did RTW and those who did not RTW (NRTW).

Methods: This is a cohort study with 1-year follow-up. A survey was sent to 600 women receiving sick leave benefits from the Swedish Social Insurance Agency. In total, 208 women responded at baseline, and 141 at a 1-year follow-up. To identify whether work ability and life satisfaction predicted RTW, multiple logistic regression analyses were performed with and without adjustment for type of work and pain intensity. To assess the discriminative ability of the WAI and the LiSat-11 for women who did RTW and those who did NRTW, receiver operating characteristic curves were fitted.

Results: Work ability predicted RTW, and the results remained significant after adjusting for type of work and pain intensity (OR 1.12, 95% CI: 1.04-1.22). Life satisfaction was not significant. The WAI at baseline adequately discriminated between RTW and NRTW after 1 year (Area under curve 0.78, 95% CI: 0.70-0.86), but the LiSat-11 did not.

Conclusions: This study supports a relationship between work ability and RTW among women on sick leave for long-term neck/shoulder and/or back pain. The results indicate that the WAI, but not the LiSat-11, can discriminate between RTW and NRTW in the population under study. Although the discriminative ability of the WAI needs to be verified in new samples before it can be recommended for use in rehabilitation settings, we suggest that healthcare professionals consider how women perceive their work ability in order to better support them in their RTW.
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http://dx.doi.org/10.1186/s12889-021-10510-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992335PMC
March 2021

Epitope spreading toward wild-type melanocyte-lineage antigens rescues suboptimal immune checkpoint blockade responses.

Sci Transl Med 2021 02;13(581)

Experimental Cancer Genetics, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK.

Although immune checkpoint inhibitors (ICIs), such as anti-programmed cell death protein-1 (PD-1), can deliver durable antitumor effects, most patients with cancer fail to respond. Recent studies suggest that ICI efficacy correlates with a higher load of tumor-specific neoantigens and development of vitiligo in patients with melanoma. Here, we report that patients with low melanoma neoantigen burdens who responded to ICI had tumors with higher expression of pigmentation-related genes. Moreover, expansion of peripheral blood CD8 T cell populations specific for melanocyte antigens was observed only in patients who responded to anti-PD-1 therapy, suggesting that ICI can promote breakdown of tolerance toward tumor-lineage self-antigens. In a mouse model of poorly immunogenic melanomas, spreading of epitope recognition toward wild-type melanocyte antigens was associated with markedly improved anti-PD-1 efficacy in two independent approaches: introduction of neoantigens by ultraviolet (UV) B radiation mutagenesis or the therapeutic combination of ablative fractional photothermolysis plus imiquimod. Complete responses against UV mutation-bearing tumors after anti-PD-1 resulted in protection from subsequent engraftment of melanomas lacking any shared neoantigens, as well as pancreatic adenocarcinomas forcibly overexpressing melanocyte-lineage antigens. Our data demonstrate that somatic mutations are sufficient to provoke strong antitumor responses after checkpoint blockade, but long-term responses are not restricted to these putative neoantigens. Epitope spreading toward T cell recognition of wild-type tumor-lineage self-antigens represents a common pathway for successful response to ICI, which can be evoked in neoantigen-deficient tumors by combination therapy with ablative fractional photothermolysis and imiquimod.
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http://dx.doi.org/10.1126/scitranslmed.abd8636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130008PMC
February 2021

IgG antibody response demonstrates inverse correlation with viral load in Bangladeshi women with acute hepatitis E virus genotype 1 infection.

Int J Infect Dis 2021 Mar 15;104:482-490. Epub 2021 Jan 15.

Laboratory of Infectious Diseases, Institute for Developing Science and Health Initiatives, Mohakhali, Dhaka 1212, Bangladesh; Laboratory of Genetics and Genomics, Institute for Developing Science and Health Initiatives, Mohakhali, Dhaka 1212, Bangladesh. Electronic address:

Objectives: To determine IgG immune responses and hepatitis E virus (HEV) viral load, and to explore the associations with pregnancy.

Methods: A total of 121 HEV-infected women (57 pregnant, 64 non-pregnant) were analysed. Quantitative reverse transcription PCR (RT-qPCR) was done for 78 HEV IgM-positive patients to determine viral load, and Sanger sequencing was performed for 62 HEV-RNA-positive patients to confirm genotyping. ELISA was conducted to determine HEV antibody and avidity indices.

Results: The HEV genotype was identified as variant 1. Significant negative correlations were observed between log HEV copy number and log hepatitis E virus IgG antibody index in the late acute phase of jaundice for both pregnant women (r = -0.7971, p = 0.0002) and non-pregnant women (r = -0.9117, p = 0.0002). Pregnant women had significantly higher serum log viral copy numbers and lower IgG antibody indices than non-pregnant women in the late acute phase of HEV-induced jaundice (p = 0.0196 and p = 0.0303, respectively). Moreover, pregnant women with acute HEV hepatitis had higher cross-reactive IgG antibodies compared to the non-pregnant women (p = 0.0017). Five patients with HEV hepatitis died, of whom four were pregnant.

Conclusions: Pregnancy might be associated with higher viral loads and a lower IgG response in the HEV-induced late acute phase of jaundice.
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http://dx.doi.org/10.1016/j.ijid.2020.12.081DOI Listing
March 2021

Hepatitis E Virus Capsid Antigen (HEV-Ag) - A practical diagnostic biomarker in the HEV outbreak scenario.

J Clin Virol 2021 01 16;134:104692. Epub 2020 Nov 16.

Bangladesh Institute Tropical Infectious Disease (BITID), Fouzderhat, Chittagong, Bangladesh.

Background: The increased global incidence of hepatitis E virus (HEV) infections, warrants accurate and affordable diagnostics across different geographical regions. The soluble and highly conserved HEV open reading frame 2 (ORF2) capsid antigen (HEV-Ag) is detectable in self-limited acute enteric hepatitis by HEV-Ag ELISA which is a promising serological assay in settings where HEV-RNA testing is not feasible. Our aim was to assess the HEV-Ag biomarker in an HEV outbreak in a low income country.

Methods: A prospective single center longitudinal study during HEV outbreaks in the Chittagong, Bangladesh region between October 2018 and October 2019 was conducted based on recruitment of acute jaundice cases with clinical signs and symptoms of suspect HEV infections. Acute HEV infection was defined as a positive test result for anti-HEV IgM antibodies.

Results: Forty four of the 51 enrolled enteric hepatitis cases (86 %) were confirmed HEV by anti-HEV IgM ELISA at day 0 hospital entry. The anti-HEV-IgM and IgG were positive in all patients and did not reveal significant differences; neither between the time points day 0 and follow-up hospitalization on day 2-6 or day 7-10 nor between RNA-positive (n = 36) versus RNAnegative (n = 8) HEV groups. The HEV-Ag positivity was higher in viral RNA-positive (29/36, 81 %) than the viral RNA-negative (1/8, 12 %) group, p < 0.001 and the HEV-Ag levels positively correlated with viremia, r = 0.77, p < 0.0001. All non-HEV cases; n = 7 tested negative anti-HEV IgM and HEV-Ag and 5 of 7 (71 %) tested anti-HAV IgM positive.

Conclusions: The HEV-Ag ELISA is a reliable and practical diagnostic tool in this acute HEV outbreak.
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http://dx.doi.org/10.1016/j.jcv.2020.104692DOI Listing
January 2021

Genomic landscape and clonal architecture of mouse oral squamous cell carcinomas dictate tumour ecology.

Nat Commun 2020 11 9;11(1):5671. Epub 2020 Nov 9.

Centre for Stem Cells & Regenerative Medicine, King's College London, Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK.

To establish whether 4-nitroquinoline N-oxide-induced carcinogenesis mirrors the heterogeneity of human oral squamous cell carcinoma (OSCC), we have performed genomic analysis of mouse tongue lesions. The mutational signatures of human and mouse OSCC overlap extensively. Mutational burden is higher in moderate dysplasias and invasive SCCs than in hyperplasias and mild dysplasias, although mutations in p53, Notch1 and Fat1 occur in early lesions. Laminin-α3 mutations are associated with tumour invasiveness and Notch1 mutant tumours have an increased immune infiltrate. Computational modelling of clonal dynamics indicates that high genetic heterogeneity may be a feature of those mild dysplasias that are likely to progress to more aggressive tumours. These studies provide a foundation for exploring OSCC evolution, heterogeneity and progression.
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http://dx.doi.org/10.1038/s41467-020-19401-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7652942PMC
November 2020

Evaluation of Strip Meniscometry and Association with Clinical and Demographic Variables in a Community Eye Study (in Bangladesh).

J Clin Med 2020 Oct 20;9(10). Epub 2020 Oct 20.

Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Drive, Singapore 117597, Singapore.

Strip meniscometry (SM) is a relatively new technique for evaluating inferior tear meniscus. We described SM in an epidemiology study and its potential associations with clinical and tear parameters. This cross-sectional study involved 1050 factory garment workers in Gazipur, Bangladesh. The Ocular Surface Disease Index (OSDI) questionnaire and a standard examination for dry eye and meibomian gland dysfunction (MGD), including the five-second SM, were performed by a single ophthalmologist. The participants' ages were 35.56 ± 12.12 years (range 18-59), with 53.8% women. The overall SM was 7.7 ± 3.6 mm, with skewness of 0.126 and kurtosis of 1.84 in frequency distribution. SM values were significantly lower in men than women, and significantly correlated with schirmers (r = 0.71) and tear break up time (TBUT) (r = 0.89). A lower SM value was associated with higher OSDI, lower Schirmer test, increased MG severity and lower TBUT. In multivariable analysis, when adjusted by age, SM values remained associated with schirmers and TBUT, and inversely associated with OSDI. In a separate regression model, higher SM was associated with increasing age, reduced severity of MGD grading, and increased TBUT. To conclude, SM is a rapid clinical test associated with dry eye symptoms and signs, with findings affected by both tear secretion and tear stability.
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http://dx.doi.org/10.3390/jcm9103366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589173PMC
October 2020

Prevalence and Risk Factors of Severe Dry Eye in Bangladesh-Based Factory Garment Workers.

Diagnostics (Basel) 2020 Aug 26;10(9). Epub 2020 Aug 26.

Singapore Eye Research Institute, The Academia, 20 College Road, Disovery Tower Level 6, Singapore 169856, Singapore.

This study sought to evaluate the prevalence of dry eye and meibomian gland dysfunction (MGD) and the associated factors of severe dry eye symptoms (SDES) among garments worker of Gazipur, Bangladesh. We prospectively collected cross-sectional data for 1050 garments workers of a factory (70% response). All participants had an evaluation of the Ocular Surface Disease Index (OSDI), and a detailed ophthalmic examination including tear breakup time (TBUT), ocular surface fluorescein staining, and Schirmer's I test. MGD grading was based on the viscosity/color and ease of manual expression of meibum. Mean age of participants was 35.5 ± 12.1 years; 53.8% were women. The prevalence of dry eye (OSDI > 12) was 64.2% (95% CI 61.2-67.1%). OSDI was not significantly different between sex or age-groups but associated with increasing MGD grade ( < 0.001), reduced TBUT (<5 s) [ < 0.001], and reduced Schirmer's test (<5 mm) [ < 0.001]. Thirty-five percent had SDES (OSDI > 32). Using univariate logistic regressions, SDES was associated with older age (Odds Ratio (OR) 1.01, 95% Confidence Interval [1.005-1.03] per year increase) and male sex (OR 1.76, 95% CI: 1.36-2.27). When adjusted for age and sex, SDES were strongly associated with increase in MGD severity grading (OR 188, 95% CI: 91-390). However, in multivariate regression, TBUT, but not MGD severity, became the only significant determinant of SDES (OR 13.0, 95% CI: 6.3-27.0, for every 1 s decrease in TBUT). MGD is common in garments workers, contributing to dry eye symptoms in addition to other tear parameters. Reduced tear stability is associated with SDES.
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http://dx.doi.org/10.3390/diagnostics10090634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555208PMC
August 2020

Analysis of CRISPR-Cas9 screens identifies genetic dependencies in melanoma.

Pigment Cell Melanoma Res 2021 01 7;34(1):122-131. Epub 2020 Sep 7.

Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands.

Targeting the MAPK signaling pathway has transformed the treatment of metastatic melanoma. CRISPR-Cas9 genetic screens provide a genome-wide approach to uncover novel genetic dependencies that might serve as therapeutic targets. Here, we analyzed recently reported CRISPR-Cas9 screens comparing data from 28 melanoma cell lines and 313 cell lines of other tumor types in order to identify fitness genes related to melanoma. We found an average of 1,494 fitness genes in each melanoma cell line. We identified 33 genes, inactivation of which specifically reduced the fitness of melanoma. This set of tumor type-specific genes includes established melanoma fitness genes as well as many genes that have not previously been associated with melanoma growth. Several genes encode proteins that can be targeted using available inhibitors. We verified that genetic inactivation of DUSP4 and PPP2R2A reduces the proliferation of melanoma cells. DUSP4 encodes an inhibitor of ERK, suggesting that further activation of MAPK signaling activity through its loss is selectively deleterious to melanoma cells. Collectively, these data present a resource of genetic dependencies in melanoma that may be explored as potential therapeutic targets.
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http://dx.doi.org/10.1111/pcmr.12919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818247PMC
January 2021

Current Status, Challenges, and Possible Solutions of EEG-Based Brain-Computer Interface: A Comprehensive Review.

Front Neurorobot 2020 3;14:25. Epub 2020 Jun 3.

Faculty of Electrical & Electronics Engineering Technology, Universiti Malaysia Pahang, Pekan, Malaysia.

Brain-Computer Interface (BCI), in essence, aims at controlling different assistive devices through the utilization of brain waves. It is worth noting that the application of BCI is not limited to medical applications, and hence, the research in this field has gained due attention. Moreover, the significant number of related publications over the past two decades further indicates the consistent improvements and breakthroughs that have been made in this particular field. Nonetheless, it is also worth mentioning that with these improvements, new challenges are constantly discovered. This article provides a comprehensive review of the state-of-the-art of a complete BCI system. First, a brief overview of electroencephalogram (EEG)-based BCI systems is given. Secondly, a considerable number of popular BCI applications are reviewed in terms of electrophysiological control signals, feature extraction, classification algorithms, and performance evaluation metrics. Finally, the challenges to the recent BCI systems are discussed, and possible solutions to mitigate the issues are recommended.
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http://dx.doi.org/10.3389/fnbot.2020.00025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283463PMC
June 2020

A comprehensive review on contaminants removal from pharmaceutical wastewater by electrocoagulation process.

Sci Total Environ 2020 Jul 6;726:138095. Epub 2020 Apr 6.

Department of Environmental Science, SRM University-AP, Amaravati, Andhra Pradesh - 522502, India. Electronic address:

The pharmaceuticals are emergent contaminants, which can create potential threats for human health and the environment. All the pharmaceutical contaminants are becoming enormous in the environment as conventional wastewater treatment cannot be effectively implemented due to toxic and intractable action of pharmaceuticals. For this reason, the existence of pharmaceutical contaminants has brought great awareness, causing significant concern on their transformation, occurrence, risk, and fate in the environments. Electrocoagulation (EC) treatment process is effectively applied for the removal of contaminants, radionuclides, pesticides, and also harmful microorganisms. During the EC process, an electric current is employed directly, and both electrodes are dissoluted partially in the reactor under the special conditions. This electrode dissolution produces the increased concentration of cation, which is finally precipitated as hydroxides and oxides. Different anode materials usage like aluminum, stainless steel, iron, etc. are found more effective in EC operation for efficient removal of pharmaceutical contaminants. Due to the simple procedure and less costly material, EC method is extensively recognized for pharmaceutical wastewater treatment over further conventional treatment methods. The EC process has more usefulness to destabilize the pharmaceutical contaminants with the neutralization of charge and after that coagulating those contaminants to produce flocs. Thus, the review places particular emphasis on the application of EC process to remove pharmaceutical contaminants. First, the operational parameters influencing EC efficiency with the electroanalysis techniques are described. Second, in this review emerging challenges, current developments and techno-economic concerns of EC are highlighted. Finally, future recommendations and prospective on EC are envisioned.
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http://dx.doi.org/10.1016/j.scitotenv.2020.138095DOI Listing
July 2020

Pharmacological approaches to mitigate neuroinflammation in Alzheimer's disease.

Int Immunopharmacol 2020 Jul 27;84:106479. Epub 2020 Apr 27.

King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia; Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia. Electronic address:

Alzheimer's disease (AD) is one of the most prevalent neurodegenerative diseases characterized by the formation of extracellular amyloid beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs). Growing evidence suggested that there is an association between neuronal dysfunction and neuroinflammation (NI) in AD, coordinated by the chronic activation of astrocytes and microglial cells along with the subsequent excessive generation of the proinflammatory molecule. Therefore, a better understanding of the relationship between the nervous and immune systems is important in order to delay or avert the neurodegenerative events of AD. The inflammatory/immune pathways and the mechanisms to control these pathways may provide a novel arena to develop new drugs in order to target NI in AD. In this review, we represent the influence of cellular mediators which are involved in the NI process, with regards to the progression of AD. We also discuss the processes and the current status of multiple anti-inflammatory agents which are used in AD and have gone through or going through clinical trials. Moreover, new prospects for targeting NI in the development of AD drugs have also been highlighted.
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http://dx.doi.org/10.1016/j.intimp.2020.106479DOI Listing
July 2020

Mechanistic exploration of quercetin against metronidazole induced neurotoxicity in rats: Possible role of nitric oxide isoforms and inflammatory cytokines.

Neurotoxicology 2020 07 6;79:1-10. Epub 2020 Mar 6.

Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow, 226031, India. Electronic address:

Aim: Metronidazole, a nitroimidazole derived antibiotic used to treat many bacterial infections, is reported to penetrate the blood brain barrier after long term administration resulting into neuronal toxicity. Further, quercetin, a polyphenol flavonoid is reported to exhibit neuroprotective activity but its pharmacodynamics interaction against metronidazole induced neurotoxicity. Therefore, the present study was designed to evaluate the postulated mechanism of metronidazole induced neurotoxicity and potential neuroprotective role of quercetin.

Main Methods: Animals (Sprague Dawley) rats were randomly divided into five groups such as control, metronidazole (135 mg/kg), quercetin (100 mg/kg), metronidazole (135 mg/kg) + quercetin (50 mg/kg), and metronidazole (135 mg/kg) + quercetin (100 mg/kg). The brain tissues were evaluated for tissue cyclo-oxygenase, lipoxygenase, nitrite levels, inflammatory and antioxidant biomarkers. The brain tissues were further scrutinized histopathologically for neuronal degeneration. Western blotting analysis was performed for the localization of protein expression for Bax, Bcl, iNOS, eNOS and caspase-3.

Key Findings: The metronidazole significantly alters the antioxidant levels, inflammatory mediators and morphological changes in the brain tissue. Metronidazole also induces iNOS, Bax and caspase 3 protein expressions whilst decreases the expression of Bcl and eNOS in the brain tissue. Metronidazole administration causes a momentous increase in tissue inflammatory markers.

Significance: The metronidazole (oral) administration causes remarkably neurotoxicity effects and the same could be attributed to the fact that metronidazole has the ability to cross the blood brain barrier and transforms the enzymatic activity of various biomarkers present in the brain. From the results, it could be hypothesized that metronidazole causes neurotoxicity by hindering the proportion of antioxidants in the brain tissue and inducing nitric oxide synthesis along with apoptosis. However, quercetin demonstrated a significant protective effect on neuronal toxicity precipitated through metronidazole.
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http://dx.doi.org/10.1016/j.neuro.2020.03.002DOI Listing
July 2020

Skeletal restoration by phosphodiesterase 5 inhibitors in osteopenic mice: Evidence of osteoanabolic and osteoangiogenic effects of the drugs.

Bone 2020 Jun 29;135:115305. Epub 2020 Feb 29.

Division of Endocrinology, Central Drug Research Institute (CDRI), Council of Scientific and Industrial Research (CSIR), Lucknow 226031, India. Electronic address:

Phosphodiesterases (PDEs) hydrolyze cyclic nucleotides and thereby regulate diverse cellular functions. The reports on the skeletal effects of PDE inhibitors are conflicting. Here, we screened 17 clinically used non-xanthine PDE inhibitors (selective and non-selective) using mouse calvarial osteoblasts (MCO) where the readout was osteoblast differentiation. From this screen, we identified sildenafil and vardenafil (both PDE5 inhibitors) having the least osteogenic EC. Both drugs significantly increased vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2) expressions in MCO and the nitric oxide synthase inhibitor L-NAME completely blocked VEGF expression induced by these drugs. Sunitinib, a tyrosine receptor kinase inhibitor that also blocks VEGFR2 blocked sildenafil-/vardenafil-induced osteoblast differentiation. At half of their human equivalent doses, i.e. 6.0 mg/kg sildenafil and 2.5 mg/kg vardenafil, the maximum bone marrow level of sildenafil was 32% and vardenafil was 21% of their blood levels. At these doses, both drugs enhanced bone regeneration at the femur osteotomy site and completely restored bone mass, microarchitecture, and strength in OVX mice. Furthermore, both drugs increased surface referent bone formation and serum bone formation marker (P1NP) without affecting the resorption marker (CTX-1). Both drugs increased the expression of VEGF and VEGFR2 in bones and osteoblasts and increased skeletal vascularity. Sunitinib completely blocked the bone restorative and vascular effects of sildenafil and vardenafil in OVX mice. Taken together, our study suggested that sildenafil and vardenafil at half of their adult human doses completely reversed osteopenia in OVX mice by an osteogenic mechanism that was associated with enhanced skeletal vascularity.
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http://dx.doi.org/10.1016/j.bone.2020.115305DOI Listing
June 2020

Mutational signatures in tumours induced by high and low energy radiation in Trp53 deficient mice.

Nat Commun 2020 01 20;11(1):394. Epub 2020 Jan 20.

UCSF Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, 94158, USA.

Ionising radiation (IR) is a recognised carcinogen responsible for cancer development in patients previously treated using radiotherapy, and in individuals exposed as a result of accidents at nuclear energy plants. However, the mutational signatures induced by distinct types and doses of radiation are unknown. Here, we analyse the genetic architecture of mammary tumours, lymphomas and sarcomas induced by high (Fe-ions) or low (gamma) energy radiation in mice carrying Trp53 loss of function alleles. In mammary tumours, high-energy radiation is associated with induction of focal structural variants, leading to genomic instability and Met amplification. Gamma-radiation is linked to large-scale structural variants and a point mutation signature associated with oxidative stress. The genomic architecture of carcinomas, sarcomas and lymphomas arising in the same animals are significantly different. Our study illustrates the complex interactions between radiation quality, germline Trp53 deficiency and tissue/cell of origin in shaping the genomic landscape of IR-induced tumours.
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http://dx.doi.org/10.1038/s41467-019-14261-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6971050PMC
January 2020

Bioavailability, tissue distribution and excretion studies of a potential anti-osteoporotic agent, medicarpin, in female rats using validated LC-MS/MS method.

J Pharm Biomed Anal 2020 Feb 18;180:112978. Epub 2019 Nov 18.

Academcy of Scientific and Innovative Research, New Delhi, India; Pharmaceutics and Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India. Electronic address:

Medicarpin, one of the active constituents isolated from the extract of Butea monosperma, has been shown to have various pharmacological activities including potent anti-osteoporotic properties. The aim of this study was to investigate the oral pharmacokinetics, tissue distribution and excretion of medicarpin following single oral dose administration in female rats. Oral pharmacokinetics was explored at 5 and 20 mg/kg while tissue distribution, urinary and fecal excretion were studied following 20 mg/kg oral dose. Medicarpin was quantified in rat plasma, urine, feces and tissue samples using a validated LC-MS/MS method following reverse-phase HPLC separation on RP18 column (4.6 mm × 50 mm, 5.0 μm) using methanol and 10 mM ammonium acetate (pH 4.0) as mobile phase in the ratio of 80:20 (v/v) at a flow rate of 0.8 mL/min. The oral bioavailability of medicarpin was found to be low with low systemic levels. The concentration in tissues was significantly higher than plasma. Highest tissue concentrations were found in the liver followed by bone marrow. Urinary and fecal excretion of medicarpin was < 1 %. In conclusion, medicarpin was found to be highly distributed in body tissues and minimally excreted via urine or feces.
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http://dx.doi.org/10.1016/j.jpba.2019.112978DOI Listing
February 2020

LC-ESI-MS/MS method for the simultaneous determination of isoformononetin, daidzein, and equol in rat plasma: Application to a preclinical pharmacokinetic study.

J Chromatogr B Analyt Technol Biomed Life Sci 2019 Oct 28;1129:121776. Epub 2019 Aug 28.

Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow, India; Academy of Scientific and Innovative Research, New Delhi, India. Electronic address:

Isoformononetin (methoxy isoflavone) is a potent osteogenic isoflavone abundantly present in Butea monosperma, Pisum sativum, Mung bean, Machaerium villosum, Medicago sativa, and Glycine max. In the current study, an LC-ESI-MS/MS method for the simultaneous evaluation of isoformononetin (IFN), daidzein (DZN) and equol (EQL) was developed and validated in rat plasma using biochanin A as an internal standard. IFN, DZN, and EQL separation was achieved by using acetonitrile and acetic acid (0.1%) in the ratio of 90:10 (% v/v) as mobile phase under isocratic conditions at a flow rate of 0.6 mL/min on Atlantis C (4.6 × 250 mm, 5.0 μm) column. The achieved method was linear within the concentration range of 0.5-500 ng/mL. The method was effectively applied to investigate the permeability, protein binding estimation and pharmacokinetics studies of IFN in rats. The PAMPA permeability of IFN was found to be high at pH 4.0 and 7.0. The protein binding was found to be about 91% of IFN. The oral bioavailability of IFN was found to be poor (21.6%). IFN was found to have a moderate clearance (2.9 L/h/kg) and a large apparent volume of distribution (12.1 L/kg). The plasma half-life (t) and maximum attainable concentration (C) of IFN at systemic circulation was found to be 1.9 ± 0.6 h and 269.3 ± 0.4 after oral administration.
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http://dx.doi.org/10.1016/j.jchromb.2019.121776DOI Listing
October 2019

Epithelial NOTCH Signaling Rewires the Tumor Microenvironment of Colorectal Cancer to Drive Poor-Prognosis Subtypes and Metastasis.

Cancer Cell 2019 09;36(3):319-336.e7

Cancer Research UK Beatson Institute, Glasgow, UK; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, UK. Electronic address:

The metastatic process of colorectal cancer (CRC) is not fully understood and effective therapies are lacking. We show that activation of NOTCH1 signaling in the murine intestinal epithelium leads to highly penetrant metastasis (100% metastasis; with >80% liver metastases) in Kras-driven serrated cancer. Transcriptional profiling reveals that epithelial NOTCH1 signaling creates a tumor microenvironment (TME) reminiscent of poorly prognostic human CRC subtypes (CMS4 and CRIS-B), and drives metastasis through transforming growth factor (TGF) β-dependent neutrophil recruitment. Importantly, inhibition of this recruitment with clinically relevant therapeutic agents blocks metastasis. We propose that NOTCH1 signaling is key to CRC progression and should be exploited clinically.
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http://dx.doi.org/10.1016/j.ccell.2019.08.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6853173PMC
September 2019

β-Amino acid derivatives as mitochondrial complex III inhibitors of L. donovani: A promising chemotype targeting visceral leishmaniasis.

Eur J Med Chem 2019 Nov 20;182:111632. Epub 2019 Aug 20.

Parasitology Division, CSIR-Central Drug Research Institute, BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, New Delhi, India. Electronic address:

β-amino acids and their analogues are gathering increased attention not only because of their antibacterial and antifungal activity, but also for their use in designing peptidomimetics with increased oral bioavailability and resistance to metabolic degradation. In this study, a series of α-phenyl substituted chalcones, α-phenyl, β-amino substituted dihydrochalcones and β-amino acid derivatives were synthesized and evaluated for their antileishmanial efficacy against experimental visceral leishmaniasis (VL). Among all synthesized derivatives, 10c showed promising antileishmanial efficacy against both extracellular promastigote and intracellular amastigote (IC 8.2 μM and 20.5 μM respectively) of L. donovani with negligible cytotoxic effect towards J774 macrophages and Vero cells. 10c effectively reduced spleen and liver parasite burden (>90%) in both hamster and Balb/c model of VL without any hepatotoxicity. In vitro pharmacokinetic analysis showed that 10c was stable in gastric fluid and plasma of Balb/c mice at 10 μg/ml. Further analysis of the molecular mechanism revealed that 10c entered into the parasite by depolarizing the plasma membrane rather than forming nonspecific pores and induced molecular events like loss in mitochondrial membrane potential with a gradual decline in ATP production. This, in turn, did not induce programmed cell death of the parasite; rather 10c induced bioenergetic collapse of the parasite by decreasing ATP synthesis through specific inhibition of mitochondrial complex III activity. Altogether, our results allude to the therapeutic potential of β-amino acid derivatives as novel antileishmanials, identifying them as lead compounds for further exploration in the design of potent candidates for the treatment of visceral leishmaniasis.
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http://dx.doi.org/10.1016/j.ejmech.2019.111632DOI Listing
November 2019

Reversal of Osteopenia in Ovariectomized Rats by Pentoxifylline: Evidence of Osteogenic and Osteo-Angiogenic Roles of the Drug.

Calcif Tissue Int 2019 Sep 7;105(3):294-307. Epub 2019 Jun 7.

Division of Endocrinology, CSIR-Central Drug Research Institute, Council of Scientific and Industrial Research, Lucknow, 226031, India.

Pentoxifylline (PTX) is a non-selective phosphodiesterase inhibitor and is used for the management of intermittent claudication. We tested whether PTX has oral efficacy in stimulating new bone formation. Rat calvarial osteoblasts (RCO) were used to study the effect of PTX on osteoblast differentiation and angiogenesis. Pharmacokinetic and pharmacodynamic studies were carried out in rats to determine an oral dose of PTX. In ovariectomized (OVX) rats with osteopenia, the effect of PTX on various skeletal parameters was studied, and compared with teriparatide. Effect of PTX on angiogenic signaling was studied by immunoblotting and relevant pharmacologic inhibitors. Bone vascularity was measured by intravenous injection of polystyrene fluorospheres followed by in vivo imaging, and angiogenesis was studied in vitro by tubulogenesis of endothelial cells and in vivo by Matrigel plug assay. Effective concentration (EC) of PTX in RCO was 8.2 nM and plasma PTX level was 7 nM/mL after single oral dosing of 25 mg/kg, which was 1/6th the clinically used dose. At this dose, PTX enhanced bone regeneration at femur osteotomy site and completely restored bone mass, microarchitecture, and strength in OVX rats. Furthermore, PTX increased surface referent bone formation parameters and serum bone formation marker (PINP) without affecting the resorption marker (CTX-1). PTX increased the expression of vascular endothelial growth factor and its receptor in bones and osteoblasts. PTX also increased skeletal vascularity, tubulogenesis of endothelial cells and in vivo angiogenesis. Taken together, our study suggested that PTX at 16% of adult human oral dose completely reversed osteopenia in OVX rats by osteogenic and osteo-angiogenic mechanisms.
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http://dx.doi.org/10.1007/s00223-019-00567-4DOI Listing
September 2019

Synthesis, Biological Evaluation, Structure-Activity Relationship, and Mechanism of Action Studies of Quinoline-Metronidazole Derivatives Against Experimental Visceral Leishmaniasis.

J Med Chem 2019 06 24;62(11):5655-5671. Epub 2019 May 24.

Academy of Scientific and Innovative Research (AcSIR) , Anusandhan Bhawan , New Delhi 110025 , India.

In our efforts to identify novel chemical scaffolds for the development of antileishmanial agents, a series of quinoline-metronidazole hybrid compounds was synthesized and tested against the murine model of visceral leishmaniasis. Among all synthesized derivatives, 15b and 15i showed significant antileishmanial efficacy against both extracellular promastigote (IC 9.54 and 5.42 μM, respectively) and intracellular amastigote (IC 9.81 and 3.75 μM, respectively) forms of Leishmania donovani with negligible cytotoxicity toward the host (J774 macrophages, Vero cells). However, compound 15i effectively inhibited the parasite burden in the liver and spleen (>80%) of infected BALB/c mice. Mechanistic studies revealed that 15i triggers oxidative stress which induces bioenergetic collapse and apoptosis of the parasite by decreasing ATP production and mitochondrial membrane potential. Structure-activity analyses and pharmacokinetic studies suggest 15i as a promising antileishmanial lead and emphasize the importance of quinoline-metronidazole series as a suitable platform for the future development of antileishmanial agents.
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http://dx.doi.org/10.1021/acs.jmedchem.9b00628DOI Listing
June 2019

ALPK1 hotspot mutation as a driver of human spiradenoma and spiradenocarcinoma.

Nat Commun 2019 05 17;10(1):2213. Epub 2019 May 17.

Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Cambridge, CB10 1SA, UK.

Spiradenoma and cylindroma are distinctive skin adnexal tumors with sweat gland differentiation and potential for malignant transformation and aggressive behaviour. We present the genomic analysis of 75 samples from 57 representative patients including 15 cylindromas, 17 spiradenomas, 2 cylindroma-spiradenoma hybrid tumors, and 24 low- and high-grade spiradenocarcinoma cases, together with morphologically benign precursor regions of these cancers. We reveal somatic or germline alterations of the CYLD gene in 15/15 cylindromas and 5/17 spiradenomas, yet only 2/24 spiradenocarcinomas. Notably, we find a recurrent missense mutation in the kinase domain of the ALPK1 gene in spiradenomas and spiradenocarcinomas, which is mutually exclusive from mutation of CYLD and can activate the NF-κB pathway in reporter assays. In addition, we show that high-grade spiradenocarcinomas carry loss-of-function TP53 mutations, while cylindromas may have disruptive mutations in DNMT3A. Thus, we reveal the genomic landscape of adnexal tumors and therapeutic targets.
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http://dx.doi.org/10.1038/s41467-019-09979-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6525246PMC
May 2019

Novel Tetrahydroquinazolinamines as Selective Histamine 3 Receptor Antagonists for the Treatment of Obesity.

J Med Chem 2019 05 29;62(9):4638-4655. Epub 2019 Apr 29.

Academy of Scientific and Innovative Research (AcSIR) , New Delhi 110001 , India.

The histamine 3 receptor (H3R) is a presynaptic receptor, which modulates several neurotransmitters including histamine and various essential physiological processes, such as feeding, arousal, cognition, and pain. The H3R is considered as a drug target for the treatment of several central nervous system disorders. We have synthesized and identified a novel series of 4-aryl-6-methyl-5,6,7,8-tetrahydroquinazolinamines that act as selective H3R antagonists. Among all the synthesized compounds, in vitro and docking studies suggested that the 4-methoxy-phenyl-substituted tetrahydroquinazolinamine compound 4c has potent and selective H3R antagonist activity (IC < 0.04 μM). Compound 4c did not exhibit any activity on the hERG ion channel and pan-assay interference compounds liability. Pharmacokinetic studies showed that 4c crosses the blood brain barrier, and in vivo studies demonstrated that 4c induces anorexia and weight loss in obese, but not in lean mice. These data reveal the therapeutic potential of 4c as an anti-obesity candidate drug via antagonizing the H3R.
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http://dx.doi.org/10.1021/acs.jmedchem.9b00241DOI Listing
May 2019

Neuropharmacokinetics: a bridging tool between CNS drug development and therapeutic outcome.

Drug Discov Today 2019 05 18;24(5):1166-1175. Epub 2019 Mar 18.

Academy of Scientific and Innovative Research, New Delhi, India; Pharmaceutics and Pharmacokinetics Division, CSIR - Central Drug Research Institute, Lucknow, Uttar Pradesh, India. Electronic address:

WHO classified neurological disorders to be among 6.3% of the global disease burden. Among the most central aspects of CNS drug development is the ability of novel molecules to cross the blood-brain barrier (BBB) to reach the target site over a desired time period for therapeutic action. Based on various aspects, brain pharmacokinetics is considered to be one of the foremost perspectives for the higher attrition rate of CNS biologics. Although drug traits are important, the BBB and blood-cerebrospinal fluid barrier together with transporters become the mechanistic approach behind CNS drug delivery. The present review emphasizes neuropharmacokinetic parameters, their importance, an assessment approach and the vast effect of transporters to brain drug distribution for CNS drug discovery.
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http://dx.doi.org/10.1016/j.drudis.2019.02.007DOI Listing
May 2019
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