Search

Numerous malignancies, including breast cancer, non-small cell lung cancer, and chronic myeloid leukemia, are brought on by aberrant tyrosine kinase signaling. Since the current chemotherapeutic medicines are toxic, there is a great need and demand from cancer patients to find novel chemicals that are toxic-free or have low toxicity and that can kill tumor cells and stop their growth. This work describes the in-silico examination of substances from the drug bank as EGFR inhibitors. Firstly, drug-bank was screened using the pharmacophore technique to select the ligands and Erlotinib (DB00530) was used as matrix compound. The selected ligands were screened using ADMET and the hit compounds were subjected to docking. The lead compound from the docking was subjected to DFT and MD simulation study. Using the pharmacophore technique, 23 compounds were found through virtual drug bank screening. One hit molecule from the ADMET prediction was the subject of docking study. According to the findings, DB03365 molecule fits to the EGFR active site by several hydrogen bonding interactions with amino acids. Furthermore, DFT analysis revealed high reactivity for DB03365 compound in the binding pocket of the target protein, based on E LUMO , E HOMO and band energy gap. Furthermore, MD simulations for 100 ns revealed that the ligand interactions with the residues of EGFR protein were part of the essential residues for structural stability and functionality. However, DB03365 was a promising lead molecule that outperformed the reference compound in terms of performance and in-vitro and in-vivo experiments needs to validate the study.Communicated by Ramaswamy H. Sarma.

Hormone replacement therapy is used to treat postmenopausal syndrome caused by estrogen deficiency, but it has been linked to an increased risk of breast cancer. In India, Achyranthes aspera L. is traditionally used to treat menstrual problems; however, there is a lack of mechanistic evidence of its phytoestrogenicity. Therefore, this study investigated the estrogenic activity of A. aspera on estrogen-responsive MCF-7 breast cancer cells. In a cell proliferation assay, the MeOH fraction (100 μg/mL) exhibited the highest proliferation effect (PE) of 138 % (p < 0.001) and relative proliferation effect (RPE) of 96.5 %, compared to 17β-estradiol (0.01 μM: 143 % PE, p < 0.001; 100 % RPE). The MeOH fraction was shown to upregulate the oestrogen marker genes trefoil factor 1 and progesterone receptor by 20.14-23.94 folds and 10.83-14.83 folds, respectively. Twelve phenolics were identified by LC-MS/MS in the active MeOH fraction, i.e. quinic acid, kaempferol hexoside, kaempferol 3-O-(2″-O-galloyl)-glucoside)-β-D-glucoside, geniposide, 3-O-(6'-O-(9Z,12Z-octadecadienoyl)-β-D-glucopyranosyl)-stigmast-5,22E-dien-3β-ol, kaempferol-3-O-glucoside (astragalin), 3,30-di-O-methylellagic acid isomer, procyanidin, naringin, propapyriogenin A2, (3β,22E,24R)-23-methylergosta-5,7,22-trien-3-ol and 6-prenylapigenin. Through network pharmacology, the potential effects, and mechanisms of these compounds in osteoporosis were revealed. About 55 target genes were linked to osteoporosis. GO and KEGG enrichment suggest regulation of female reproductive hormone related signaling pathways, which are also associated with estrogen dependent osteoporosis. Molecular docking analysis of the compounds revealed potential interactions with hERα receptor for 3-O-(6'-O-(9Z,12Z-octadecadienoyl)-β-D-glucopyranosyl)-stigmast-5,22E-dien-3β-ol and kaempferol-3-O-glucoside (astragalin) (docking scores of -9.3 and -10.1 kcal/mol, respectively) as compared to 17β-estradiol (-9.3 kcal/mol). These results suggest the estrogenicity of A. aspera via an ERα-associated mechanism and support its traditional usage in the management of menopausal-related problems., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

Aedes aegypti is the primary vector for the transmission of the dengue virus, which causes dengue fever, dengue hemorrhagic illness and dengue shock syndrome. There is now no antiviral medication available to treat DENV, which kills thousands of people each year and infects millions of individuals. A possible target for the creation of fresh and efficient dengue treatments is the DENV-3 NS5 MTase. So, Nigella sativa quinones were examined using in silico methods to find natural anti-DENV compounds. The in silico docking was conducted utilising the Discovery Studio software on the quinones of N. sativa and the active site of the target protein DENV-3 NS5 MTase. In addition, the druggability and pharmacokinetics of the lead compound were assessed. Dithymoquinone was comparable to the reference compound in terms of its ability to bind to the active site of target protein. Dithymoquinone met the requirements for drug likeness and Lipinski's principles, as demonstrated by the ADMET analysis and drug likeness results. The current study indicated that the dithymoquinone from N. sativa had anti-DENV activity, suggesting further drug development and dengue treatment optimisation.Communicated by Ramaswamy H. Sarma.

The epidermal growth factor receptor (EGFR) dimerizes upon ligand bindings to the extracellular domain that initiates the downstream signaling cascades and activates intracellular kinase domain. Thus, activation of autophosphorylation through kinase domain results in metastasis, cell proliferation, and angiogenesis. The main objective of this research is to discover more promising anti-cancer lead compound against EGRF from the phenolic acids of marine natural products using in-silico approaches. Phenolic compounds reported from marine sources are reviewed from previous literatures. Furthermore, molecular docking was carried out using the online tool CB-Dock. The molecules with good docking and binding energies scores were subjected to ADME, toxicity and drug-likeness analysis. Subsequently, molecules from the docking experiments were also evaluated using the acute toxicity and MD simulation studies. Fourteen phenolic compounds from the reported literatures were reviewed based on the findings, isolation, characterized and applications. Molecular docking studies proved that the phenolic acids have good binding fitting by forming hydrogen bonds with amino acid residues at the binding site of EGFR. Chlorogenic acid, Chicoric acid and Rosmarinic acid showed the best binding energies score and forming hydrogen bonds with amino acid residues compare to the reference drug Erlotinib. Among these compounds, Rosmarinic acid showed the good pharmacokinetics profiles as well as acute toxicity profile. The MD simulation study further revealed that the lead complex is stable and could be future drug to treat the cancer disease. Furthermore, in a wet lab environment, both in-vitro and in-vivo testing will be employed to validate the existing computational results.Communicated by Ramaswamy H. Sarma.

Outcome of acute ST-elevation myocardial infarction patients varies time to time. The present study was intended to find out the short-term treatment outcome of the patients admitted in hospital. This descriptive study was carried out in Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh from 15 January 2014 to 14 July 2014. A total of 100 patients admitted with Acute ST-elevation Myocardial Infarction confirmed on the presence of the (a) Typical chest pain of acute ST-elevation Myocardial Infarction (b) Electrocardiogram (ECG) evidence of ST segment elevation in two or more contiguous leads (c) Raised cardiac marker (Troponin I) were included in the study. Patients were randomly enrolled according to the inclusion and exclusion criteria and observe for one week. Data were processed and analyzed by using computer bases software SPSS version 19.0. Descriptive statistical methods were applied for data analysis. P value was considered as statistically significant when it is less than 0.05. Short-term treatment outcome of acute ST-elevation myocardial infarction include mechanical, arrhythmic, ischemic and inflammatory sequelae, as well as left ventricular mural thrombus. In addition to these broad categories, heart failure, arrhythmia, death are other common complications of AMI. The initiation of the complications usually results in explicit sign and symptoms of the acute MI patients. Learning of the complications in the post infarction period and the clinical syndromes develop with each complication, will allow the health care worker to evaluate and manage the complication appropriately.

Posterior reversible encephalopathy syndrome (PRES) is a clinical syndrome characterized by acute or subacute onset of neurological symptoms (e.g., headache, seizure, confusion, vomiting, and diminished eyesight) and impaired endothelial barrier function of the cerebral circulation that leads to bilateral subcortical vasogenic edema, while exhibiting a "reversible" feature in most cases. Clinically, various predisposing or precipitating conditions have been identified, such as hypertension, autoimmune diseases, renal dysfunction/failure, preeclampsia/eclampsia, post-transplantation conditions, and certain therapeutic agents. Among several putative mechanisms, the immune activation hypothesis prevails, as up to 50% of patients with PRES harbor abnormalities related to autoimmunity, such as concurrent systemic lupus erythematosus. In this Review, we summarize the clinical and laboratory evidence that places PRES in the context of autoimmunity., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 Elsevier B.V. All rights reserved.)

NSTEMI patients, in comparison to STEMI patients, are more at risk of bleeding, access site complication and MACE after PCI during index hospitalization. Because they get, multiple adjuvant anti-thrombotic agents before PCI than do the STEMI patients undergoing primary PCI. Transradial access (TRA) is proven to decrease those adverse in-hospital outcomes compared to transfemoral access (TFA) in STEMI patients. But very few studies were conducted in this regard considering NSTEMI patients. We observed prospectively the adverse in-hospital outcomes of total 180 NSTEMI patients who had undergone PCI through TRA (Group I = 80) and TFA (Group II = 100) during index hospitalization between October 2017 to September 2018 in National Institute of Cardiovascular Disease (NICVD), Dhaka, Bangladesh. Samples were selected purposively. Patients were followed up 2 hours after PCI and thereafter every day until discharge. Demographic and risk factor variables were almost same in both groups. TRA, compared with TFA, yielded less major bleeding (0% versus 3%, p=0.12) which was statistically non-significant. Minor bleeding was significantly less in Group I (2.5% versus 13.0%, p=0.04). Overall bleeding was also significantly less in Group I (2.5% and 10.0%; p=0.002). Access site complication was non-significantly less in Group I (0% versus 1%, p=0.91). TRA caused non-significant reduction in MACE (2.5% versus 5%; p=0.38) but significant reduction of total adverse in-hospital outcome (5% versus 20%, p=0.006%). In this study TRA seems to have less adverse in-hospital outcome than TFA in NSTEMI patients undergoing PCI during index hospitalization.

This research investigated a UPLC-QTOF/ESI-MS-based phytochemical profiling of Combretum indicum leaf extract (CILEx), and explored its in vitro antioxidant and in vivo antidiabetic effects in a Long-Evans rat model. After a one-week intervention, the animals' blood glucose, lipid profile, and pancreatic architectures were evaluated. UPLC-QTOF/ESI-MS fragmentation of CILEx and its eight docking-guided compounds were further dissected to evaluate their roles using bioinformatics-based network pharmacological tools. Results showed a very promising antioxidative effect of CILEx. Both doses of CILEx were found to significantly ( p < 0.05) reduce blood glucose, low-density lipoprotein (LDL), and total cholesterol (TC), and increase high-density lipoprotein (HDL). Pancreatic tissue architectures were much improved compared to the diabetic control group. A computational approach revealed that schizonepetoside E, melianol, leucodelphinidin, and arbutin were highly suitable for further therapeutic assessment. Arbutin, in a Gene Ontology and PPI network study, evolved as the most prospective constituent for 203 target proteins of 48 KEGG pathways regulating immune modulation and insulin secretion to control diabetes. The fragmentation mechanisms of the compounds are consistent with the obtained effects for CILEx. Results show that the natural compounds from CILEx could exert potential antidiabetic effects through in vivo and computational study.

The current data report describes the predictive identification of phytochemical constituents in the bioactive extract of Ipomoea mauritiana (IM) whole plant. For several formulations this plant was commonly used as 'Vidari' for Ayurvedic medicine. Traditionally, IM tubers are used to alleviate spinal cord pain, improve breast milk, as a tonic, increase sperm count and treating jaundice. The methanol extract can potentially scavenge free radicals and possess antibacterial activity that could be correlated with its chemical composition. So it is crucial to identify the major compounds of IM. An ultra-performance liquid chromatography coupled electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC-ESI-QTOF/MS) method was adopted to detect the flavonoids, saponins, alkaloids, terpenoids in IM methanol extract . Data presented here is related to a published work Antioxidant and antibacterial activity of Ipomoea mauritiana Jacq.: A traditionally used medicinal plant in Bangladesh (Alam et al., 2020). Secondary metabolites were analyzed by the comparison of the mass fragmentation arrangements with Waters UNIFI library that enables for positive identification of the compounds based on the spectral match., Competing Interests: Authors declare no conflict of interest., (© 2021 The Authors.)

Hormone replacement therapy has been a conventional treatment for postmenopausal symptoms in women. However, it has potential risks of breast and endometrial cancers. The aim of this study was to evaluate the oestrogenicity of a plant-based compound, mimosine, in MCF-7 cells by in silico model. Cell viability and proliferation, ERα-SRC1 coactivator activity and expression of specific ERα-dependent marker TFF1 and PGR genes were evaluated. Binding modes of 17β-oestradiol and mimosine at the ERα ligand binding domain were compared using docking and molecular dynamics simulation experiments followed by binding interaction free energy calculation with molecular mechanics/Poisson-Boltzmann surface area. Mimosine showed increased cellular viability (64,450 cells/ml) at 0.1 μM with significant cell proliferation (120.5%) compared to 17β-oestradiol (135.2%). ER antagonist tamoxifen significantly reduced proliferative activity mediated by mimosine (49.9%). Mimosine at 1 μM showed the highest ERα binding activity through increased SRC1 recruitment at 186.9%. It expressed TFF1 (11.1-fold at 0.1 μM) and PGR (13.9-fold at 0.01 μM) genes. ERα-mimosine binding energy was -49.9 kJ/mol, and it interacted with Thr347, Gly521 and His524 of ERα-LBD. The results suggested that mimosine has oestrogenic activity., (© 2018 John Wiley & Sons A/S.)

It is estimated that ∼1% of the world's population has intellectual disability, with males affected more often than females. OGT is an X-linked gene encoding for the enzyme O- GlcNAc transferase (OGT), which carries out the reversible addition of N -acetylglucosamine (GlcNAc) to Ser/Thr residues of its intracellular substrates. Three missense mutations in the tetratricopeptide (TPR) repeats of OGT have recently been reported to cause X-linked intellectual disability (XLID). Here, we report the discovery of two additional novel missense mutations (c.775 G>A, p.A259T, and c.1016 A>G, p.E339G) in the TPR domain of OGT that segregate with XLID in affected families. Characterization of all five of these XLID missense variants of OGT demonstrates modest declines in thermodynamic stability and/or activities of the variants. We engineered each of the mutations into a male human embryonic stem cell line using CRISPR/Cas9. Investigation of the global O- GlcNAc profile as well as OGT and O- GlcNAc hydrolase levels by Western blotting showed no gross changes in steady-state levels in the engineered lines. However, analyses of the differential transcriptomes of the OGT variant-expressing stem cells revealed shared deregulation of genes involved in cell fate determination and liver X receptor/retinoid X receptor signaling, which has been implicated in neuronal development. Thus, here we reveal two additional mutations encoding residues in the TPR regions of OGT that appear causal for XLID and provide evidence that the relatively stable and active TPR variants may share a common, unelucidated mechanism of altering gene expression profiles in human embryonic stem cells., (© 2018 Selvan et al.)

Mutations in the ATP1A2 gene cause familial hemiplegic migraine type 2, alternating hemiplegia of childhood, and cerebellar function deficits, epilepsy, and mental retardation. These symptoms are likely related to glutamatergic hyperexcitability. Our patient is a 12-year-old boy with a history of complex partial seizures, attention-deficit/hyperactivity disorder, and fine motor difficulty. During early childhood, he had episodes of a self-resolving right-sided hemiparesis and focal epilepsy. His seizures did not respond to several antiepileptic medications but stopped after he received valproate. His intermittent episodes of hemiplegia persisted. Additionally, he had pronounced bilateral fine motor impairment and significant executive deficits that gradually worsened. The whole exome sequencing revealed a de novo missense mutation in the ATP1A2 gene and a maternally inherited POLG gene mutation of unknown clinical significance. We hypothesized that glutamatergic excitotoxicity due to the ATP1A2 mutation contributed to the pathogenesis of our patient's condition. He was started on N-methyl-D-aspartate receptor antagonists (memantine and dextromethorphan), as well as coenzyme Q 10 One year later, he showed significant improvement in sustained attention, learning efficiency, general cognitive efficiency, and fine motor dexterity. We postulate that N-methyl-D-aspartate receptor antagonists were effective for behavioral, cognitive, and cerebellar symptoms in our patient with ATP1A2 gene mutation., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2018 by the American Academy of Pediatrics.)

PURA syndrome is a recently described developmental encephalopathy presenting with neonatal hypotonia, feeding difficulties, global developmental delay, severe intellectual disability, and frequent apnea and epilepsy. We describe 18 new individuals with heterozygous sequence variations in PURA. A neuromotor disorder starting with neonatal hyptonia, but ultimately allowing delayed progression to walking, was present in nearly all individuals. Congenital apnea was present in 56% during infancy, but all cases in this cohort resolved during the first year of life. Feeding difficulties were frequently reported, with gastrostomy tube placement required in 28%. Epilepsy was present in 50% of the subjects, including infantile spasms and Lennox-Gastaut syndrome. Skeletal complications were found in 39%. Disorders of gastrointestinal motility and nystagmus were also recurrent features. Autism was diagnosed in one individual, potentially expanding the neurodevelopmental phenotype associated with this syndrome. However, we did not find additional PURA sequence variations in a cohort of 120 subjects with autism. We also present the first neuropathologic studies of PURA syndrome, and describe chronic inflammatory changes around the arterioles within the deep white matter. We did not find significant correlations between mutational class and severity, nor between location of the sequence variation in PUR repeat domains. Further studies are required in larger cohorts of subjects with PURA syndrome to clarify these genotype-phenotype associations., (© 2017 Wiley Periodicals, Inc.)

Objective: A recent study focusing on a response to antiepileptic drugs (AED) among siblings for epilepsy showed a similar response among epileptic siblings to specific AEDs or AED combinations. Currently, however, family history of treatment response to AEDs is not readily employed in deciding which initial medication to use when treating patients with epilepsy. We tested the hypothesis that sibling response to initial AED predicts treatment success., Methods: Presumed siblings were identified from a single-center database of patients diagnosed with epilepsy by matching last name, address, and name of parent(s). We identified 28 sibling pairs and two sibling trios with epilepsy. Seventeen of these sibling pairs were started on the same initial AED, with 15 sibling pairs having the same type of epilepsy. The remaining 11 pairs were started on a different initial AED, with 8 of these sibling pairs having the same type of epilepsy. Subjects with seizure freedom for a period of ≥1year were classified as a "responder"., Results: When at least one of the sibling pair responded to an initial AED, the proportion of the other siblings also responding to the initial AED was significantly higher if the siblings were treated with the same AED (8/11) compared to siblings who were treated with different AED (1/10) (Fisher's exact test, p-value=0.0075)., Significance: These findings suggest that sibling response to initial AED is predictive of the success of AED therapy. This study is limited by a small cohort and retrospective design. Future, larger prospective studies are needed to reproduce and further validate these findings., (Copyright © 2017. Published by Elsevier B.V.)

Background: Synaptic vesicle protein 2A (SV2a) is the binding site of the antiepileptic drug levetiracetam and the only known synaptic vesicle target of an epilepsy medication. To date, no pathogenic mutation in SV2A, which is the gene encoding synaptic vesicle glycoprotein 2A, has been identified in humans. We report a homozygous mutation in the SV2A gene in a patient with intractable epilepsy., Methods: We investigated a patient with intractable epilepsy, involuntary movements, microcephaly, and developmental and growth retardation. Both parents were multiply consanguineous and an earlier-born brother of the proband had a similar course and died at 7 months of age. Detailed clinical history, imaging, electroencephalograph and metabolic testing were obtained. Full exome sequencing was performed using genomic DNA isolated from the patient and both parents., Results: Exome sequencing identified a homozygous arginine to glutamine mutation in amino acid position 383 (R383Q) in exon 5 of the SV2A gene. Both parents were carriers for the R383Q variant, suggesting that R383Q is a recessive mutation. There were no other candidate alterations in the exome that could explain the phenotype in the proband. The amino acid arginine at position 383 of SV2a gene is evolutionally conserved throughout vertebrates. R383Q change is not observed in known healthy cohorts, exome databases, or the Database of Single Nucleotide Polymorphisms. The R383Q mutation is located in the second adenine binding domain in SV2a protein and may alter adenine nucleotides binding to SV2a., Conclusion: Our report provides the elusive evidence that an SV2A mutation can be a cause of epilepsy in humans. Levetiracetam, which binds to SV2A, was not effective as an antiepileptic medication. The location of the mutation in our patient supports an important role of adenine nucleotides binding in SV2A function., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Ten members of a 3-generation pedigree with 7 showing Tourette syndrome/chronic tic phenotype (TS-CTD) were evaluated with whole exome sequencing. We identified 3 novel, nonsynonymous single nucleotide variants in the MRPL3, DNAJC13, and OFCC1 genes that segregated with chronic tic phenotype. These variants were not present in 100 control subjects or in dbSNP/1000 Genomes databases. A novel variant in the 5' untranslated region of the OFCC1 gene was found in 2 TS-CTD patients from a different pedigree. Further studies will clarify the importance of variants in MRPL3, DNAJC13, and OFCC1 genes in TS., (Copyright © 2011 American Neurological Association.)