Publications by authors named "Sudipta Saha"

108 Publications

Managing drug shortages during a pandemic: tocilizumab and COVID-19.

CMAJ 2021 05 5;193(21):E771-E776. Epub 2021 May 5.

Li Ka Shing Knowledge Institute (Verma, Saha, Razak), St. Michael's Hospital, Unity Health Toronto; Department of Medicine (Verma, Fralick, Kwan, Lapointe-Shaw, Tang, Morris, Razak); Institute of Health Policy, Management and Evaluation (Verma, Gibson, Razak); Dalla Lana School of Public Health (Bean, Gibson); Joint Centre for Bioethics (Bean, Gibson); and Department of Paediatrics (Greenberg), University of Toronto; Sunnybrook Health Sciences Centre (Bean); Sinai Health System (Fralick, Greenberg, Kwan, Morris); Department of Medicine (Lapointe-Shaw), and Toronto General Hospital Research Institute (Lapointe-Shaw), University Health Network; Women's Institute for Health System Solutions and Virtual Care (Lapointe-Shaw), Women's College Hospital; ICES Central (Lapointe-Shaw); Institute for Better Health (Tang), Trillium Health Partners; Division of Infectious Diseases (Morris), Sinai Health System and University Health Network, Toronto, Ont.; Department of Medicine (Pai), McMaster University; Hamilton Regional Laboratory Medicine Program (Pai); Hamilton Health Sciences (Pai), Hamilton, Ont.

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http://dx.doi.org/10.1503/cmaj.210531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8177913PMC
May 2021

G protein β5-ATM complexes drive acetaminophen-induced hepatotoxicity.

Redox Biol 2021 Jul 28;43:101965. Epub 2021 Apr 28.

Centre of Biomedical Research, Sanjay Gandhi Post-Graduate Institute of Medical Sciences Campus, Raebareli Road, Lucknow, Uttar Pradesh, 226014, India. Electronic address:

Excessive ingestion of the common analgesic acetaminophen (APAP) leads to severe hepatotoxicity. Here we identify G protein β5 (Gβ), elevated in livers from APAP overdose patients, as a critical regulator of cell death pathways and autophagic signaling in APAP-exposed liver. Liver-specific knockdown of Gβ in mice protected the liver from APAP-dependent fibrosis, cell loss, oxidative stress, and inflammation following either acute or chronic APAP administration. Conversely, overexpression of Gβ in liver was sufficient to drive hepatocyte dysfunction and loss. In hepatocytes, Gβ depletion ameliorated mitochondrial dysfunction, allowed for maintenance of ATP generation and mitigated APAP-induced cell death. Further, Gβ knockdown also reversed impacts of APAP on kinase cascades (e.g. ATM/AMPK) signaling to mammalian target of rapamycin (mTOR), a master regulator of autophagy and, as a result, interrupted autophagic flux. Though canonically relegated to nuclear DNA repair pathways, ATM also functions in the cytoplasm to control cell death and autophagy. Indeed, we now show that Gβ forms a direct, stable complex with the FAT domain of ATM, important for autophosphorylation-dependent kinase activation. These data provide a viable explanation for these novel, G protein-independent actions of Gβ in liver. Thus, Gβ sits at a critical nexus in multiple pathological sequelae driving APAP-dependent liver damage.
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http://dx.doi.org/10.1016/j.redox.2021.101965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105674PMC
July 2021

Fabrication of Imatinib Mesylate-Loaded Lactoferrin-Modified PEGylated Liquid Crystalline Nanoparticles for Mitochondrial-Dependent Apoptosis in Hepatocellular Carcinoma.

Mol Pharm 2021 03 23;18(3):1102-1120. Epub 2020 Dec 23.

Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raibareli Road, Lucknow 226025, India.

Hepatocellular carcinoma (HCC) is a major cause of concern as it has substantial morbidity associated with it. Previous reports have ascertained the antiproliferative activity of imatinib mesylate (IMS) against diverse types of carcinomas, but limited bioavailability has also been reported. The present study envisaged optimized IMS-loaded lactoferrin (LF)-modified PEGylated liquid crystalline nanoparticles (IMS-LF-LCNPs) for effective therapy of IMS to HCC via asialoglycoprotein receptor (ASGPR) targeting. Results displayed that IMS-LF-LCNPs presented an optimum particle size of 120.40 ± 2.75 nm, a zeta potential of +12.5 ± 0.23 mV, and 73.94 ± 2.69% release. High-resolution transmission electron microscopy and atomic force microscopy were used to confirm the surface architecture of IMS-LF-LCNPs. The results of cytotoxicity and 4,6-diamidino-2-phenylindole revealed that IMS-LF-LCNPs had the highest growth inhibition and significant apoptotic effects. Pharmacokinetics and biodistribution studies showed that IMS-LF-LCNPs have superior pharmacokinetic performance and targeted delivery compared to IMS-LCNPs and plain IMS, which was attributed to the targeting action of LF that targets the ASGPR in hepatic cells. Next, our in vivo experiment established that the HCC environment existed due to suppression of BAX, cyt , BAD, e-NOS, and caspase (3 and 9) genes, which thus owed upstream expression of Bcl-xl, iNOS, and Bcl-2 genes. The excellent therapeutic potential of IMS-LF-LCNPs began the significant stimulation of caspase-mediated apoptotic signals accountable for its anti-HCC prospect. H nuclear magnetic resonance (serum) metabolomics revealed that IMS-LF-LCNPs are capable of regulating the disturbed levels of metabolites linked to HCC triggered through -nitrosodiethylamine. Therefore, IMS-LF-LCNPs are a potentially effective formulation against HCC.
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http://dx.doi.org/10.1021/acs.molpharmaceut.0c01024DOI Listing
March 2021

Determining the serotype composition of mixed samples of pneumococcus using whole-genome sequencing.

Microb Genom 2021 01;7(1)

Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, Connecticut, USA.

Serotyping of is a critical tool in the surveillance of the pathogen and in the development and evaluation of vaccines. Whole-genome DNA sequencing and analysis is becoming increasingly common and is an effective method for pneumococcal serotype identification of pure isolates. However, because of the complexities of the pneumococcal capsular loci, current analysis software requires samples to be pure (or nearly pure) and only contain a single pneumococcal serotype. We introduce a new software tool called SeroCall, which can identify and quantitate the serotypes present in samples, even when several serotypes are present. The sample preparation, library preparation and sequencing follow standard laboratory protocols. The software runs as fast as or faster than existing identification tools on typical computing servers and is freely available under an open source licence at https://github.com/knightjimr/serocall. Using samples with known concentrations of different serotypes as well as blinded samples, we were able to accurately quantify the abundance of different serotypes of pneumococcus in mixed cultures, with 100 % accuracy for detecting the major serotype and up to 86 % accuracy for detecting minor serotypes. We were also able to track changes in serotype frequency over time in an experimental setting. This approach could be applied in both epidemiological field studies of pneumococcal colonization and experimental laboratory studies, and could provide a cheaper and more efficient method for serotyping than alternative approaches.
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http://dx.doi.org/10.1099/mgen.0.000494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115901PMC
January 2021

Depth-resolved Mueller matrix polarimetry microscopy of the rat cornea.

Biomed Opt Express 2020 Oct 30;11(10):5982-5994. Epub 2020 Sep 30.

Department of Biomedical Engineering, College of Engineering and Computing, Florida International University, 10555 West Flagler Street, Miami, FL 33174, USA.

Mueller matrix polarimetry (MMP) is a promising linear imaging modality that can enable visualization and measurement of the polarization properties of the cornea. Although the distribution of corneal birefringence has been reported, depth resolved MMP imaging of the cornea has not been archived and remains challenging. In this work, we perform depth-resolved imaging of the cornea using an improved system that combines Mueller matrix reflectance and transmission microscopy together with nonlinear microscopy utilizing second harmonic generation (SHG) and two photon excitation fluorescence (TPEF). We show that TPEF can reveal corneal epithelial cellular network while SHG can highlight the presence of corneal stromal lamellae. We then demonstrate that, in confocal reflectance measurement, as depth increases from 0 to 80 m both corneal depolarization and retardation increase. Furthermore, it is shown that the spatial distribution of corneal depolarization and retardation displays similar complexity in both reflectance (confocal and non-confocal) and transmission measurement, likely due to the strong degree of heterogeneity in the stromal lamellae.
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http://dx.doi.org/10.1364/BOE.402201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7587284PMC
October 2020

The Direct and Indirect Impact of SARS-CoV-2 Infections on Neonates: A Series of 26 Cases in Bangladesh.

Pediatr Infect Dis J 2020 12;39(12):e398-e405

From the Child Health Research Foundation, Dhaka, Bangladesh.

Background: The impact of SARS-CoV-2 on neonates remains largely unknown in low- and middle-income countries (LMICs). We provide an epidemiologic and clinical report of SARS-CoV-2 infections in neonates hospitalized in Bangladesh.

Methods: Outborn neonates admitted to Dhaka Shishu Hospital, a tertiary-care referral hospital, between 29 March and 1 July were screened for SARS-CoV-2. We reviewed clinical data, including chest radiograph and laboratory reports, and conducted SARS-CoV-2 genome sequencing. Patients were followed-up for 27-75 days. A subset of caregivers was also tested.

Results: Of 83 neonates tested, 26 were positive (median age 8 days). Most neonates were admitted with diagnosis unrelated to SARS-CoV-2: 11 presented with serious non-communicable diseases, 7 with early-onset sepsis, 5 with late-onset sepsis and 2 with pneumonia. In 3 of 5 chest radiograph, infiltrates and ground-glass or patchy opacities were noted. Two neonates developed metabolic acidosis, one developed disseminated intravascular coagulation. Most SARS-CoV-2 positive neonates were referred to government-designated COVID-19 hospitals, leading to gaps in treatment. Twenty-three neonates could be followed-up: 12 were healthy, 8 died and 3 were still seeking medical care. Of 9 caregivers tested, 8 were positive.

Conclusions: SARS-CoV-2 may have serious adverse effects on children born in LMICs. The virus likely contributed directly to two deaths, but the remaining 6 neonates who died had serious comorbidities. Positive SARS-CoV-2 test results led to gaps in immediate clinical care for other morbidities, which likely contributed to adverse outcomes. This case series emphasizes the need to understand COVID-19 in neonates in LMICs and its indirect impacts.
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http://dx.doi.org/10.1097/INF.0000000000002921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654949PMC
December 2020

Assessments of and antineoplastic potentials of β-sitosterol-loaded PEGylated niosomes against hepatocellular carcinoma.

J Liposome Res 2020 Sep 23:1-12. Epub 2020 Sep 23.

Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Lucknow, India.

β-sitosterol (BS), a phytosterol, exhibits ameliorative effects on hepatocellular carcinoma (HCC) due to its antioxidant activities. However, its poor aqueous solubility and negotiated bioavailability and short elimination half-life is a huge limitation for its therapeutic applications. To overcome these two shortcomings, BS-loaded niosomes were made to , film hydration method and process parameters were optimized using a three-factor Box-Behnken design. The optimized formulation (BSF) was further surface-modified with polyethylene glycol (PEG). The resulting niosomes (BSMF) have spherical shapes, particle sizes, 219.6 ± 1.98 nm with polydispersity index (PDI) and zeta potential of 0.078 ± 0.04 and -19.54 ± 0.19 mV, respectively. The drug loading, entrapment efficiency, and drug release at 24 h of the BSMF were found to be 16.72 ± 0.09%, 78.04 ± 0.92%, and 75.10 ± 3.06%, respectively. Moreover, BSMF showed significantly greater cytotoxic potentials on Hep G2 cells with an enhanced cellular uptake relative to pure BS and BSF. The BSMF also displayed potentially improved curative property of HCC in albino wistar rat. Thus, the BSMF could be one of the promising therapeutic modalities for HCC treatment in terms of targeting potential resulting in enhanced therapeutic efficacy.
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http://dx.doi.org/10.1080/08982104.2020.1820520DOI Listing
September 2020

Mapping disparities in homicide trends across Brazil: 2000-2014.

Inj Epidemiol 2020 Sep 7;7(1):47. Epub 2020 Sep 7.

Department of Health Surveillance, Ministry of Health, Brasilia, Brazil.

Background: Homicides are a major problem in Brazil. Drugs and arms trafficking, and land conflicts are three of the many factors driving homicide rates in Brazil. Understanding long-term spatiotemporal trends and social structural factors associated with homicides in Brazil would be useful for designing policies aimed at reducing homicide rates.

Methods: We obtained data from 2000 to 2014 from the Brazil Ministry of Health (MOH) Mortality Information System and sociodemographic data from the Brazil Institute of Geography and Statistics (IBGE). First, we quantified the rate of change in homicides at the municipality and state levels. Second, we used principal component regression and k-medoids clustering to examine differences in temporal trends across municipalities. Lastly, we used Bayesian hierarchical space-time models to describe spatio-temporal patterns and to assess the contribution of structural factors.

Results: There were significant variations in homicide rates across states and municipalities. We noted the largest decrease in homicide rates in the western and southeastern states of Sao Paulo, Rio de Janeiro and Espirito Santo, which coincided with an increase in homicide rates in the northeastern states of Ceará, Alagoas, Paraiba, Rio Grande Norte, Sergipe and Bahia during the fifteen-year period. The decrease in homicides in municipalities with populations of at least 250,000 coincided with an increase in municipalities with 25,000 people or less. Structural factors that predicted municipality-level homicide rates included crude domestic product, urbanization, border with neighboring countries and proportion of population aged fifteen to twenty-nine.

Conclusions: Our findings support both a dissemination hypothesis and an interiorization hypothesis. These findings should be considered when designing interventions to curb homicide rates.
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http://dx.doi.org/10.1186/s40621-020-00273-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487619PMC
September 2020

Safeguarding long-lived excitons from excimer traps in H-aggregated dye-assemblies.

Chem Sci 2020 Jun 21;11(22):5710-5715. Epub 2020 May 21.

Department of Chemical Sciences , Indian Institute of Science Education and Research (IISER) Kolkata , Mohanpur 741246 , India . Email:

The fate of perylene bisimide (PBI) H-aggregates as energy-harvesting materials depends on the ability to circumvent an extremely deleterious but efficient self-trapping process that scavenges the long-lived excitons to form deep excimeric traps. We present the first ever report of an ambient-stable, bright, steady-state photoluminescence (PL) from the long-lived exciton of an H-aggregated PBI crystal. The crystal structure reveals a rotationally displaced H-aggregated arrangement of PBI chromophores, in which transition from the lowest energy exciton state is partially allowed. Polarized absorption spectroscopy on single microcrystals confirms an unusually large exciton splitting of ∼1265 cm that stabilizes the lower exciton state, and inhibits excimer formation. A PL Mueller matrix study shows an increase in the excited state polarization anisotropy, indicating a strong localization of the nascent exciton, which further safeguards it from the self-trapping process. Finally, the possibility of achieving excimer-free excitonic PL in solution self-assembly is also demonstrated.
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http://dx.doi.org/10.1039/d0sc01784aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7441499PMC
June 2020

Biphasic changes in TGF-β1 signaling drive NSAID-induced multi-organ damage.

Free Radic Biol Med 2020 11 1;160:125-140. Epub 2020 Aug 1.

Centre of Biomedical Research, Sanjay Gandhi Post-Graduate Institute of Medical Sciences Campus, Raebareli Road, Lucknow, Uttar Pradesh, 226014, India. Electronic address:

The clinical utility of non-steroidal anti-inflammatory drugs (NSAIDs), used extensively worldwide, is limited by adverse cardiac events resulting from chronic drug exposure. Here, we provide evidence identifying transforming growth factor β (TGF-β1), released from multiple tissues, as a critical driver of NSAID-induced multi-organ damage. Biphasic changes in TGF-β1 levels in liver and heart were accompanied by ROS generation, cell death, fibrotic remodeling, compromised cardiac contractility and elevated liver enzymes. Pharmacological inhibition of TGF-βRI signaling markedly improved heart and liver function and increased overall survival of animals exposed to multiple NSAIDs, effects likely mediated by reductions in NOX-dependent ROS generation. Notably, the beneficial impact of TGF-βRI blockade was confined to a critical window wherein consecutive, but not concurrent, inhibitor administration improved cardiac and hepatic endpoints. Remarkably, in addition to ameliorating indomethacin-mediated myofilament disruptions, cardiac TGF-βRI knockdown lead to drastic reductions in TGF-β1 production accompanied by lessening in intestinal lesioning underscoring the importance of endocrine TGF-β1 signaling in NSAID-driven tissue injury. Indeed, gastric ulceration was associated with a higher incidence of cardiac complications in a human cohort underscoring the critical importance of circulation-facilitated peripheral organ system interconnectedness in efforts seeking to mitigate the toxic side effects of chronic NSAID use.
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http://dx.doi.org/10.1016/j.freeradbiomed.2020.06.026DOI Listing
November 2020

Survival of Patients With Short-Bowel Syndrome on Home Parenteral Nutrition: A Prospective Cohort Study.

JPEN J Parenter Enteral Nutr 2020 Aug 2. Epub 2020 Aug 2.

Department of Medicine, Toronto General Hospital, University of Toronto, Toronto, Canada.

Background: Survival of patients with short-bowel syndrome (SBS) receiving home parenteral nutrition (HPN) and associated factors have not been reported recently in North America. The objective of this study was to determine the long-term survival of adult patients with SBS as the primary indication for HPN and assess factors that may affect survival by using the Canadian HPN Registry.

Methods: This is a retrospective analysis of prospectively collected data extracted from the HPN registry, prior to approval of teduglutide in Canada. Using only incident cases, survival probabilities were estimated by using the Kaplan-Meier method for both full-cohort and nonmalignant SBS. Log-rank test was also used to test the differences in survival distributions between subgroups in the univariate analysis. To identify potential variables that are affecting survival distribution of patients for the multivariable analysis, Least Absolute Shrinkage and Selection Operator and stepwise selection procedure were used.

Results: There were 321 patients with a known duration receiving HPN (total, 2287 years), of whom 218 were entered into the registry within 1 year of initiation of HPN. Of 218 incident cases, 22 had active malignancy, along with SBS, and their survival time was significantly lower than those with nonmalignant SBS (P-value < .0001). The 5-year survival of nonmalignant-SBS patients was 81.9%. In this subgroup, there was no significant association between patients' survival and known intestinal anatomy, age, or sex.

Conclusion: Patients with nonmalignant SBS who receive HPN have a 5-year survival of >80%. Known intestinal anatomical factors did not affect survival.
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http://dx.doi.org/10.1002/jpen.1984DOI Listing
August 2020

Malignant Brenner tumour of the ovary manifesting as distal intestinal obstruction and perforation.

BMJ Case Rep 2020 Jun 11;13(6). Epub 2020 Jun 11.

Department of Surgical Disciplines, All India Institute of Medical Sciences, New Delhi, India

A rare case of malignant Brenner tumour of ovary manifesting with intestinal perforation due to colonic infiltration is elaborated in the present report. Brenner's tumour accounts for 1%-2% of all ovarian neoplasms and malignant Brenner tumour is even rarer and only about 5% of Brenner tumours are malignant. A 62-year-old woman came to surgical emergency with 1-month history of abdominal pain, vomiting and constipation with a palpable mass in right iliac fossa. Abdominal radiograph was suggestive of colonic obstruction. Contrast-enhanced CT of the abdomen revealed cystic right ovarian mass of 10.2×8.8 cm with pneumoperitoneum. Exploratory laparotomy was done, which revealed mass arising from right ovary involving terminal ileum, cecum and ascending colon. Possibility of ovarian malignancy was kept. Patient underwent debulking surgery along with ileostomy and descending colon mucous fistula was created. Histology was compatible with malignant Brenner tumour of the ovary.
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http://dx.doi.org/10.1136/bcr-2020-235394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295371PMC
June 2020

Self validating Mueller matrix Micro-Mesoscope (SAMMM) for the characterization of biological media.

Opt Lett 2020 Apr;45(8):2168-2171

Reflectance Mueller matrix (MM) polarimetry is being used to characterize biological media in multiple clinical applications. The origin of the reflectance polarimetric data is often unclear due to the impact of multiple scattering and tissue heterogeneity. We have developed a new, to the best of our knowledge, multimodal imaging technique combining MM reflectance, MM digital confocal imaging, and co-registered nonlinear microscopy techniques. The instrument unveils the origin of reflectance polarimetric signature in terms of confocal reflectance data. The reconstructed reflected MM demonstrates the capability of our method to provide depth-resolved 3D polarization response from complex biological media in terms of depolarization, retardance, and orientation parameters.
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http://dx.doi.org/10.1364/OL.387747DOI Listing
April 2020

Mechanistic exploration of the activities of poly(lactic--glycolic acid)-loaded nanoparticles of betulinic acid against hepatocellular carcinoma at cellular and molecular levels.

Arch Physiol Biochem 2020 Mar 6:1-13. Epub 2020 Mar 6.

Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Lucknow, Uttar Pradesh, India.

The effectiveness of betulinic acid (B) and PLGA loaded nanoparticles of B (Bnp) against hepatocellular carcinoma (HCC) was established and reported earlier. In continuation of our previous report, the present study described the molecular mechanisms of their antineoplastic responses. In this context, the antineoplastic properties of both B and Bnp were evaluated on DEN-induced HCC rat model. The quantitative real-time polymerase chain reaction and western blot analyses revealed that HCC was developed through lower expressions of e-NOS, BAX, BAD, Cyt C and higher expressions of i-NOS, Bcl-xl, Bcl-2. B and Bnp normalised the expressions of these apoptogenic markers. Particularly, both activated i-NOS and e-NOS mediated Bcl-2 family proteins→CytC→Caspase 3 and 9 signalling cascades. The H-NMR-based metabolomics study also demonstrated that the perturbed metabolites in DEN-induced rat serum restored to the normal level following both treatments. Moreover, the antineoplastic potential of Bnp was found to be comparable with the marketed product, 5-flurouracil.
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http://dx.doi.org/10.1080/13813455.2020.1733024DOI Listing
March 2020

Study of correlation of urodynamic profile with symptom scoring and ultrasonographic parameters in patients with benign prostatic hyperplasia.

J Family Med Prim Care 2020 Jan 28;9(1):215-220. Epub 2020 Jan 28.

Department of General Surgery, Lady Hardinge Medical College, New Delhi, India.

Context: Urodynamic study (UDS) and ultrasonography (USG) both are established investigations to assess the patients of benign prostatic hyperplasia (BPH). It is known that the prostate mass (PM) and post-void residual urine volume (PVR) are not significantly related to the patients' symptoms and degree of obstruction; however, the relation between the UDS, USG and patient's International Prostate Symptom Scoring (IPSS) has not been defined.

Aims: To correlate the urodynamic parameters with IPSS, PM and PVR in patients with lower urinary tract symptoms (LUTS) suggestive of BPH.

Settings And Design: An observational study carried out as a thesis project.

Methods And Materials: Thirty male patients aged more than 40 years with LUTS suggestive of BPH were selected and underwent USG, UDS and IPSS. In UDS, the parameters studied were the maximum flow rate (Q), detrusor pressure (P) and bladder compliance (BC). PM and PVR were studied in the USG.

Statistical Analysis Used: IBM Statistical Package for the Social Sciences (SPSS) software version 16 (SPSS Inc., Chicago, USA). Pearson's correlation and two-sided significance levels were determined.

Results: 1. Significant negative correlation between Q and PVR ( = -0.404, = 0.027); PM ( = -0.655, = <0.001) and IPSS ( = -0.563, = 0.001). 2. Significant positive correlation between P and PVR ( = 0.535, = 0.002); PM ( = 0.719, = <0.001) and IPSS ( = 0.649, = <0.001). 3. Significant negative correlation between BC and PVR ( = -0.490, = 0.006); PM ( = -0.654, = <0.001) and IPSS ( = -0.667, = <0.001).

Conclusions: UDS has a significant correlation with IPSS and USG findings and urodynamic parameters give a more specific diagnosis in BPH patients when it is combined with USG and IPSS.
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http://dx.doi.org/10.4103/jfmpc.jfmpc_698_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7014908PMC
January 2020

Author Correction: Novel Indole-fused benzo-oxazepines (IFBOs) inhibit invasion of hepatocellular carcinoma by targeting IL-6 mediated JAK2/STAT3 oncogenic signals.

Sci Rep 2020 Feb 6;10(1):2391. Epub 2020 Feb 6.

Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raibareli Road, Lucknow, 226025, India.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-020-59134-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002741PMC
February 2020

Appraisal of anti-gout potential of colchicine-loaded chitosan nanoparticle gel in uric acid-induced gout animal model.

Arch Physiol Biochem 2019 Dec 18:1-11. Epub 2019 Dec 18.

Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Lucknow, India.

Present study is aimed at transdermal delivery of colchicine-loaded chitosan nanoparticles. The nanoformulations were prepared utilising spontaneous emulsification method and optimised through 2 factorial designs. The optimised formulation (CHNP-OPT) displayed an average particle size of 294 ± 3.75 nm, entrapment efficiency 92.89 ± 1.1% and drug content 83.45 ± 2.5%, respectively. release study demonstrated 89.34 ± 2.90% release over a period of 24 h. Further, CHNP-OPT incorporated into HPMC-E4M (hydroxypropyl methylcellulose) to form transdermal gel. CHNP displayed 74.65 ± 1.90% permeation and stability over a period of 90 days. The anti-gout potential of CHNP formulation was evaluated against monosodium urate (MSU) crystal-induced gout in animal model. There was significant reduction in uric acid level, during MSU administration, when compared with the conventional gel of colchicine. The enhanced therapeutic potential was witnessed through X-ray. The study revealed that colchicine-loaded CHNP proved their supremacy over plain colchicine and can be an efficient delivery system for gout treatment.
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http://dx.doi.org/10.1080/13813455.2019.1702702DOI Listing
December 2019

Malabaricone C Attenuates Nonsteroidal Anti-Inflammatory Drug-Induced Gastric Ulceration by Decreasing Oxidative/Nitrative Stress and Inflammation and Promoting Angiogenic Autohealing.

Antioxid Redox Signal 2020 04 10;32(11):766-784. Epub 2020 Jan 10.

Centre of Biomedical Research, Sanjay Gandhi Post-Graduate Institute of Medical Sciences Campus, Lucknow, India.

Nonsteroidal anti-inflammatory drugs (NSAIDs), among the most commonly used drugs worldwide, are associated with gastrointestinal (GI) complications that severely limit the clinical utility of this essential class of pain medications. Here, we mechanistically dissect the protective impact of a natural product, malabaricone C (Mal C), on NSAID-induced gastropathy. Mal C dose dependently diminished erosion of the stomach lining and inflammation in mice treated with NSAIDs with the protective impact translating to improvement in survival. By decreasing oxidative and nitrative stress, Mal C treatment prevented NSAID-induced mitochondrial dysfunction and cell death; nuclear factor κ-light-chain enhancer of activated B cell induction, release of proinflammatory cytokines and neutrophil infiltration; and disruptions in the vascular endothelial growth factor/endostatin balance that contributes to mucosal autohealing. Importantly, Mal C failed to impact the therapeutic anti-inflammatory properties of multiple NSAIDs in a model of acute inflammation. In all assays tested, Mal C proved as or more efficacious than the current first-line therapy for NSAID-dependent GI complications, the proton pump inhibitor omeprazole. Given that omeprazole-mediated prophylaxis is, itself, associated with a shift in NSAID-driven GI complications from the upper GI to the lower GI system, there is a clear and present need for novel therapeutics aimed at ameliorating NSAID-induced gastropathy. Mal C provided significant protection against NSAID-induced gastric ulcerations impacting multiple critical signaling cascades contributing to inflammation, cell loss, extracellular matrix degradation, and angiogenic autohealing. Thus, Mal C represents a viable lead compound for the development of novel gastroprotective agents.
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http://dx.doi.org/10.1089/ars.2019.7781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7071091PMC
April 2020

Antineoplastic properties of zafirlukast against hepatocellular carcinoma via activation of mitochondrial mediated apoptosis.

Regul Toxicol Pharmacol 2019 Dec 9;109:104489. Epub 2019 Oct 9.

Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raibareli Road, Lucknow, 226025, India. Electronic address:

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwideand haslimited treatment options. In view of this, zafirlukast (ZAF) was administered orally to DEN-induced HCC rats to evaluate its antineoplastic properties. ELISA, qRT-PCR and Western blot were used to determine the molecular mechanism associated with ZAF therapy for HCC. We found that HCC developed as a result of lower expression of caspases 3 and 9, but their levels returned to normal when the expression of eNOS, BAX, BAD, and Cyt C was decreased and when the expression of iNOS, Bcl-xl, and Bcl-2 was increased. Again, ZAF (80 mg/kg dose) treatment normalized the expression of caspase-mediated apoptotic factors, i.e. BAX and Bcl-2 proteins, as established through Western blot analysis. Later, H NMR-based serum metabolomics study revealed that levels of perturbed metabolites in DEN-induced rat serum returned to normal after ZAF administration. Altogether, the antineoplastic potential of ZAF was found to be comparable, and to some degree better, than the marketed chemotherapeutic 5-flurouracil, which may be beneficial for anti-HCC treatment from a future drug design perspective.
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http://dx.doi.org/10.1016/j.yrtph.2019.104489DOI Listing
December 2019

Towards making global health research truly global.

Lancet Glob Health 2019 09;7(9):e1175

Child Health Research Foundation, Department of Microbiology, Dhaka Shishu Hospital, Dhaka 1207, Bangladesh; Bangladesh Institute of Child Health, Dhaka Shishu Hospital, Dhaka, Bangladesh.

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http://dx.doi.org/10.1016/S2214-109X(19)30259-1DOI Listing
September 2019

"Dial-In" Emission from a Unique Flexible Material with Polarization Tuneable Spectral Intensity.

Chemistry 2019 Oct 13;25(59):13514-13522. Epub 2019 Sep 13.

Polymer Research Centre (PRC), Centre for Advanced, Functional Materials (CAFM), Department of Chemical Sciences, Indian Institute of Science Education and Research Kolkata (IISER K), Mohanpur, West Bengal, 741 246, India.

The development of organic photoluminescent materials, which show promising roles as catalysts, sensors, organic light-emitting diodes, logic gates, etc., is a major demand and challenge for the global scientific community. In this context, a photoclick polymerization method is adopted for the growth of a unique photoluminescent three-dimensional (3D) polymer film, E, as a model system that shows emission tunability over the range 350-650 nm against the excitation range 295-425 nm. The DFT analysis of energy calculations and π-stacking supports the spectroscopic observations for the material exhibiting a broad range of emission owing to newly formed chromophoric units within the film. Full polarization spectroscopic Mueller matrix studies were employed to extract and quantify the molecular orientational order of both the ground (excitation) and excited (emission) state anisotropies through a set of newly defined parameters, namely the fluorescence diattenuation and fluorescence polarizance. The information contained in the recorded fluorescence Mueller matrix of the organic polymer material provided a useful way to control the spectral intensity of emission by using pre- and post-selection of polarization states. The observation was based on the assumption that the longer lifetime of the excited dipolar orientation is attributed to the compactness of the film.
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http://dx.doi.org/10.1002/chem.201902333DOI Listing
October 2019

Zolmitriptan attenuates hepatocellular carcinoma via activation of caspase mediated apoptosis.

Chem Biol Interact 2019 Aug 23;308:120-129. Epub 2019 May 23.

Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raibareli Road, Lucknow, 226025, India. Electronic address:

A preclinical study using DEN-induced HCC rat model was attempted to evaluate the antitumor potential of zolmitriptan (ZOL). The molecular insights were investigated using ELISA, qRT-PCR and Western blot techniques. The result confirmed that the HCC condition was developed in response to lower expressions of caspase 3 and 9 which, in turn, was due to the upstream regulation of iNOS, Bcl-xl and Bcl-2, and downstream regulation of eNOS, BAX, BAD and Cyt C. The treatment with ZOL caused the significant activation of caspase mediated apoptotic signals that could be responsible for its anti-HCC potential. Later, H NMR based serum metabolomics study confirmed that ZOL restored the perturbed metabolites associated with DEN-induced HCC. The antineoplastic potential of ZOL was found comparable or to some degree better than the marketed chemotherapeutics, 5-flurouracil.
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http://dx.doi.org/10.1016/j.cbi.2019.05.033DOI Listing
August 2019

Regulation of HDAC1 and HDAC2 during consolidation and extinction of fear memory.

Brain Res Bull 2019 08 17;150:86-101. Epub 2019 May 17.

Department of Biotechnology, Babasaheb Bhimrao Ambedkar University, Lucknow, India; Department of Biotech, Mahatma Gandhi Central University, Motihari, Bihar, India. Electronic address:

Histone deacetylases (HDACs) regulate gene expression epigenetically through synchronized removal of acetyl groups from histones required towards memory consolidation. Moreover, dysregulated epigenetic machinery during fear or extinction learning may result in altered expression of some of these genes and result in Post Traumatic Stress Disorder (PTSD). In the present study, region-specific expression of Histone deacetylase 1 (HDAC1) and Histone deacetylase 2 (HDAC2) was correlated to the acetylation of histones H3 and H4 and the resultant conditioned response, in rats undergone fear and extinction learning. The neuronal activation, histone acetylation at H3/H4 and expression of HDAC1/HDAC2 in centrolateral amygdala (CeL) and centromedial amygdala (CeM) of central Amygdala (CeA) and prelimbic (PL) and infralimbic (IL) of Prefrontal cortex (PFC) were found to be associated in a differential manner following fear and extinction learning. Moreover in CeM, the main output of the fear circuitry, the level of HDAC1 was down-regulated following conditioning and up-regulated following extinction as opposed to which HDAC2 was down-regulated in CeM following conditioning but not following extinction. Furthermore, in CeL the HDAC1 was upregulated and HDAC2 was downregulated following conditioning and extinction. This has important implications in speculating of the role of HDACs in fear memory consolidation and its extinction.
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http://dx.doi.org/10.1016/j.brainresbull.2019.05.011DOI Listing
August 2019

Biological Efficacy of Medicinal Plant Extracts in Preventing Oxidative Damage.

Oxid Med Cell Longev 2018;2018:7904349. Epub 2018 Sep 13.

Babasaheb Ambedkar University, Lucknow, India.

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http://dx.doi.org/10.1155/2018/7904349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6158943PMC
December 2018

Barriers in Bangladesh.

Elife 2018 09 20;7. Epub 2018 Sep 20.

Child Health Research Foundation, Department of Microbiology, Dhaka Shishu Hospital, Dhaka, Bangladesh.

Research laboratories in low- and middle-income countries, where the global burden of disease is highest, face systemic challenges in conducting research and public health surveillance. An international effort is needed to overcome the paywalls, customs regulations and lack of local suppliers that hinder the scientific community in these countries.
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http://dx.doi.org/10.7554/eLife.41926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6147737PMC
September 2018

Betulinic acid as apoptosis activator: Molecular mechanisms, mathematical modeling and chemical modifications.

Life Sci 2018 Sep 1;209:24-33. Epub 2018 Aug 1.

Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raebareli Road, Lucknow 226025, India. Electronic address:

A natural product betulinic acid (BA) has gained a huge significance in the recent years for its strong cytotoxicity. Surprisingly, in spite of being an interesting cancer protecting agent on a variety of tumor cells, the normal cells and tissues are rarely affected by BA. Betulinic acid and analogues (BAs) generally exert through the mechanisms that provokes an event of direct cell death and bypass the resistance to normal chemotherapeutics. Although the major mechanism associated with its ability to induce direct cell death is mitochondrial apoptosis, there are several other mechanisms explored recently. Importantly, mathematical modeling of apoptosis has been an important tool to explore the precise mechanism involved in mitochondrial apoptosis. Thus, this review is an endeavor to sum up the molecular mechanisms underlying the action of BA and future directions to apply mathematical modeling technique to better understand the precise mechanism of BA-induced apoptosis. The last section of the review encompasses the plausible structural modifications and formulations to enhance the therapeutic efficacy of BA.
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http://dx.doi.org/10.1016/j.lfs.2018.07.056DOI Listing
September 2018

Decreased level of histone acetylation in the infralimbic prefrontal cortex following immediate extinction may result in deficit of extinction memory.

Brain Res Bull 2018 06 15;140:355-364. Epub 2018 Jun 15.

Department of Biotechnology, Babasaheb Bhimrao Ambedkar University, Lucknow, India; Department of Biotech, Mahatma Gandhi Central University, Bihar, India. Electronic address:

In the last few decades, there has been exponential increase in studies aiming to trace the molecular mechanism of fear extinction with a hope to minimize the return of fear after exposure therapy required for operational treatment of anxiety disorders. The present study explored how the timing of extinction training after developing a specific fear, affects the consequent return of the extinguished fear and the role of histone acetylation in controlling the circuitry, thereof. It was found that rats undergone extinction training 10 min. after fear memory acquisition (Immediate Extinction) had deficits in retention of extinction memory as compared to one which underwent extinction 24 h after fear acquisition (Delayed Extinction). When the differences were sorted at the circuitry level the relative activity of the infralimbic prefrontal cortex (IL) to prelimbic cortex (PL) was found to be lower in the immediate extinction group as compared to the delayed extinction group as evidenced by the c-fos expression in the mPFC of these groups. Further investigation showed that acetylation of histone H3/H4 along with the levels of CREB binding protein (CBP) which is a histone acetyltransferase (HAT), was associated with neuronal activation and was significantly lower in the IL of the immediate extinction group than the delayed extinction group. In conclusion, the observed deficits in the immediate extinction group may be the result of compromised activation of IL, which in turn may be associated with changes in histone acetylation.
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http://dx.doi.org/10.1016/j.brainresbull.2018.06.004DOI Listing
June 2018

Localization of MIF-II on mammalian spermatozoa: A study revealing its structure, function and motility inhibitory pathway.

Int J Biol Macromol 2018 Sep 30;116:633-647. Epub 2018 Apr 30.

Sperm Biology Laboratory, Cell Biology and Physiology Division, CSIR-Indian Institute of Chemical Biology, Kolkata - 700032, India. Electronic address:

Motility of spermatozoa is a crucial factor for determining semen quality. Here we report motility inhibitory factor (MIF-II) from goat epididymal plasma, revealing its structure, function, localization and motility inhibitory pathway. Structural characterization with MALDI revealed novelty of this protein while circular dichroism data confirmed its alpha helical nature. Higher dilutions of MIF-II antibody increased cauda sperm motility and induced immature/immotile caput sperm motility as tested microscopically. Higher number of sperm cells and lower dilutions of antibody induced agglutination in cauda sperm showing surface localization. Indirect immuno-fluorescence showed MIF-II localization throughout the caput sperm surface which relocated more towards acrosomal region with maturation. ELISA assay revealed gradual increase and decrease in concentration of MIF-II in epididymal plasma and plasma membrane respectively from caput to cauda. Signaling cascade that leads to sperm motility inhibition elevates nitric oxide levels through cAMP dependent pathway. MIF-II treatment doesn't alter sperm surface morphology. Expression pattern of MIF-II during epididymal maturation goes hand-in-hand with gaining motility potential as well as dormancy of spermatozoa before ejaculation. Both MIF-II and its antibody inhibit fertilization in-vitro thus expected to open new gateway for future male infertility and contraceptive development research.
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http://dx.doi.org/10.1016/j.ijbiomac.2018.04.143DOI Listing
September 2018

Novel Indole-fused benzo-oxazepines (IFBOs) inhibit invasion of hepatocellular carcinoma by targeting IL-6 mediated JAK2/STAT3 oncogenic signals.

Sci Rep 2018 04 12;8(1):5932. Epub 2018 Apr 12.

Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raibareli Road, Lucknow, 226025, India.

Inspired by the well-documented tumor protecting ability of paullones, recently, we synthesized novel paullone-like scaffolds, indole-fused benzo-oxazepines (IFBOs), and screened them against hepatocellular carcinoma (HCC) specific Hep-G2 cells. Three of the synthesized compounds significantly attenuated the progression of HCC in vitro. By computational studies, we further discovered that IFBOs exhibited a stable binding complex with the IL-6 receptor. In this context, we investigated in vivo study using the nitrosodiethyl amine (NDEA)-induced HCC model, which strengthened our previous findings by showing the blockade of the IL-6 mediated JAK2/STAT3 oncogenic signaling pathway. Treatment with IFBOs showed remarkable attenuation of cellular proliferation, as evidenced through a decrease in the number of nodules, restoration of body weight, oxidative stress parameters, liver marker enzymes and histological architecture. Interestingly, using a metabolomic approach we further discovered that IFBOs can restore the perturbed metabolic profile associated with the HCC condition to normalcy. Particularly, the efficacy of compound 6a for an anti-HCC response was significantly better than the marketed chemotherapeutic drug, 5-fluorouracil. Altogether, these remarkable findings open up possibilities of developing IFBOs as novel future candidate molecules for plausible alternatives for HCC treatment.
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http://dx.doi.org/10.1038/s41598-018-24288-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5897576PMC
April 2018