In-silico Studies, Design, and Synthesis of Pyrimidine-linked Benzothiazoles for its Anticonvulsant Potential.

BACKGROUND: The objective of the study was to design and synthesize a series of N-(6-substituted-1,3-benzothiazole- 2-yl)-2-{[6-(3-substitutedphenyl)-5-cyano-2-sulfanylpyrimidine-4-yl)]amino}acetamide derivatives BPD (1-15) that contains key pharmacophores required for anticonvulsant action. METHODS: The titled compounds (BPD 1-15) were synthesized by reacting 2-substituted-N-(6-chlorobenzo[d]thiazol2-yl)acetamide with 4-amino-6-(4-substituted phenyl)-2-mercapto pyrimidine 5-carbonitrile in the presence of potassium carbonate and dry acetone. The synthesized compounds BPD (1-15) were assessed in vivo by the maximum electric shock (MES) test and the subcutaneous pentylenetetrazol (scPTZ) test in mice. The neurotoxicity test was performed by the rotarod test. A molecular docking study of title compounds with a sodium channel receptor (PDB ID: 1BYY) was carried out using the SP Docking protocol of the Glide module of the Maestro. Pharmacophore modeling was used to qualitatively identify the chemical characteristics for ligand binding and their spatial configurations in the 3D space of the active site. RESULT: Among the studied compounds, BPD-15 and BPD-5 compounds showed significant action in both the MES and scPTZ models, with no neurotoxicity. BPD-15 & BPD-5 were relatively safe in acute toxicity testing. Compounds BPD-15 and BPD-5 showed good dock scores of -6.434 and -6.191, respectively. CONCLUSION: Thus, the compounds BPD-15 and BPD-5 have shown a considerable affinity towards the sodium channel as compared to the standard drug Riluzole. Compound BPD-14 showed good drug compatibility, and compounds BPD-1, BPD-2, BPD-11, BPD-12, BPD-13, BPD-14, BPD-15 showed good ADME values.

Unlocking the potential of nanocarrier-mediated mRNA delivery across diverse biomedical frontiers: A comprehensive review.

Messenger RNA (mRNA) has gained marvelous attention for managing and preventing various conditions like cancer, Alzheimer's, infectious diseases, etc. Due to the quick development and success of the COVID-19 mRNA-based vaccines, mRNA has recently grown in prominence. A lot of products are in clinical trials and some are already FDA-approved. However, still improvements in line of optimizing stability and delivery, reducing immunogenicity, increasing efficiency, expanding therapeutic applications, scalability and manufacturing, and long-term safety monitoring are needed. The delivery of mRNA via a nanocarrier system gives a synergistic outcome for managing chronic and complicated conditions. The modified nanocarrier-loaded mRNA has excellent potential as a therapeutic strategy. This emerging platform covers a wide range of diseases, recently, several clinical studies are ongoing and numerous publications are coming out every year. Still, many unexplained physical, biological, and technical problems of mRNA for safer human consumption. These complications were addressed with various nanocarrier formulations. This review systematically summarizes the solved problems and applications of nanocarrier-based mRNA delivery. The modified nanocarrier mRNA meaningfully improved mRNA stability and abridged its immunogenicity issues. Furthermore, several strategies were discussed that can be an effective solution in the future for managing complicated diseases.

Comparing rare variants versus common in the pathogenesis of nonalcoholic fatty liver disease: a whole exome sequencing approach.

BACKGROUND/PURPOSE: Genome-wide association studies have reported the association of common variants with nonalcoholic fatty liver disease in genes, namely, PNPLA3/TM6SF2/MBOAT7/HSD17B13, across ethnicities. However, the approach does not identify rarer variants with a higher effect size. We therefore sequenced the complete exonic regions of patients with nonalcoholic steatohepatitis and controls to compare rare and common variants with a role in the pathogenesis. METHODS: This is a prospective study that recruited 54 individuals with/without fatty infiltration. Patients with biopsy-proven nonalcoholic steatohepatitis and persistently elevated liver enzymes were included. Controls were with normal CT/MR fat fraction. DNA was isolated from whole blood, amplified (SureSelectXT Human All Exon V5 + UTR kit) and sequenced (Illumina). Data were filtered for quality, aligned (hg19), and annotated (OpenCRAVAT). Pathogenic (Polyphen-2/SIFT/ClinVar) variants and variants reported to be associated with NAFLD based on published literature were extracted from our data and compared between patients and controls. RESULTS: The mean age of controls (N = 17) and patients (N = 37) was 46.88 ± 6.94 and 37.46 ± 13.34 years, respectively. A total of 251 missense variants out of 89 286 were classified as pathogenic. Of these, 106 (42.23%) were unique to the patients and remaining (n = 145; 57.77%) were found in both patients and controls. Majority (25/37; 67.57%) patients had a minimum of one or more rare pathogenic variant(s) related to liver pathology that was not seen in the controls. CONCLUSION: Elucidating the contribution of rare pathogenic variants would enhance our understanding of the pathogenesis. Including the rarer genes in the polygenic risk scores would enhance prediction power.

Virtual Screening, Molecular Docking, and Dynamic Simulations Revealed TGF-ß1 Potential Inhibitors to Curtail Cervical Cancer Progression.

Cervical cancer is one of the main causes of cancer death in women globally, and its epidemiology is similar to that of a low-infectious venereal illness. Many sexual partners and early age at first intercourse have been demonstrated to have a significant influence on risk. TGF-ß1 is a multifunctional cytokine that is required for cervical carcinoma metastasis, tumor development, progression, and invasion. The TGF-ß1 signaling system plays a paradoxical function in cancer formation, suppressing early-stage tumor growth while increasing tumor progression and metastasis. Importantly, TGF-ß1 and TGF-ß receptor 1 (TGF-ßR1), two components of the TGF-ß signaling system, are substantially expressed in a range of cancers, including breast cancer, colon cancer, gastric cancer, and hepatocellular carcinoma. The current study aims to investigate possible inhibitors targeting TGF-ß1 using molecular docking and dynamic simulations. To target TGF-ß1, we used anti-cancer drugs and small molecules. MVD was utilized for virtual screening, and the highest scoring compound was then subjected to MD simulations using Schrodinger software package v2017-1 (Maestro v11.1) to identify the most favorable lead interactions against TGF-ß1. The Nilotinib compound has shown the least XP Gscore of -2.581 kcal/mol, 30ns MD simulations revealing that the Nilotinib- TGF-ß1 complex possesses the lowest energy of -77784.917 kcal/mol. Multiple parameters, including Root Mean Square Deviation, Root Mean Square Fluctuation, and Intermolecular Interactions, were used to analyze the simulation trajectory. Based on the results; we conclude that the ligand nilotinib appears to be a promising prospective TGF-ß1inhibitor for reducing TGF-ß1 expression ad halting cervical cancer progression.

Validated Stability-Indicating RP-HPLC Method for Daclatasvir in Tablets.

Objectives: The current study goal was to create a precise, sensitive, and validated reverse phase-high performance liquid chromatography (RP-HPLC) method for assessing the direct-acting antiviral daclatasvir (DCV) as well as to evaluate the stability of DCV in both drug and tablet formulations. The current investigation was to display stability indicating methods under different stress conditions, including hydrolysis (acidic, basic, and neutral), oxidation, and photolysis. Materials and Methods: All experiments were performed on HPLC Agilent 1100 with a stainless steel Hypersil C18 column having a particle size of 5 µm and a dimension of 4.6 x 250 mm. The mobile phase chosen was acetonitrile: 0.05% o-phosphoric acid (50:50 v/v) in isocratic mode with 0.7 mL/min flow rate and wavelength 315 nm was selected for detection. Results: This method was validated for linearity and range, accuracy, precision, limit of detection, limit of quantification, and robustness in accordance with International Council for Harmonisation (ICH) requirements. The results were satisfactory. It was observed that retention time (tR) was 3.760 ± 0.01 min. In acidic conditions, DCV degradans show tR at 3.863, 4.121, and 4.783 min and tandem mass spectrometry (MS/MS) spectra scans had m/z 339.1, 561.2 fragment ions. In basic condition, DCV degradans show tR at 5.188, 5.469 min and MS/MS spectra scans having m/z 294.1, 339.1, 505.2, 527.2 fragment ions. In oxidation conditions, DCV degradans shows tR at 4.038 min and MS/MS spectra scans having m/z 301.1 and 339.1 fragment ions were observed. Conclusion: All the mass fragments exhibited additional degradation observed for different stress conditions. This will help to identify the structure of the degradant and its pathways. No degradation was observed in neutral and photolytic conditions.

Homology Modeling, Screening, and Identification of Potential FOXO6 Inhibitors Curtail Gastric Cancer Progression: an In Silico Drug Repurposing Approach.

Gastric cancer is the world's second leading cause of cancer-related fatalities, with the epidemiology changing over the previous several decades. FOXOs are the O subfamily of the forkhead box (FOX) transcription factor family, which consists of four members: FOXO1, FOXO3, FOXO4, and FOXO6. FOXO6 mRNA and protein levels are increased in gastric cancer tissues. FOXO6 forced overexpression enhances gastric cancer cell growth, while knockdown decreases proliferation. In our study, the GEPIA, Kaplan-Meier, KEGG, and STRING databases were used to determine FOXO6 mRNA expression, overall survival ratio, interactive pathways, and top 10 associated proteins in gastric cancer respectively. Due to the lack of a solved structure for FOXO6, homology modeling was performed to obtain a 3D structure model, and we used anti-cancer drugs and small molecules to target FOXO6 for identifying a potential selective FOXO6 inhibitor. The chemical composition of the proteins and ligands has a significant impact on docking procedure performance. With this in mind, a critical evaluation of the performance of three regularly used docking routines was carried out: MVD, AutoDock Vina in PyRx, and ArgusLab. The binding affinities, docking scores, and intermolecular interactions were used as assessment criteria. In the study, the porfimer sodium showed excellent binding affinity to the FOXO6 protein. The major three docking software packages were used to analyze the scoring/H-bonding energy and intermolecular interactions. Based on the results, we concluded that FOXO6 was upregulated in gastric cancer and the ligand porfimer sodium emerges as a promising potential FOXO6 inhibitor to curtail gastric cancer progression.

Entrectinib a Plausible Inhibitor for Osteopontin (SPP1) in Cervical Cancer-Integrated Bioinformatic Approach.

Cervical cancer is one of the major causes of death in women, especially in developing countries bearing more than a quarter of the global burden. Secreted phosphoprotein-1, also known as OPN (osteopontin), is an integrin-binding glycophosphoprotein that is overexpressed in a variety of tumors. OPN is a chemokine-like calcified ECM-associated protein that plays a crucial role in evaluating the metastatic potential of various cancers. However, the role of SPP1 in the tumor microenvironment and associated signaling pathways in CC is still unclear. In our study, three CC microarray datasets (GSE9750, GSE46857, and GSE67522) were obtained from the GEO database to identify the differentially expressed genes. Enrichment analysis was carried out by Enrichr and ShinyGO and the PPI interaction network was created by using String and Cytoscape. GEPIA datasets were used to validate the top 10 hub genes, and virtual screening, docking, and dynamic simulation studies were used to identify a suitable inhibitor against the OPN protein using MVD, PyRx, and GROMACS respectively. Our results show that a total of 11 DEGs were common for three datasets and gene ontology pathway enrichment analysis revealed that 2 biological processes i.e. programmed cell death and animal organ development commonly affected mechanisms in all three datasets. Docking and dynamic studies revealed that Entrectinib showed excellent binding affinity against OPN protein. Based on the results, we conclude that OPN is one of the most upregulated genes in cervical cancer and Entrectinib emerges to be a promising potential OPN inhibitor to curtail cervical cancer progression. Schematic representation: The schematic representation of methodology steps is illustrated in the graphical abstract. Schematic representation of methodology.

Importance of Pharmacophore in Designing Anticonvulsant Agents.

Drug design is one of the critical aspects of the drug development process. The present review focused on different heterocyclic molecules having anticonvulsant activity with structural diversity and common pharmacophoric features. For the first time (1995), Dimmock and his team introduced specific arrangements of three important pharmacophores for anticonvulsant activity. These pharmacophores include two hydrophobic binding sites and one hydrogen binding site. After a few years (2012), Pandeya modified Dimmock's concept by adding one more pharmacophoric feature as an electron donor in the previously suggested pharmacophoric arrangement of the anticonvulsant. As a result, numerous scientists designed anticonvulsant drugs based on Dimmock's and Pandeya's concept. In addition, marketed anticonvulsant preparation containing Riluzole, Phenobarbital, Progabide, Ralitoline, etc., also holds the suggested pharmacophores by Dimmock and Pandeya's pharmacophoric concept. This review mainly focuses on the compilation of reported scientific literature in the last decade on the pharmacophoric features of different heterocyclic anticonvulsants, which will help develop new anticonvulsants.

Molecular docking, synthesis, and biological evaluation of 7-azaindole-derivative (7AID) as novel anti-cancer agent and potent DDX3 inhibitor:-an in silico and in vitro approach.

The DEAD-box helicase family member DDX3 is involved in many diseases, such as viral infection, inflammation, and cancer. Many studies in the last decade have revealed the role of DDX3 in tumorigenesis and metastasis. DDX3 has both tumour suppressor and oncogenic effect, in the present study we have evaluated the expression levels of DDX3 in cervical squamous cell carcinoma at mRNA level via real-time PCR and protein level via Immunohistochemistry. DDX3 has become a molecule of interest in cancer biology that promotes drug resistance by adaptive response inevitably leading to treatment failure. One approach to avoid the development of resistant to disease is to create novel drugs that target the overexpressed proteins, we designed and synthesized a novel 7-azaindole derivative (7-AID) compound, {5-[1H-pyrrolo (2, 3-b) pyridin-5-yl] pyridin-2-ol]} that could lodge within the adenosine-binding pocket of the DDX3 (PDB ID: 2I4I). The binding efficacy of 7-AID compound with DDX3 was analysed by molecular docking studies. 7-AID was found to interact with the key residues Tyr200 and Arg202 from the Q-motif rendered by π-interactions and hydrogen bonds within the binding pocket with good docking score - 7.99 kcal/mol. The cytotoxicity effect of 7-AID compound was evaluated using MTT assay on human cervical carcinoma cells (HeLa) and breast cancer cells (MCF-7 and MDA MB-231) and the compound shown effective inhibitory concentration (IC50) on Hela cells 16.96 µM/ml and 14.12 and 12.69 µM/ml on MCF-7 and MDA MB-231, respectively. Further, the in-vitro, in-vivo anti-cancer and anti-angiogenic assessment of 7-AID compound was evaluated on Hela cells using scratch wound-healing assay, DAPI staining, cell cycle analysis, immunoblotting, and chorioallontoic membrane assay. Furthermore, the inhibitory effect of derivative compound on DDX3 was investigated in HeLa, MCF-7, and MDA MB-231 cells at the mRNA and protein levels. The results showed that the 7-AID compound effectively inhibited DDX3 in a dose-dependent manner, and the findings suggest that the compound could be used as a potential DDX3 inhibitor.

Inhibition of DDX3 and COX-2 by forskolin and evaluation of anti-proliferative, pro-apoptotic effects on cervical cancer cells: molecular modelling and in vitro approaches.

Several studies have reported up-regulation of both cyclooxygenase-2 (COX-2) and DEAD-box RNA helicase3 (DDX3) and have validated their oncogenic role in many cancers. Inhibition of COX-2 and DDX3 offers a potential pharmacological strategy for prevention of cancer progression. The COX-2 isoform is expressed in response to pro-inflammatory stimuli in premalignant lesions, including cervical tissues. This study elucidates the potential role of plant derived compound Forskolin (FSK) in plummeting the expression of COX-2 and DDX3 in cervical cancer. To establish this, the cervical cancer cells were treated with the FSK compound which induced a dose dependent significant inhibition of COX-2 and DDX3 expression. The FSK treatment also significantly induced apoptosis in cancer cells by modulating the expression of apoptotic markers like caspase-3, cleaved caspase-3, caspase-9, cleaved caspase-9, full length-poly ADP ribose polymerase (PARP), cleaved-poly ADP ribose polymerase (C-PARP) and Bcl2 in dose dependent manner. Further FSK significantly modulated the cell survival pathway Phosphatidylinositol 3-kinase (PI3-K)/Akt signalling pathway upon 24 h of incubation in cervical cancer cells. The molecular docking studies revealed that the FSK engaged the active sites of both the targets by interacting with key residues.

Overexpression of Secreted Phosphoprotein 1 (SPP1) predicts poor survival in HPV positive cervical cancer.

Cervical cancer (CC) is the most prevalent malignant gynecological tumor with limited treatments. The present study describes the role of SPP1 in cancer progression, SPP1 emerged as one of the most overexpressed genes identified through clariom D transcriptome microarray. This investigation aims towards identifying a potential gene with significant prognostic value for detection and early diagnosis of cervical cancer. The elevated expression of SPP1 in cervical squamous cell carcinoma tissue was validated across GEO (Gene Expression Omnibus) microarray data sets, TCGA (The Cancer Genome Atlas), and Oncomine databases. SPP1 expression was found to be prognostically significant, showing association with poor survival rate of the patients. Our study intended to assess the expression of secreted phosphoprotein (SPP1) gene at mRNA and protein levels, and to explore the association of single nucleotide polymorphisms of SPP1 with risk of CC. Further, receiver operating characteristics (ROC) curve was plotted to determine the levels of SPP1 to differentiate CC against control. Results revealed significant (p < 0.01) stage-wise upregulation of SPP1 in CC compared to the normal cervical tissue and this was further confirmed using Immunohistochemistry and real-time PCR. The ROC for SPP1 demonstrated good selective power to differentiate malignant CC and non-malignant cervical tissues. The SPP1 gene -443 T > C promoter polymorphisms are found to be significantly predominant in the disease group and Insilico analysis by the TRANSFAC software confirms its association with loss of STAT6 transcription factor binding site leading to overexpression of the SPP1.

Screening and Identification of Potential iNOS Inhibitors to Curtail Cervical Cancer Progression: an In Silico Drug Repurposing Approach.

Cervical cancer is the second most common cause of cancer deaths in women worldwide and remains the main reason of mortality among women of reproductive age in developing countries. Nitric oxide is involved in several physiological functions inclusive of inflammatory and immune responses. However, the function of NO in tumor biology is debatable. The inducible NOS (iNOS/NOS2) isoform is the one responsible to maintain the levels of NO, and it exhibits pleotropic effects in various cancers with concentration-dependent pro- and anti-tumor effects. iNOS triggers angiogenesis and endothelial cell migration in tumors by regulating the levels of vascular endothelial growth factor (VEGF). In drug discovery, drug repurposing involves investigations of approved drug candidates to treat various other diseases. In this study, we used anti-cancer drugs and small molecules to target iNOS and identify a potential selective iNOS inhibitor. The structures of ligands were geometrically optimized and energy minimized using Hyperchem software. Molecular docking was performed using Molegro virtual docker, and ligands were selected based on MolDock score, Rerank score, and H-bonding energy. In the study shown, venetoclax compound demonstrated excellent binding affinity to iNOS protein. This compound exhibited the lowest MolDock score and Rerank score with better H-bonding energy to iNOS. The binding efficacy of venetoclax was analyzed by performing molecular docking and molecular dynamic simulations. Multiple parameters were used to analyze the simulation trajectory, like root mean square deviation (RMSD), radius of gyration (Rg), and hydrogen bond interactions. Based on the results, venetoclax emerges to be a promising potential iNOS inhibitor to curtail cervical cancer progression.

Inhibition of Inducible Nitric Oxide Synthase (iNOS) by Andrographolide and In Vitro Evaluation of Its Antiproliferative and Proapoptotic Effects on Cervical Cancer.

This work is aimed at investigating the expression levels of inducible nitric oxide synthase (iNOS) in cervical cancer and identifying a potential iNOS inhibitor. The data mining studies performed advocated iNOS to be a promising biomarker for cancer prognosis, as it is highly overexpressed in several malignant cancers. The elevated iNOS was found to be associated with poor survival and increased tumor aggressiveness in cervical cancer. Immunohistochemical and RT-PCR investigations of iNOS showed significant upregulation of endogenous iNOS expression in the cervical tumor samples, thus making iNOS a potent target for decreasing tumor inflammation and aggressiveness. Andrographolide, a plant-derived diterpenoid lactone, is widely reported to be effective against infections and inflammation, causing no adverse side effects on humans. In the current study, we investigated the effect of andrographolide on the prognostic value of iNOS expression in cervical cancer, which has not been reported previously. The binding efficacy of andrographolide was analyzed by performing molecular docking and molecular dynamic simulations. Multiple parameters were used to analyze the simulation trajectory, like root mean square deviation (RMSD), torsional degree of freedom, protein-root mean square fluctuations (P-RMSF), ligand RMSF, total number of intramolecular hydrogen bonds, secondary structure elements (SSE) of the protein, and protein complex with the time-dependent functions of MDS. Ligand-protein interactions revealed binding efficacy of andrographolide with tryptophan amino acid of iNOS protein. Cancer cell proliferation, cell migration, cell cycle analysis, and apoptosis-mediated cell death were assessed in vitro, post iNOS inhibition induced by andrographolide treatment (demonstrated by Western blot). Results. Andrographolide exhibited cytotoxicity by inhibiting the in vitro proliferation of cervical cancer cells and also abrogated the cancer cell migration. A significant increase in apoptosis was observed with increasing andrographolide concentration, and it also induced cell cycle arrest at G1-S phase transition. Our results substantiate that andrographolide significantly inhibits iNOS expression and exhibits antiproliferative and proapoptotic effects on cervical cancer cells.

Identification of Differentially Expressed Genes in Cervical Cancer Patients by Comparative Transcriptome Analysis.

Cervical cancer is one of the most malignant reproductive diseases seen in women worldwide. The identification of dysregulated genes in clinical samples of cervical cancer may pave the way for development of better prognostic markers and therapeutic targets. To identify the dysregulated genes (DEGs), we have retrospectively collected 10 biopsies, seven from cervical cancer patients and three from normal subjects who underwent a hysterectomy. Total RNA isolated from biopsies was subjected to microarray analysis using the human Clariom D Affymetrix platform. Based on the results of principal component analysis (PCA), only eight samples are qualified for further studies; GO and KEGG were used to identify the key genes and were compared with TCGA and GEO datasets. Identified genes were further validated by quantitative real-time PCR and receiver operating characteristic (ROC) curves, and the highest Youden index was calculated in order to evaluate cutoff points (COPs) that allowed distinguishing of tissue samples of cervical squamous carcinoma patients from those of healthy individuals. By comparative microarray analysis, a total of 108 genes common across the six patients' samples were chosen; among these, 78 genes were upregulated and 26 genes were downregulated. The key genes identified were SPP1, LYN, ARRB2, COL6A3, FOXM1, CCL21, TTK, and MELK. Based on their relative expression, the genes were ordered as follows: TTK > ARRB2 > SPP1 > FOXM1 > LYN > MELK > CCL21 > COL6A3; this generated data is in sync with the TCGA datasets, except for ARRB2. Protein-protein interaction network analysis revealed that TTK and MELK are closely associated with SMC4, AURKA, PLK4, and KIF18A. The candidate genes SPP1, FOXM1, LYN, COL6A3, CCL21, TTK and MELK at mRNA level, emerge as promising candidate markers for cervical cancer prognosis and also emerge as potential therapeutic drug targets.

Identification of Promising RILs for High Grain Zinc Through Genotype × Environment Analysis and Stable Grain Zinc QTL Using SSRs and SNPs in Rice (Oryza sativa L.).

Polished rice is one of the commonly consumed staple foods across the world. However, it contains limited nutrients especially iron (Fe) and zinc (Zn). To identify promising recombinant inbred lines (RILs) for grain Zn and single plant yield, 190 RILs developed from PR116 and Ranbir Basmati were evaluated in two environments (E1 and E2). A subset of 44 contrasting RILs for grain Zn was screened in another two environments (E3 and E4). Phenotypic data was collected for 10 traits, viz., days to 50% flowering, plant height, panicle length, number of tillers, single plant yield (SPY), test weight, Fe and Zn in brown (IBR, ZBR), and polished rice (IPR, ZPR). Stepwise regression analysis of trait data in 190 RILs and a subset of 44 RILs revealed the interdependence of ZPR, ZBR, IPR, and IBR and the negative association of grain Zn with single plant yield. Based on the additive main effect and multiplicative interaction (AMMI) and genotype and genotype × environment interaction (GGE) analyses of the subset of 44 RILs across four environments (E1-E4), six promising RILs were identified for ZPR with >28 ppm. Mapping of 190 RILs with 102 simple sequence repeats (SSRs) resulted in 13 QTLs for best linear unbiased estimates (BLUEs) of traits including advantage over check (AOC). Using genotype-based sequencing (GBS), the subset of 44 RILs was mapped with 1035 single-nucleotide polymorphisms (SNPs) and 21 QTLs were identified. More than 100 epistatic interactions were observed. A major QTL qZPR.1.1 (PV 37.84%) and another QTL qZPR.11.1 (PV 15.47%) were identified for grain Zn in polished rice. A common major QTL (qZBR.2.1 and qZPR.2.1) was also identified on chromosome 2 for grain Zn content across SSR and SNP maps. Two potential candidate genes related to transporters were identified based on network analyses in the genomic regions of QTL < 3 Mb. The RILs identified for grain Zn and SPY were nominated for national evaluation as under rice biofortification, and two QTLs identified based on BLUEs could be used in the rice biofortification breeding programs.

Role of Biosynthesized Ag-NPs Using Aspergillus niger (MK503444.1) in Antimicrobial, Anti-Cancer and Anti-Angiogenic Activities.

Green synthesis of nanoparticles is regarded as a safe and non-toxic process over conventional synthesis. Owing to the medicinal value of biologically derived biomolecules and utilizing them in synergy with nanoscience to offer more accurate therapeutic options to various diseases is an emerging field. One such study we present here with highlights of the synthesis and efficacy of biogenic silver nanoparticles produced from the extract of Aspergillus niger SAP2211 (accession number: MK503444.1) as an antimicrobial, anti-cancerous and anti-angiogenic agent. The synthesized Ag-NPs were characterized following UV-vis, FTIR, XRD, SEM and TEM, and were found to possess bactericidal activity against the selected pathogenic microbes, such as Staphylococcus aureus, Escherichia coli, and Salmonella typhi. Further, we evaluated cytotoxicity effect of this biogenic Ag-NPs using MMT assay on normal cardio myoblast (H9C2) and cancerous human cervical carcinoma (HeLa) cells. Doxorubicin used as positive control. This Ag-NPs have shown trivial cytotoxicity at the IC50 concentration on normal cells (IC50 = 47.17 µg/ml) over the cancer cells (IC50 = 8.609 µg/ml) with nearly 7 fold difference, indicating it as a selective anti-cancerous agent in contrast to standard drug doxorubicin (IC50 = 6.338 µg/ml). Further in-vitro assessment of wound healing capability by scratch wound healing assay, invasion by transwell matrigel invasion assay, and apoptosis via DAPI and annexin V-FITC assays were studied in HeLa cells. Synthesized biogenic Ag-NPs have shown to be anti-angiogenic in nature, which was established by in-vivo chick chorioallantois membrane assay. Overall, in vitro studies revealed that biogenic Ag-NPs positively inhibited migration, invasion, and induced apoptosis, and in-vivo CAM assay revealed that intercapillary network was reduced and the angiogenesis was inhibited.

Recent Development in Substituted Benzothiazole as an Anticonvulsant Agent.

Heterocyclic compounds and their derivatives gained more attention due to their valuable biological and pharmacological properties. Benzothiazole is a heterocyclic structure containing a bicyclic ring system with a large panel of applications. The benzothiazole is present in many new products undergoing research hoping that it possesses various biological activities. Epilepsy is a diverse group of diseases marked by neuronal excitability and hypersynchronous neuronal activity of motor, sensory or autonomic events with or without loss of consciousness. Presently, many antiepileptic drugs like lamotrigine, stiripentol tiagabine, pregabalin, felbamate, and topiramate are available and effective towards 60-80% of patients only, along with undesirable side effects, such as hepatotoxicity, gastrointestinal disturbance, drowsiness, gingival hyperplasia, and hirsutism. Thus, many attempts are still on-going to develop antiepileptic drugs with a safer profile. This review is mainly focused on the compilation of reported scientific literature data in the recent one-decade on the anticonvulsant activity of benzothiazole compounds.

Retraction Note: Type IV collagen α1-chain noncollagenous domain blocks MMP-2 activation both in-vitro and in-vivo.

Editor's Note: this Article has been retracted; the Retraction Note is available at https://www.nature.com/articles/s41598-020-76500-9.

Crotalaria verrucosa Leaf Extract Mediated Synthesis of Zinc Oxide Nanoparticles: Assessment of Antimicrobial and Anticancer Activity.

In this work, we present an ecofriendly, non-hazardous, green synthesis of zinc oxide nanoparticles (ZnO NPs) by leaf extract of Crotalaria verrucosa (C. verrucosa). Total phenolic content, total flavonoid and total protein contents of C. verrucosa were determined. Further, synthesized ZnO NPs was characterized by UV-visible spectroscopy (UV-vis), X-ray diffractometer (XRD), Fourier transform infra-red (FTIR) Spectra, transmission electron microscope (TEM), and Dynamic light scattering (DLS) analysis. UV-vis shows peak at 375 nm which is unique to ZnO NPs. XRD analysis demonstrates the hexagonal phase structures of ZnO NPs. FTIR spectra demonstrates the molecules and bondings associated with the synthesized ZnO NPs and assures the role of phytochemical compounds of C. verrucosa in reduction and capping of ZnO NPs. TEM image exhibits that the prepared ZnO NPs is hexagonal shaped and in size ranged between 16 to 38 nm which is confirmed by DLS. Thermo-gravimetric analysis (TGA) was performed to determine the thermal stability of biosynthesized nanoparticles during calcination. The prepared ZnO NPs showed significant antibacterial potentiality against Gram-positive (S. aureus) and Gram-negative (Proteus vulgaris, Klebsiella pneumoniae, and Escherichia coli) pathogenic bacteria and SEM image shows the generalized mechanism of action in bacterial cell after NPs internalization. In addition, NPs are also found to be effective against the studied cancer cell lines for which cytotoxicity was assessed using MTT assay and results demonstrate highest growth of inhibition at the concentration of 100 µg/mL with IC50 value at 7.07 µg/mL for HeLa and 6.30 µg/mL for DU145 cell lines, in contrast to positive control (C. verrucosa leaf extract) with IC50 of 22.30 µg/mL on HeLa cells and 15.72 µg/mL on DU145 cells. Also, DAPI staining was performed in order to determine the effect on nuclear material due to ZnO NPs treatment in the studied cell lines taking leaf extract as positive control and untreated negative control for comparison. Cell migration assay was evaluated to determine the direct influence of NPs on metastasis that is potential suppression capacity of NPs to tumor cell migration. Outcome of the synthesized ZnO NPs using C. verrucosa shows antimicrobial activity against studied microbes, also cytotoxicity, apoptotic mediated DNA damage and antiproliferative potentiality in the studied carcinoma cells and hence, can be further used in biomedical, pharmaceutical and food processing industries as an effective antimicrobial and anti-cancerous agent.