Publications by authors named "Milon Mondal"

32 Publications

Antioxidant mediated protective effect of leaf extract against carbofuran induced oxidative hepatic toxicity.

Toxicol Rep 2021 8;8:1369-1380. Epub 2021 Jul 8.

Department of Pharmacy, Jahangirnagar University, Savar, Dhaka, 1342, Bangladesh.

is a traditional medicinal plant for treating diverse ailments. Hence, we designed our study to scrutinize the protective effect of the methanol extract of leaf (BTL) against carbofuran-induced oxidative stress-mediated hepato-toxicity in Sprague-Dawley rats for the first time, along with the identification and quantification of phenolic acids and flavonoids by high-performance liquid chromatography (HPLC) and evaluation of antioxidant and antiradical activities of this extract. HPLC analysis confirmed the existence of tannic acid, gallic acid, salicylic acid, and naringin in leaf extract which showed in-vitro antioxidant potentialities with DPPH, nitric oxide, hydrogen peroxide, and hydroxyl radical scavenging properties. Co-administration of leaf extract with carbofuran showed dose-dependent significant protective effects of hepatic toxicity on serum markers such as alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, γ-glutamyl-transferase, lactate dehydrogenase, total bilirubin, total protein, albumin, globulin, lipid profile, urea, uric acid, and creatinine. Carbofuran intoxication also revealed an upsurge in malondialdehyde (MDA) and a decline in cellular endogenous antioxidant enzyme levels in rats compared with the control group. However, leaf extract co-treatment increased the levels of hepatic antioxidant enzymes, such as superoxide dismutase, catalase, and glutathione peroxidase, and amended the MDA level. Similarly, histopathological evaluation further assured that BTL could keep the hepatocyte from carbofuran-induced damage. Therefore, all of our findings may conclude that the phenolic acids and flavonoids of leaf extract are responsible to neutralize the toxic free radical-mediated oxidative hepatic damages.
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http://dx.doi.org/10.1016/j.toxrep.2021.07.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278150PMC
July 2021

Role of L. Fruits Extract in Combatting the Hematological and Hepatic Toxic Effects of Carbofuran.

Chem Res Toxicol 2021 Jul 15. Epub 2021 Jul 15.

Department of Pharmacy, Jahangirnagar University, Savar, Dhaka 1342, Bangladesh.

L. is rich in numerous vital bioactive constituents, though it is an underutilized among the citrus genus. Therefore, the aim of the present investigation was to evaluate the protective role of the fruit (CMF) methanol extract against carbofuran (CF)-induced toxicity in experimental rats. In addition, this work aims at detecting and measuring polyphenolic compounds by means of high-performance liquid chromatography (HPLC) and evaluation of the antioxidant activity of this extract. For this, studies dealing with serum hematological and biochemical parameters, liver endogenous antioxidants, as well as hepatic histo-architectural features have been carried out to assess the protective ability of CMF against CF-induced toxicity. Additionally, total phenol, flavonoid, and antioxidant capability were measured and the antioxidant action was investigated using DPPH and nitric oxide radical scavenging assays as well as reducing power assessments. HPLC results revealed the presence of benzoic acid, cinnamic acid, gallic acid, quercetin, and salicylic acid in CMF extract. Furthermore, results showed that CMF has considerable total phenol, flavonoid, and antioxidant capability and exhibits significant free radical scavenging and reducing potentialities. On the other hand, CF intoxication of rats significantly altered the hematological and serum biochemical parameters with hepatocytes disruption. Carbofuran also caused an upsurge in malondialdehyde (MDA) level and a decline in hepatic cellular antioxidant enzymes levels in rats compared to the control group. Co-administration of CMF amended the anomalies and improved the histo-architectural arrangement of hepatocytes in treated groups. CMF also inhibited the alteration of endogenous antioxidant enzymes and MDA levels as compared to the carbofuran treated group and returned them to their normal state. Taken all together, results from this investigation highlight the protective role of CMF against CF-induced toxicity which might be attributed to the polyphenolic constituents of the extract.
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http://dx.doi.org/10.1021/acs.chemrestox.1c00166DOI Listing
July 2021

L.: From Farm to a Source of Bioactive Compounds with Therapeutic Activity.

Evid Based Complement Alternat Med 2021 1;2021:9965481. Epub 2021 Jun 1.

Natural and Medical Sciences Research Centre, University of Nizwa, Birkat Almouz 616, Oman.

This study aimed to summarize the available data on the ethnomedicinal and phytopharmacological activities of L. based on database reports. For this purpose, an up-to-date literature search was carried out in the Google Scholar, Scopus, Springer Link, Web of Science, ScienceDirect, ResearchGate, PubMed, Chem Spider, Elsevier, BioMed Central, and patent offices (e.g., USPTO, CIPO, NPI, Google patents, and Espacenet) for the published materials. The findings suggest that the plant contains many important phytochemicals, including pyrrolizidine alkaloids, indicine, echinitine, supinine, heleurine, heliotrine, lasiocarpine, acetyl indicine, indicinine, indicine -oxide, cynoglossine, europine -oxide, heleurine -oxide, heliotridine -oxide, heliotrine -oxide, heliotrine, volatile oils, triterpenes, amines, and sterols. Scientific reports revealed that the herb showed antioxidant, analgesic, antimicrobial, anticancer, antituberculosis, antiplasmodial, anticataract, antifertility, wound healing, antiinflammatory, antinociceptive, antihyperglycemic, anthelmintic, diuretic, antitussive, antiglaucoma, antiallergic, and larvicidal activity. In conclusion, studies with animal models seem to show the potential beneficial effects of against a wide variety of disorders and as a source of phytotherapeutic compounds. However, clinical studies are necessary to confirm the effects observed in animal models, determine the toxicity of the therapeutic dose and isolate the truly bioactive components.
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http://dx.doi.org/10.1155/2021/9965481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187075PMC
June 2021

Effects of nerol on paracetamol-induced liver damage in Wistar albino rats.

Biomed Pharmacother 2021 Aug 12;140:111732. Epub 2021 Jun 12.

Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Electronic address:

Nerol, a monoterpene is evident to possess diverse biological activities, including antioxidant, anti-microbial, anti-spasmodic, anthelmintic, and anti-arrhythmias. This study aims to evaluate its hepatoprotective effect against paracetamol-induced liver toxicity in a rat model. Five groups of rats (n = 7) were orally treated (once daily) with 0.05% tween 80 dissolved in 0.9% NaCl solution (vehicle), paracetamol 640 mg/kg (negative control), 50 mg/kg silymarin (positive control), or nerol (50 and 100 mg/kg) for 14 days, followed by the hepatotoxicity induction using paracetamol (PCM). The blood samples and livers of the animals were collected and subjected to biochemical and microscopical analysis. The histological findings suggest that paracetamol caused lymphocyte infiltration and marked necrosis, whereas maintenance of the normal hepatic structural was observed in group pre-treated with silymarin and nerol. The rats pre-treated with nerol significantly and dose-dependently reduced the hepatotoxic markers in animals. Nerol at 100 mg/kg significantly reversed the paracetamol-induced altered situations, including the liver enzymes, plasma proteins, antioxidant enzymes and serum bilirubin, lipid peroxidation (LPO) and cholesterol [e.g., total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c)] levels in animals. Taken together, nerol exerted significant hepatoprotective activity in rats in a dose-dependent manner. PCM-induced toxicity and nerol induced hepatoprotective effects based on expression of inflammatory and apoptosis factors will be future line of work for establishing the precise mechanism of action of nerol in Wistar albino rats.
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http://dx.doi.org/10.1016/j.biopha.2021.111732DOI Listing
August 2021

Therapeutic perspectives of the black cumin component thymoquinone: A review.

Food Funct 2021 Jul 4;12(14):6167-6213. Epub 2021 Jun 4.

Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj-8100, Bangladesh.

The dietary phytochemical thymoquinone (TQ), belonging to the family of quinones, mainly obtained from the black and angular seeds of Nigella sativa, is one of the promising monoterpenoid hydrocarbons, which has been receiving massive attention for its therapeutic potential and pharmacological properties. It plays an important role as a chemopreventive and therapeutic agent in the treatment of various diseases and illnesses. The aim of this review is to present a summary of the most recent literature pertaining to the use of TQ for the prevention and treatment of various diseases along with possible mechanisms of action, and the potential use of this natural product as a complementary or alternative medicine. Research findings indicated that TQ exhibits numerous pharmacological activities including antioxidant, anti-inflammatory, cardioprotective, hepatoprotective, antidiabetic, neuroprotective, and anticancer, among others. Conclusions of this review on the therapeutic aspects of TQ highlight the medicinal and folk values of this compound against various diseases and ailments. In short, TQ could be a novel drug in clinical trials, as we hope.
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http://dx.doi.org/10.1039/d1fo00401hDOI Listing
July 2021

Photochemical Probe Identification of a Small-Molecule Inhibitor Binding Site in Hedgehog Acyltransferase (HHAT)*.

Angew Chem Int Ed Engl 2021 06 14;60(24):13542-13547. Epub 2021 May 14.

Department of Chemistry, Imperial College London, London, W12 0BZ, UK.

The mammalian membrane-bound O-acyltransferase (MBOAT) superfamily is involved in biological processes including growth, development and appetite sensing. MBOATs are attractive drug targets in cancer and obesity; however, information on the binding site and molecular mechanisms underlying small-molecule inhibition is elusive. This study reports rational development of a photochemical probe to interrogate a novel small-molecule inhibitor binding site in the human MBOAT Hedgehog acyltransferase (HHAT). Structure-activity relationship investigation identified single enantiomer IMP-1575, the most potent HHAT inhibitor reported to-date, and guided design of photocrosslinking probes that maintained HHAT-inhibitory potency. Photocrosslinking and proteomic sequencing of HHAT delivered identification of the first small-molecule binding site in a mammalian MBOAT. Topology and homology data suggested a potential mechanism for HHAT inhibition which was confirmed by kinetic analysis. Our results provide an optimal HHAT tool inhibitor IMP-1575 (K =38 nM) and a strategy for mapping small molecule interaction sites in MBOATs.
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http://dx.doi.org/10.1002/anie.202014457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252026PMC
June 2021

Evaluation of the Binding Affinity of Anti-Viral Drugs against Main Protease of SARS-CoV-2 through a Molecular Docking Study.

Infect Disord Drug Targets 2020 Dec 7. Epub 2020 Dec 7.

Department of Chemistry, The University of Jordan, Amman 11942. Jordan.

Background: Coronavirus disease 2019 (COVID-19) is a life intimidating viral infection caused by a positive sense RNA virus belonging to the Coronaviridae family, named severe acute respiratory distress syndrome coronavirus 2 (SARA-CoV-2). Since its outbreak in December 2019, the pandemic has spread to more than 200 countries, infected more than 26 million, and claimed the lives of more than 800,000 people. As a disease, COVID-19 can lead to severe and occasionally fatal respiratory problems in humans. Infection with this virus is associated with fever, cough, dyspnea, and muscle aches, and it may progress to pneumonia, multiple organ failure, and death. To date, there is no specific antiviral treatment against this virus. However, the main viral protease has been recently discovered and it is regarded as an appropriate target for antiviral agents in the search for treatment of COVID-19, due to its pivotal role in polyproteins processing during viral replication.

Aim: Consequently, this study intends to evaluate the effectiveness of FDA-approved anti-viral drugs against SARA-CoV-2 through a molecular docking study.

Methods: AutoDock Vina in PyRx platform was used for docking analysis against the main viral protease (Mpro) (PDB ID 6LU7), and Computed Atlas of Surface Topography of proteins (CASTp 3.0) was applied for detecting and characterizing cavities, pockets, and channels of this protein structure.

Results: Results revealed that among the conventional antiviral drugs, the protease inhibitors, lopinavir, amprenavir, indinavir, maraviroc, saquinavir, and daclatasvir showed high binding affinity and interacted with amino acid residues of the binding site.

Conclusion: In conclusion, protease inhibitors may be effective potential antiviral agents against Mpro to combat SARSCoV-2.
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http://dx.doi.org/10.2174/1871526520666201207124408DOI Listing
December 2020

Therapeutic promises of ginkgolide A: A literature-based review.

Biomed Pharmacother 2020 Dec 1;132:110908. Epub 2020 Nov 1.

Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Electronic address:

Ginkgolide A is a highly active platelet activating factor antagonist cage molecule which was isolated from the leaves of the Ginkgo biloba L. It is known for its inflammatory and immunological potentials. This review aims to sketch a current scenario on its therapeutic activities on the basis of scientific reports in the databases. A total 30 articles included in this review suggests that ginkgolide A has many important biological activities, including anti-inflammatory, anticancer, anxiolytic-like, anti-atherosclerosis and anti-atherombosis, neuro- and hepatoprotective effects. There is a lack of its toxicological (e.g. toxicity, cytotoxicity, genotoxicity and mutagenitcity) profile. In conclusion, ginkgolide A may be one of the potential therapeutic lead compounds, especially for the treatment of cardiovascular, hepatological, and neurological diseases and disorders. More studies are necessary on this hopeful therapeutic agent.
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http://dx.doi.org/10.1016/j.biopha.2020.110908DOI Listing
December 2020

Potential Therapeutic Options for COVID-19: Current Status, Challenges, and Future Perspectives.

Front Pharmacol 2020 15;11:572870. Epub 2020 Sep 15.

Department of Clinical Pharmacy, University of Medicine and Pharmacy of Craiova, Craiova, Romania.

The COVID-19 pandemic represents an unprecedented challenge for the researchers to offer safe, tolerable, and effective treatment strategies for its causative agent known as SARS-CoV-2. With the rapid evolution of the pandemic, even the off-label use of existing drugs has been restricted by limited availability. Several old antivirals, antimalarial, and biological drugs are being reconsidered as possible therapies. The effectiveness of the controversial treatment options for COVID-19 such as nonsteroidal antiinflammatory drugs, angiotensin 2 conversion enzyme inhibitors and selective angiotensin receptor blockers was also discussed. A systemic search in the PubMed, Science Direct, LitCovid, Chinese Clinical Trial Registry, and ClinicalTrials.gov data bases was conducted using the keywords "coronavirus drug therapy," passive immunotherapy for COVID-19', "convalescent plasma therapy," (CPT) "drugs for COVID-19 treatment," "SARS-CoV-2," "COVID-19," "2019-nCoV," "coronavirus immunology," "microbiology," "virology," and individual drug names. Systematic reviews, case presentations and very recent clinical guidelines were included. This narrative review summarizes the available information on possible therapies for COVID-19, providing recent data to health professionals.
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http://dx.doi.org/10.3389/fphar.2020.572870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7522523PMC
September 2020

Recent advances, approaches and challenges in targeting pathways for potential COVID-19 vaccines development.

Immunol Res 2020 12 1;68(6):315-324. Epub 2020 Oct 1.

Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

During the COVID-19 pandemic in a modern era, there is a global consensus on the need for the rapid development of a vaccine against SARS-CoV-2 for effective and sustainable control. Developing these vaccines is fundamental to public health. This urgent need is supported by the scientific explosion in structural and genomic biology that facilitates the urgent development of an ideal COVID-19 vaccine, using new pathways to facilitate its large-scale development, testing, and manufacture. Here, we summarize the types of COVID-19 candidate vaccines, their current stage in early testing in human clinical trials, and the challenges for their implementation.
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http://dx.doi.org/10.1007/s12026-020-09154-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529090PMC
December 2020

Anti-diarrheal activities of phytol along with its possible mechanism of action through in-vivo and in-silico models.

Cell Mol Biol (Noisy-le-grand) 2020 Jun 25;66(4):243-249. Epub 2020 Jun 25.

Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Phytol (PHY), a chlorophyll-derived diterpenoid, exhibits numerous pharmacological properties, including antioxidant, antimicrobial, and anticancer activities. This study evaluates the anti-diarrheal effect of phytol (PHY) along with its possible mechanism of action through in-vivo and in-silico models. The effect of PHY was investigated on castor oil-induced diarrhea in Swiss mice by using prazosin, propranolol, loperamide, and nifedipine as standards with or without PHY. PHY at 50 mg/kg (p.o.) and all other standards exhibit significant (p < 0.05) anti-diarrheal effect in mice. The effect was prominent in the loperamide and propranolol groups. PHY co-treated with prazosin and propranolol was found to increase in latent periods along with a significant reduction in diarrheal section during the observation period than other individual or combined groups. Furthermore, molecular docking studies also suggested that PHY showed better interactions with the α- and β-adrenergic receptors, especially with α-ADR1a and β-ADR1. In the former case, PHY showed interaction with hydroxyl group of Ser192 at a distance of 2.91Å, while in the latter it showed hydrogen bond interactions with Thr170 and Lys297 with a distance of 2.65 and 2.72Å, respectively. PHY exerted significant anti-diarrheal effect in Swiss mice, possibly through blocking α- and β-adrenergic receptors.
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June 2020

Discovery of a Potent and Selective Covalent Inhibitor and Activity-Based Probe for the Deubiquitylating Enzyme UCHL1, with Antifibrotic Activity.

J Am Chem Soc 2020 07 1;142(28):12020-12026. Epub 2020 Jul 1.

Department of Chemistry, Molecular Sciences Research Hub, Imperial College London, London, W12 0BZ, U.K.

Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) is a deubiquitylating enzyme that is proposed as a potential therapeutic target in neurodegeneration, cancer, and liver and lung fibrosis. Herein we report the discovery of the most potent and selective UCHL1 probe (IMP-1710) to date based on a covalent inhibitor scaffold and apply this probe to identify and quantify target proteins in intact human cells. IMP-1710 stereoselectively labels the catalytic cysteine of UCHL1 at low nanomolar concentration in cells. We further demonstrate that potent and selective UCHL1 inhibitors block pro-fibrotic responses in a cellular model of idiopathic pulmonary fibrosis, supporting the potential of UCHL1 as a potential therapeutic target in fibrotic diseases.
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http://dx.doi.org/10.1021/jacs.0c04527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7366380PMC
July 2020

Hepatoprotective and Antioxidant Capacity of Ethyl Acetate Stem Extract against d-Galactosamine-Induced Hepatotoxicity in Rats.

ACS Omega 2020 Mar 18;5(12):6523-6531. Epub 2020 Mar 18.

Department of Chemistry, The University of Jordan, Amman 11942, Jordan.

() is traditionally used to treat muscle pain, itching, fever, rheumatic arthritis, and a variety of liver disorders. The aim of the present work was to evaluate the hepatoprotective activity and the antioxidant potential of the ethyl acetate stem extract of (ESMR) against d-galactosamine (d-GalN)-induced hepatopathy, along with a possible mechanism of action in rats. In vivo hepatoprotective activity of ESMR was examined using d-galactosamine (d-GalN)-induced hepatotoxicity in Sprague-Dawley rats. For this purpose, levels of serum diagnostic markers, activity of hepatic antioxidant enzymes, and liver histo-architecture were employed to assess the protective efficacy of ESMR. Furthermore, the total phenolic, flavonoid, and tannin contents were quantitated, and the antioxidant capacity of the extract was evaluated using different methods such as 2,2'-diphenyl-1-picrylhydrazyl (DPPH), nitric oxide (NO), hydrogen peroxide (HO), and hydroxyl radical (OH) scavenging assays. Intraperitoneal d-GalN injection triggered hepatotoxicity, as shown by the noticeable increase in the serum hepatic marker enzymes, bilirubin content, γ-glutamyl transferase (GGT), total cholesterol (TC), triglycerides (TGs), and malondialdehyde (MDA), whereas glutathione, superoxide dismutase, and catalase levels were significantly lower compared with that of the control. Pretreatment with ESMR reduced the hepatic enzyme levels along with bilirubin, GGT, and MDA compared to the d-GalN-intoxicated group. These results were supported by histopathological studies, where d-galactosamine caused coagulative necrosis, hemorrhage, and inflammation. However, pretreatment with ESMR ameliorated the histo-architectural changes and brought them back to normal. Results also revealed that the total polyphenolic, flavonoid, and tannin content, and total antioxidant capacity of ESMR were 136.30 ± 0.78 mg GAE/g mg, 38.72 ± 0.85 mg QE/g, 75.88 ± 0.54 mg TAE/g, and 123.16 ± 0.24 mg AAE/g, respectively. In addition, ESMR inhibited free radicals with IC values of 94.47 ± 0.51, 127.33 ± 0.36, 164.12 ± 0.45, and 254.14 ± 0.35 μg/mL in DPPH, NO, HO, and OH free radical scavenging assays, respectively. These findings highlight the protective role of ESMR against hepatic injury induced by d-GalN, which may be attributed to its higher antioxidant properties, thereby scientifically justifying its traditional use.
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http://dx.doi.org/10.1021/acsomega.9b04189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7114618PMC
March 2020

Recent Developments in Cell Permeable Deubiquitinating Enzyme Activity-Based Probes.

Front Chem 2019 18;7:876. Epub 2019 Dec 18.

Department of Chemistry, Imperial College London, London, United Kingdom.

Deubiquitinating enzymes (DUBs) function to remove or cleave ubiquitin from post-translationally modified protein substrates. There are about 100 known DUBs in the proteome, and their dysregulation has been implicated a number of disease states, but the specific function of many subclass members remains poorly understood. Activity-based probes (ABPs) react covalently with an active site residue to report on specific enzyme activity, and thus represent a powerful method to evaluate cellular and physiological enzyme function and dynamics. Ubiquitin-based ABPs, such as HA-Ub-VME, an epitope-tagged ubiquitin carrying a C-terminal reactive warhead, are the leading tool for "DUBome" activity profiling. However, these probes are generally cell membrane impermeable, limiting their use to isolated enzymes or lysates. Development of cell-permeable ABPs would allow engagement of DUB enzymes directly within the context of an intact live cell or organism, refining our understanding of physiological and pathological function, and greatly enhancing opportunities for translational research, including target engagement, imaging and biomarker discovery. This mini-review discusses recent developments in small molecule activity-based probes that target DUBs in live cells, and the unique applications of cell-permeable DUB activity-based probes vs. their traditional ubiquitin-based counterparts.
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http://dx.doi.org/10.3389/fchem.2019.00876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930156PMC
December 2019

Hepatoprotective and Antioxidant Activities of Leaf Extract in Carbofuran-Induced Hepatic Damage in Rats.

Chem Res Toxicol 2019 12 19;32(12):2499-2508. Epub 2019 Nov 19.

Department of Chemistry , The University of Jordan , Amman 11942 , Jordan.

In folk medicines, () is used as a depurative herb for treating fever, pain, and cancer and as laxative for constipation. The aim of the present investigation was to evaluate the hepatoprotective effect of the leaf methanol extract of leaf (J gMe) against carbofuran (CF)-intoxicated liver injuries in Sprague-Dawley rats, along with the antioxidant activity of this extract. For this purpose, levels of serum diagnostic markers, hepatic antioxidant enzymes, and liver histo-architecture were employed to justify the protective efficacy of J gMe. In addition, the phenolic and flavonoid contents of the extract were quantified, and antioxidant activity was investigated using the 1,1-diphenyl-2-picrylhydrazyl (DPPH), nitric oxide, hydrogen peroxide, and hydroxyl free radical scavenging assays. Results revealed that the leaf extract caused a significant (<0.05, <0.01) decrease of the level of hepatic enzymes, triglycerides, and bilirubin and an increase of the total protein. J gMe has also significantly (<0.05, <0.01) lowered the level of malonylaldehyde. Carbofuran markedly suppressed hepatic antioxidant enzymes, however, the leaf extract significantly augmented these enzymes. The hepatoprotective effect was demonstrated by the improvement in the histo-architectural features of liver sections of CF-intoxicated rats treated with J gMe at 500 mg/kg dose. In addition, J gMe showed moderate total phenolic and total flavonoid content, whereas the IC values of DPPH, nitric oxide, hydrogen peroxide, and hydroxyl free radical scavenging assays were 71.31 ± 0.42, 134.82 ± 0.14, 47.69 ± 0.38, and 118.44 ± 0.30 μg/mL, respectively. In conclusion, the present study suggests the protective role of J gMe against hepatic injury induced by CF, which may be attributed to its higher antioxidant properties and thereby scientifically justifies its traditional use.
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http://dx.doi.org/10.1021/acs.chemrestox.9b00345DOI Listing
December 2019

Chimeric peptidomimetic antibiotics against Gram-negative bacteria.

Nature 2019 12 23;576(7787):452-458. Epub 2019 Oct 23.

Polyphor AG, Allschwil, Switzerland.

There is an urgent need for new antibiotics against Gram-negative pathogens that are resistant to carbapenem and third-generation cephalosporins, against which antibiotics of last resort have lost most of their efficacy. Here we describe a class of synthetic antibiotics inspired by scaffolds derived from natural products. These chimeric antibiotics contain a β-hairpin peptide macrocycle linked to the macrocycle found in the polymyxin and colistin family of natural products. They are bactericidal and have a mechanism of action that involves binding to both lipopolysaccharide and the main component (BamA) of the β-barrel folding complex (BAM) that is required for the folding and insertion of β-barrel proteins into the outer membrane of Gram-negative bacteria. Extensively optimized derivatives show potent activity against multidrug-resistant pathogens, including all of the Gram-negative members of the ESKAPE pathogens. These derivatives also show favourable drug properties and overcome colistin resistance, both in vitro and in vivo. The lead candidate is currently in preclinical toxicology studies that-if successful-will allow progress into clinical studies that have the potential to address life-threatening infections by the Gram-negative pathogens, and thus to resolve a considerable unmet medical need.
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http://dx.doi.org/10.1038/s41586-019-1665-6DOI Listing
December 2019

Protective Role of Leaf Extract Against Carbofuran-Induced Hematological and Hepatic Toxicities.

Chem Res Toxicol 2019 08 23;32(8):1619-1629. Epub 2019 Jul 23.

Department of Chemistry , The University of Jordan , Amman 11942 , Jordan.

The aim of the present study was to evaluate the protective effect of leaf methanol extract (SCL) against carbofuran (CF)-induced hepatotoxicity in Sprague-Dawley rats, along with the identification and quantification of polyphenolic composition by high-performance liquid chromatography (HPLC). Results revealed the presence of alkaloids, tannins, and flavonoids in SCL. Similarly, HPLC analysis suggests that SCL contains some known important antioxidants, such as rutin, benzoic acid, and salicylic acid that could be responsible for the hepatoprotective activity of the extract. In CF-exposed rats, significant hematological alterations along with histological changes were marked by the presence of necrosis, congestion, and inflammation. CF-intoxication also showed an increase in lipid peroxidation and decrease in cellular antioxidant enzymes (e.g., superoxide dismutase, catalase, and glutathione peroxidase) levels in rats compared with the control group. Furthermore, coadministration of SCL significantly ameliorated the abnormalities and improved the cellular arrangement in experimental animals. SCL also reversed the alteration of hematological and biochemical parameters and brought them back to normal levels as compared to the control group. In conclusion, may be one of the best sources of natural antioxidant compounds that can be used in the treatment of oxidative stress and stress-related diseases and disorders.
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http://dx.doi.org/10.1021/acs.chemrestox.9b00164DOI Listing
August 2019

Thanatin targets the intermembrane protein complex required for lipopolysaccharide transport in .

Sci Adv 2018 11 14;4(11):eaau2634. Epub 2018 Nov 14.

Chemistry Department, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.

With the increasing resistance of many Gram-negative bacteria to existing classes of antibiotics, identifying new paradigms in antimicrobial discovery is an important research priority. Of special interest are the proteins required for the biogenesis of the asymmetric Gram-negative bacterial outer membrane (OM). Seven Lpt proteins (LptA to LptG) associate in most Gram-negative bacteria to form a macromolecular complex spanning the entire envelope, which transports lipopolysaccharide (LPS) molecules from their site of assembly at the inner membrane to the cell surface, powered by adenosine 5'-triphosphate hydrolysis in the cytoplasm. The periplasmic protein LptA comprises the protein bridge across the periplasm, which connects LptBFGC at the inner membrane to LptD/E anchored in the OM. We show here that the naturally occurring, insect-derived antimicrobial peptide thanatin targets LptA and LptD in the network of periplasmic protein-protein interactions required to assemble the Lpt complex, leading to the inhibition of LPS transport and OM biogenesis in .
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http://dx.doi.org/10.1126/sciadv.aau2634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6235536PMC
November 2018

Anticancer activity of thymol: A literature-based review and docking study with Emphasis on its anticancer mechanisms.

IUBMB Life 2019 01 11;71(1):9-19. Epub 2018 Oct 11.

Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science & Technology University, Gopalganj, Bangladesh.

This review aims to summarize the anticancer effects of the natural monoterpene phenol derivative of cymenethymol and its derivatives as well as further molecular docking study to correlate the interaction of thymol and biomacromolecules that involved in cancer cell growth. For this, an up-to-date (till July 2018) literature study were made through using PubMed, Science Direct, Web of Science, Scopus, The American Chemical Society, Clinicaltrials.gov, and Google Scholar databases. Literature study demonstrated that thymol, melasolv (3,4,5-Trimethoxycinnamate thymol ester), and Mannich bases of thymol have potential anticancer effects in various test systems, including mice, rats and cultured cancer cells through various anticancer pathways such as antioxidant/oxidative stress induction, apoptosis, anti-inflammatory/immunomodulatory, anti-genotoxicity, chemo-, and radiopreventive ways. A few earlier scientific evidences showed that thymol is less toxic to mammalian systems. In silico study of thymol and its derivatives against 17 essential proteins revealed that 6BVH (PARP-1) and 5LIH (protein kinase C) are the most efficient receptor protein for interaction and binding of thymol and melaslov for the cancer prevention and initiation. On the basis of the summary of this review and docking study, it is evident that thymol may be one of promising plant-derived cancer chemotherapeutic agents. © 2018 IUBMB Life, 71(1):9-19, 2019.
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http://dx.doi.org/10.1002/iub.1935DOI Listing
January 2019

Design and Synthesis of Bioisosteres of Acylhydrazones as Stable Inhibitors of the Aspartic Protease Endothiapepsin.

ChemMedChem 2018 11 9;13(21):2266-2270. Epub 2018 Oct 9.

Chemical Biology, Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, 9747, AG, Groningen, The Netherlands.

Acylhydrazone-based dynamic combinatorial chemistry (DCC) is a powerful strategy for the rapid identification of novel hits. Even though acylhydrazones are important structural motifs in medicinal chemistry, their further progression in development may be hampered by major instability and potential toxicity under physiological conditions. It is therefore of paramount importance to identify stable replacements for acylhydrazone linkers. Herein, we present the first report on the design and synthesis of stable bioisosteres of acylhydrazone-based inhibitors of the aspartic protease endothiapepsin as a follow-up to a DCC study. The most successful bioisostere is equipotent, bears an amide linker, and we confirmed its binding mode by X-ray crystallography. Having some validated bioisosteres of acylhydrazones readily available might accelerate hit-to-lead optimization in future acylhydrazone-based DCC projects.
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http://dx.doi.org/10.1002/cmdc.201800446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282583PMC
November 2018

Protective effect of chloroform extract of Stereospermum chelonoides bark against amyloid beta42 induced cell death in SH-SY5Y cells and against inflammation in Swiss albino mice.

J Basic Clin Physiol Pharmacol 2018 Nov;29(6):621-630

Laboratory of Natural Products Research, Department of Pharmacy, Jahangirnagar University, Savar, Dhaka-1342, Bangladesh.

Background This study was designed to evaluate the free radical scavenging property of chloroform extract of the bark of Stereospermum chelonoides (SCBC) and to investigate its potential in Alzheimer's disease and inflammation, two oxidative stress related disorders. Methods Preliminary phytochemical analysis and in vitro antioxidant potential of SCBC were evaluated using 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging assay, ferric reducing antioxidant power (FRAP) assay, cupric reducing antioxidant capacity (CUPRAC) and total antioxidant capacity determination assay. Total phenol and total flavonoid contents were also determined. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) based cytotoxicity and cyto-protective assays were performed on human neuroblastoma SH-SY5Y cells. Thioflavin-T assay and caspase activation measurement assay were carried out to elucidate the mechanism of cytoprotection of SCBC observed here. In vivo anti-inflammatory potential was measured using croton oil and xylene induced ear edema tests. Results Phytochemical screening of SCBC revealed the presence of various phytoconstituents. Dose-dependent in vitro antioxidant activity was observed. The extract was enriched in flavonoids and polyphenolic compounds too. SCBC was found to inhibit amyloid-β peptide 1-42 (Aβ42) induced cell death in a dose-dependent manner. Encouraged by the cyto-protective effect, its effects on Aβ42 fibrillogenesis and caspase-3 activated apoptosis were observed. SCBC significantly slowed down the Aβ42 fibrillogenesis and caspase-3 activation in a concentration-dependent manner indicating its probable mechanism of rendering cyto-protection. SCBC has been able to reduce inflammation significantly in croton oil induced ear edema in both doses. Conclusions Thus, this study could form the basis for further study for the potential use of SCBC in oxidative stress associated cell death and inflammation.
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http://dx.doi.org/10.1515/jbcpp-2017-0123DOI Listing
November 2018

A Peptidomimetic Antibiotic Interacts with the Periplasmic Domain of LptD from Pseudomonas aeruginosa.

ACS Chem Biol 2018 03 23;13(3):666-675. Epub 2018 Jan 23.

Chemistry Department , University of Zurich , Winterthurerstrasse 190 , 8057 Zurich , Switzerland.

The outer membrane (OM) in Gram-negative bacteria is an asymmetric bilayer with mostly lipopolysaccharide (LPS) molecules in the outer leaflet. During OM biogenesis, new LPS molecules are transported from their site of assembly on the inner membrane to the OM by seven LPS transport proteins (LptA-G). The complex formed between the integral β-barrel OM protein LptD and the lipoprotein LptE is responsible for transporting LPS from the periplasmic side of the OM to its final location on the cell surface. Because of its essential function in many Gram-negative bacteria, the LPS transport pathway is an interesting target for the development of new antibiotics. A family of macrocyclic peptidomimetics was discovered recently that target LptD and inhibit LPS transport specifically in Pseudomonas spp. The related molecule Murepavadin is in clinical development for the treatment of life-threatening infections caused by P. aeruginosa. To characterize the interaction of these antibiotics with LptD from P. aeruginosa, we characterized the binding site by cross-linking to a photolabeling probe. We used a hypothesis-free mass spectrometry-based proteomic approach to provide evidence that the antibiotic cross-links to the periplasmic segment of LptD, containing a β-jellyroll domain and an N-terminal insert domain characteristic of Pseudomonas spp. Binding of the antibiotic to the periplasmic segment is expected to block LPS transport, consistent with the proposed mode of action and observed specificity of these antibiotics. These insights may prove valuable for the discovery of new antibiotics targeting the LPS transport pathway in other Gram-negative bacteria.
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http://dx.doi.org/10.1021/acschembio.7b00822DOI Listing
March 2018

Fragment-Based Drug Design Facilitated by Protein-Templated Click Chemistry: Fragment Linking and Optimization of Inhibitors of the Aspartic Protease Endothiapepsin.

Chemistry 2016 Oct 7;22(42):14826-14830. Epub 2016 Sep 7.

Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, 9747 AG, Groningen, The Netherlands.

There is an urgent need for the development of efficient methodologies that accelerate drug discovery. We demonstrate that the strategic combination of fragment linking/optimization and protein-templated click chemistry is an efficient and powerful method that accelerates the hit-identification process for the aspartic protease endothiapepsin. The best binder, which inhibits endothiapepsin with an IC value of 43 μm, represents the first example of triazole-based inhibitors of endothiapepsin. Our strategy could find application on a whole range of drug targets.
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http://dx.doi.org/10.1002/chem.201603001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5095814PMC
October 2016

Furoates and thenoates inhibit pyruvate dehydrogenase kinase 2 allosterically by binding to its pyruvate regulatory site.

J Enzyme Inhib Med Chem 2016 19;31(sup4):170-175. Epub 2016 Jul 19.

d Molecular Design Group, Trinity Biomedical Sciences Institute, Trinity College Dublin , Dublin , Ireland , and.

The last decade has witnessed the reawakening of cancer metabolism as a therapeutic target. In particular, inhibition of pyruvate dehydrogenase kinase (PDK) holds remarkable promise. Dichloroacetic acid (DCA), currently undergoing clinical trials, is a unique PDK inhibitor in which it binds to the allosteric pyruvate site of the enzyme. However, the safety of DCA as a drug is compromised by its neurotoxicity, whereas its usefulness as an investigative tool is limited by the high concentrations required to exert observable effects in cell culture. Herein, we report the identification - by making use of saturation-transfer difference NMR spectroscopy, enzymatic assays and computational methods - of furoate and thenoate derivatives as allosteric pyruvate-site-binding PDK2 inhibitors. This work substantiates the pyruvate regulatory pocket as a druggable target.
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http://dx.doi.org/10.1080/14756366.2016.1201812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5553292PMC
February 2017

Fragment Linking and Optimization of Inhibitors of the Aspartic Protease Endothiapepsin: Fragment-Based Drug Design Facilitated by Dynamic Combinatorial Chemistry.

Angew Chem Int Ed Engl 2016 08 12;55(32):9422-6. Epub 2016 Jul 12.

Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, 9747, AG, Groningen, The Netherlands.

Fragment-based drug design (FBDD) affords active compounds for biological targets. While there are numerous reports on FBDD by fragment growing/optimization, fragment linking has rarely been reported. Dynamic combinatorial chemistry (DCC) has become a powerful hit-identification strategy for biological targets. We report the synergistic combination of fragment linking and DCC to identify inhibitors of the aspartic protease endothiapepsin. Based on X-ray crystal structures of endothiapepsin in complex with fragments, we designed a library of bis-acylhydrazones and used DCC to identify potent inhibitors. The most potent inhibitor exhibits an IC50 value of 54 nm, which represents a 240-fold improvement in potency compared to the parent hits. Subsequent X-ray crystallography validated the predicted binding mode, thus demonstrating the efficiency of the combination of fragment linking and DCC as a hit-identification strategy. This approach could be applied to a range of biological targets, and holds the potential to facilitate hit-to-lead optimization.
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http://dx.doi.org/10.1002/anie.201603074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5113778PMC
August 2016

Structure-Based Optimization of Inhibitors of the Aspartic Protease Endothiapepsin.

Int J Mol Sci 2015 Aug 14;16(8):19184-94. Epub 2015 Aug 14.

Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, 9747 AG Groningen, The Netherlands.

Aspartic proteases are a class of enzymes that play a causative role in numerous diseases such as malaria (plasmepsins), Alzheimer's disease (β-secretase), fungal infections (secreted aspartic proteases), and hypertension (renin). We have chosen endothiapepsin as a model enzyme of this class of enzymes, for the design, preparation and biochemical evaluation of a new series of inhibitors of endothiapepsin. Here, we have optimized a hit, identified by de novo structure-based drug design (SBDD) and DCC, by using structure-based design approaches focusing on the optimization of an amide-π interaction. Biochemical results are in agreement with SBDD. These results will provide useful insights for future structure-based optimization of inhibitors for the real drug targets as well as insights into molecular recognition.
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http://dx.doi.org/10.3390/ijms160819184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4581293PMC
August 2015

Fighting malaria: structure-guided discovery of nonpeptidomimetic plasmepsin inhibitors.

J Med Chem 2015 Jul 17;58(13):5151-63. Epub 2015 Mar 17.

Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, NL-9747 AG Groningen, The Netherlands.

Plasmepsins (Plms) are aspartic proteases involved in the degradation of human hemoglobin by Plasmodium falciparum. Given that the parasite needs the resulting amino acid building blocks for its growth and development, plasmepsins are an important antimalarial drug target. Over the past decade, tremendous progress has been achieved in the development of inhibitors of plasmepsin using two strategies: structure-based drug design (SBDD) and structure-based virtual screening (SBVS). Herein, we review the inhibitors of Plms I-IV developed by SBDD or SBVS with a particular focus on obtaining selectivity versus the human Asp proteases cathepsins and renin and activity in cell-based assays. By use of SBDD, the flap pocket of Plm II has been discovered and constitutes a convenient handle to obtain selectivity. In SBVS, activity against Plms I-IV and selectivity versus cathepsins are not always taken into account. A combination of SBVS, SBDD, and molecular dynamics simulations opens up opportunities for future design cycles.
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http://dx.doi.org/10.1021/jm5014133DOI Listing
July 2015

Dynamic combinatorial chemistry: a tool to facilitate the identification of inhibitors for protein targets.

Chem Soc Rev 2015 Apr;44(8):2455-88

Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, 9747 AG Groningen, The Netherlands.

Dynamic combinatorial chemistry (DCC) has emerged as a powerful strategy to identify ligands for biological targets given that it enables the target to direct the synthesis and amplification of its strongest binder(s) from the library of interconverting compounds. Since the first report of DCC applied to the discovery of binders for a protein, this elegant tool has been employed on a range of protein targets at various stages of medicinal-chemistry projects. A series of suitable, reversible reactions that are biocompatible have been established and the portfolio of analytical techniques is growing. Despite progress, in most cases, the libraries employed remain of moderate size. We present here the most recent advances in the field of DCC applied to protein targets, paying particular attention to the experimental conditions and analytical methods chosen.
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http://dx.doi.org/10.1039/c4cs00493kDOI Listing
April 2015