Brain tumor segmentation using neuro-technology enabled intelligence-cascaded U-Net model.

According to experts in neurology, brain tumours pose a serious risk to human health. The clinical identification and treatment of brain tumours rely heavily on accurate segmentation. The varied sizes, forms, and locations of brain tumours make accurate automated segmentation a formidable obstacle in the field of neuroscience. U-Net, with its computational intelligence and concise design, has lately been the go-to model for fixing medical picture segmentation issues. Problems with restricted local receptive fields, lost spatial information, and inadequate contextual information are still plaguing artificial intelligence. A convolutional neural network (CNN) and a Mel-spectrogram are the basis of this cough recognition technique. First, we combine the voice in a variety of intricate settings and improve the audio data. After that, we preprocess the data to make sure its length is consistent and create a Mel-spectrogram out of it. A novel model for brain tumor segmentation (BTS), Intelligence Cascade U-Net (ICU-Net), is proposed to address these issues. It is built on dynamic convolution and uses a non-local attention mechanism. In order to reconstruct more detailed spatial information on brain tumours, the principal design is a two-stage cascade of 3DU-Net. The paper's objective is to identify the best learnable parameters that will maximize the likelihood of the data. After the network's ability to gather long-distance dependencies for AI, Expectation-Maximization is applied to the cascade network's lateral connections, enabling it to leverage contextual data more effectively. Lastly, to enhance the network's ability to capture local characteristics, dynamic convolutions with local adaptive capabilities are used in place of the cascade network's standard convolutions. We compared our results to those of other typical methods and ran extensive testing utilising the publicly available BraTS 2019/2020 datasets. The suggested method performs well on tasks involving BTS, according to the experimental data. The Dice scores for tumor core (TC), complete tumor, and enhanced tumor segmentation BraTS 2019/2020 validation sets are 0.897/0.903, 0.826/0.828, and 0.781/0.786, respectively, indicating high performance in BTS.

Design, synthesis, cytotoxic, and anti-inflammatory activities of some novel analogues of aloe-emodin isolated from the rhizomes of Rheum emodi.

In connection with our continuous efforts in the synthesis of derivatives from major compounds isolated from traditional medicinal plants, in the present study we have attempted to synthesize the furan-conjugated aloe-emodin derivatives (5a-j) using a three-component reaction. The synthesized derivatives were assessed for anticancer activity against five different cancer cell lines using the in vitro MTT assay and the results showed that most of the derivatives are potent against cancer cells comparing with the control. Compounds 5a and 5e showed excellent activity against all the cancer cells with less than 12.5 µM and arrested the cell cycle at the G0/G1 phase in both CAL27 and SCC9 cells. Compound 5e induces the early apoptosis in CAL27 cells and compounds 5a and 5e induce early and late apoptosis, respectively, in SCC9 cells. Moreover, compounds 5b, 5c, 5i, and 5j showed excellent anti-inflammatory activity in LPS-stimulated RAW 264.7 cells by inhibiting IL-6 production. The molecular docking studies revealed that compound 5e has strong interaction with the CLK kinase and protein kinase II through hydrogen binding Asp325 and Lys290.

Piperazine tethered bergenin heterocyclic hybrids: design, synthesis, anticancer activity, and molecular docking studies.

In an attempt to develop natural product-based anticancer agents, a series of novel piperazine-linked bergenin heterocyclic hybrids bearing arylthiazolyl (5a-e), benzothiazolyl (10a-i), and arylsulfonyl (13a-o) were synthesized using the classical Mannich reaction and evaluated for their anticancer activity. All the synthesized derivatives were assessed for in vitro cytotoxic activity against a panel of human cancer and normal cell lines and the results showed that most of the compounds exhibited significant cytotoxic activity against cancer cells and mild cytotoxicity against normal cells. In particular, the compounds 5a, 5c, 10f, and 13o showed potent cytotoxic activity against tongue and oral cancer cell lines compared to the parent compound (<100 µM). Considering the efficacy, the compounds 5a, 5c, 10f, and 13o were subjected to cell cycle analysis and the results indicated that the compounds mitigated the cell cycle progression at the G0/G1 phase in the tongue and oral cancer cell lines. Subsequently, the annexin V/PI staining assay demonstrated that the compounds 5a, 5c, 10f, and 13o induced early and late apoptosis against tongue cancer and necrosis against oral cancer. Further, gene expression analysis revealed that 5a, 5c, and 13o treatment regulated the BAX and BcL-2 expression and also the selected compounds significantly reduced the expression level of vimentin, oct-4, and nanog. In addition, molecular docking studies revealed that the selected derivatives have strong binding energy with the BcL2 protein and downregulates the expression. Taken together, the study results implied that these compounds are promising anticancer candidates by modulating the epithelial to mesenchymal transition axis and could be considered for further development of novel anticancer drugs.

Isolation, purification and structural elucidation of Mellein from endophytic fungus Lasiodiplodia theobromae strain (SJF-1) and its broad-spectrum antimicrobial and pharmacological properties.

In an on-going investigation of bioactive metabolites producing potential endophytic fungi, the strain Lasiodiplodia theobromae (SJF-1) was isolated from a medicinal plant Syzygium cumini. The cultural, morphological and molecular identification was done with the SJF-1 strain. The obtained gene sequence was deposited in NCBI with accession number MG 938644. The methanolic extract of SJF-1 strain possessed one major bioactive fraction, and it was purified by column chromatography. Further, it was identified as Mellein by various spectroscopic studies (1 H, 13 C, DEPT-135°, FT-IR, ESI-HR-MS and 2D NMR). Biologically, Mellein showed potent anti-Xanthomonas activity with minimum inhibitory concentration (MIC) values ranging from 1·9 to 62·5 µg ml-1 against 11 Xanthomonas strains, a broad-spectrum antimicrobial activity with MIC 7·8-31·25 µg ml-1 and 1·9-31·25 µg ml-1 towards both bacterial and fungal strains, respectively. The scanning electron microscope analysis proved the antimicrobial efficacy of a Mellein by rupturing the cell walls of Xanthomonas sp. Molecular docking studies further supported that the Mellein showed good binding interactions with the proteins of Xanthomonas sp. to reduce pathogenicity. Further, in silico pharmacological studies showed that this metabolite exhibited high gastrointestinal absorption properties and promising oral drug bioavailability. We report, anti-Xanthomonas, in silico docking and pharmacological studies of Mellein from (SJF-1) strain for the first time.

Design, synthesis and cytotoxic activity studies of alkyne linked analogues of Nimbolide.

A series of novel nimbolide derivatives bearing various substitutions on 28th position was designed and synthesized using Sonogashira (2a-2p) and Glaser coupling (3a-3e) reactions. The synthesized derivatives were assessed for in vitro cytotoxic activity against four different human cancer cell lines (A549 cells, MCF-7 cells, MDA-MB-231 cells, and HCT15 cells) and normal cell line (HEK cells) using MTT assay. Among the screened derivatives, the compound 3a showed potent activity against A549 cells with IC50 value of 0.23 µM as comparing with parent molecule 1 (1.48 µM) and the standard drug doxorubicin (0.82 µM). As well, the flow cytometry analysis confirmed that the compounds 1 and 3a arrest the cell cycle progress at S phase and induce the early apoptosis in the lung cancer. The qRT-PCR analysis revealed that the compounds 1 and 3a downregulate the BcL2 expression and upregulates the Bax gene expression level in A549 cells. The strong binding affinity of the compounds 1 and 3a with BcL2 was also confirmed using molecular docking analysis. Together, the results suggested that the compound 3a is a promising anticancer agent against lung cancer is deserved for further investigation.

Monitoring of Chemical Markers in Extraction of Traditional Medicinal Plants (Piper nigrum, Curcuma longa) Using In Situ ReactIR.

BACKGROUND: The fingerprinting and quantification of marker compounds from medicinal plants is a domain of the herbal industry for quality/quantity control parameters. OBJECTIVE: The main objective of this study is the application of the in situ ReactIR technique for measuring the concentration of different components during the extraction process of different medicinal plants. METHOD: In this study we have performed the extraction of two-marker compounds, viz. piperine from Piper nigrum and curcumin from Curcuma longa plants, using various solvents (dichloromethane and methanol). The progress of extraction was monitored using an in situ Fourier transform infrared (FTIR) probe instrument and an automated reactor. RESULTS: In this communication, using the in situ ReactIR technique we developed a method which demonstrates the relative quantification of marker analytes, optimizes extraction time and type of solvents to be used for different analytes during the extraction process. CONCLUSIONS: To the best of our knowledge, this is the first report of relative quantification and structural information of marker compounds during the process of extraction using in situ FTIR. HIGHLIGHTS: The present study highlights the real-time monitoring, in situ quantification, and structural information of marker compounds during the process of extraction of medicinal plants using in situ FTIR.

Design, synthesis, and biological evaluation of pyrazole-linked aloe emodin derivatives as potential anticancer agents.

In connection with our continuous efforts to generate new derivatives from lead compounds isolated from traditional medicinal plants, a series of aloe-emodin derivatives (6a-6e) were synthesized and assessed for their potential anticancer activity against a panel of cancer cell lines. The results showed that most of the derivatives are more active than the aloe-emodin and particularly, 6b and 6e manifested potent activity with IC50 values of 1.32 & 1.6 µM and 0.99 & 2.68 µM against MDA-MB-231 and MCF-7 cells, respectively. Moreover, 6b and 6e induce early and late apoptosis as well as arrest the cell cycle at the G2/M phase in MDA-MB-231 cells. In conclusion, the results confirmed that the aloe-emodin derivatives could be a potential drug candidate for better treatment of breast cancer.

Investigation of Cytotoxic Constituents from Seed Pulp of Entada Phaseoloides and Metabolite Profiling Using UPLC-QTOF-MSE.

BACKGROUND: Entada phaseoloides (Linn.) Merr. (Family: Fabaceae) is a well-known, traditional, medicinal plant that has been extensively used in the Ayurvedic system of medicine for centuries to combat a wide range of ailments. OBJECTIVE: The goal of this work was to investigate the bioactive constituents from n-butanol extracts of Entada. phaseoloides and develop a method for the comprehensive characterization of saponins using liquid chromatography with an electrospray ionization quadrupole time-of-flight mass spectrometer (LC-ESI-QTOF-MS). METHODS: A hyphenated technique, ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS/MS), has been proposed to integrate LC and MS together with NMR for structural elucidation. This method allowed comprehensive characterization of saponin glycosides from E. phaseoloides based on their MS/MS fragmentation study. RESULTS: The phytochemical study of E. phaseoloides resulted in the isolation and identification of three bio-active constituents. Further, the UPLC-QTOF-MS/MS method led the structure elucidation of saponin constituents directly from crude extracts via comparison of the exact molecular masses from their MS/MS spectra. Identified common fragments m/z 648, 630, 498, 366, and 204 were used for the screening of saponin components. CONCLUSIONS: The present study summarizes the isolation and identification of bio-compounds from n-butanol extract and the demonstration of UPLC-QTOF-MS/MS analysis for the characterization of compounds in complex crude extracts. To the best of our knowledge, this is the first systematic study in structural characterization on complex saponins and other metabolites from crude extract of E. phaseoloides using UPLC-ESI-QTOF-MSE. HIGHLIGHTS: Rapid analysis and characterizations of three new saponins from E. phaseoloides using UPLC-ESI-QTOF-MSE were tentatively identified based on the mass fragmentation study.

Synthesis and biological evaluation of Schizandrin derivatives as tubulin polymerization inhibitors.

A series of oxime ester-derivatives were prepared by utilizing the schizandrin (1), a major compound isolated from Schisandra grandiflora, which is deployed in different traditional system of medicine. The in vitro antiproliferative activities of the synthesized compounds were assessed against a selected panel of human cancer cell lines (A549, RKO P3, DU145 and Hela) and normal cell (HEK293). Several of these derivatives were found more potent in comparison to parent compound, schizandrin (1). Particularly, 4a and 4b demonstrated potent activity against DU-145 and RKOP3 cell lines with IC50 values of 3.42 µM and 3.35 µM respectively. To characterize the molecular mechanisms involved in antitumoral activity, these two compounds, 4a and 4b were selected for further studies. Cell cycle analysis revealed that both the compounds were able to induce apoptosis and cell cycle arrest at G0/G1 phase. To know the extent of apoptosis in DU145 and RKOP3 cell lines, Annexin V-FITC were performed. Moreover, the tubulin polymerization assay indicated that 4a and 4b exhibits potent inhibitory effect on the tubulin assembly. Molecular docking studies and competitive binding assay also indicated that 4a and 4b effectively bind at the colchicine binding site of the tubulin.

Isolation, semi-synthesis, free-radicals scavenging, and advanced glycation end products formation inhibitory constituents from Parmotrema tinctorum.

Bioassay-guided separation of acetone extract from lichen Parmotrema tinctorum (Delise ex Nyl.) Hale led to the isolation of six major phenolic constituents (1-6). Compounds structures were established using NMR and mass spectral techniques. Further, to develop libraries on these scaffolds, a series of semi-synthetic derivatives were prepared (1a-1f, 2a-2b, 3a, 5a) and investigated for their free-radicals (2,2-diphenyl-1-picrylhydrazyl and 2,2'-azinobis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS)) scavenging and advanced glycation end products (AGEs) formation inhibitory activities. Amongst tested derivatives, 1a, 1d, 1e, 2a, and 5a showed strong ABTS scavenging potentials comparable to Trolox. In addition, these derivatives also manifested moderate AGEs formation inhibitory activities. [Formula: see text].

Synthesis and biological evaluation of bergenin-1,2,3-triazole hybrids as novel class of anti-mitotic agents.

In continuation of our investigation of pharmacologically-motivated natural products, we have isolated bergenin (1) as a major compound from Mallotus philippensis, which is deployed in different Indian traditional systems of medicine. Here, a series of bergenin-1,2,3-triazole hybrids were synthesized and evaluated for their potentials against a panel of cancer cell lines. Several of the hybrid derivatives were found more potent in comparison to parent compound bergenin (1). Among them, 4j demonstrated potent activity against A-549 and HeLa cell lines with IC50 values of 1.86 µM and 1.33 µM, respectively, and was equipotent to doxorubicin. Cell cycle analysis showed that 4j arrested HeLa cells at G2/M phase and lead to accumulation of Cyclin B1 protein. Cell based tubulin polymerization assays and docking studies demonstrated that 4j disrupts tubulin assembly by occupying colchicine binding pocket of tubulin.

Cerium Phosphate-Cerium Oxide Heterogeneous Composite Nanozymes with Enhanced Peroxidase-Like Biomimetic Activity for Glucose and Hydrogen Peroxide Sensing.

In the present work, we focus on the development of CePO4-CeO2 composite nanorods with peroxidase mimetic activity for the sensitive detection of hydrogen peroxide and glucose. The Ce3+/PO43- molar ratio (CP10:1, CP5:1, CP2:1) in the hydrothermal reaction controlled the formation of pure CePO4, CePO4-CeO2 composite nanozymes with different percentages of CeO2, and its crystal structure. A higher Ce3+/PO43- molar ratio (CP10:1 or CP5:1) was required to obtain CePO4-CeO2 composite nanostructure, while a lower Ce3+/PO43- molar (CP2:1) ratio was sufficient to fabricate pure CePO4 nanorods. In the presence of hydrogen peroxide, the prepared nanozymes catalyze the oxidation of chromogenic substrate 3,3',5,5'-tetramethylbenzidine (TMB). Steady state kinetic analysis based on the Michaelis-Menten model revealed that CP10:1 showed excellent affinity toward the TMB ( Km = 0.236 mM and Vmax = 8.78 × 10-8 M s-1) in comparison to the catalytic activity of CP5:1 and CP2:1 and horseradish peroxidase ( Km = 0.434 mM and Vmax = 10.0 × 10-8 M s-1). The superior peroxidase activity of CePO4-CeO2 composite nanozymes can be ascribed to the enhanced redox switching between Ce3+ ↔ Ce4+ sites from the CePO4 and CeO2 lattice, respectively. The colorimetric detection of hydrogen peroxide and glucose showed a linear response around 150 µM concentration with the limits of detection (LOD) of 2.9 and 4.1 µM, respectively.

Synthesis and biological evaluation of Schizandrin derivatives as potential anti-cancer agents.

A new series of Schizandrin (1) derivatives were synthesized utilizing the C-9 position of the Schizandrin core and evaluated for their cytotoxic activities against HeLa (cervical cancer), A549 (lung cancer), MCF-7 (breast cancer) and DU-145 (prostate cancer) cell lines. Among the synthesized series, 4e, 4f, 4g and 5 showed potent activities against tested cell lines. More significantly, compound 5 exhibited most potent cytotoxic activity against DU-145 with an IC50 value of 1.38 µM which is comparable to the standard agent, doxorubicin. Further, flow cytometry analysis indicated that 5 arrested cells in G2/M phase and consequently leading to apoptosis. Molecular docking analysis showed that 5 occupied the colchicine binding pocket of tubulin. Overall, the present study demonstrates that 5, as a mitotic-agent.

Rapid identification of limonoids from Cipadessa baccifera and Xylocarpus granatum using ESI-Q-ToF-MS/MS and their structure-fragmentation study.

Limonoids found to be chemotaxonomic markers from the plants of the Meliaceae and Rutaceae families. In the present study, rapid identification of limonoids from Cipadessa baccifera and Xylocarpus granatum were achieved using fast and simple electrospray ionization quadruple time-of-flight mass spectrometry (ESI-Q-ToF-MS/MS) in positive-ion mode. Although the structures of these compounds were found to be similar, Collision Induced Dissociation (CID) mass spectrometric analysis of these protonated/sodiated molecules indicated different fragmentation patterns by which the structures were confirmed. The fragment ions were formed due to the loss of neutral components like H2O, CO2, methanol, as well as McLafferty rearrangement and Retro-ene reaction. Furthermore, MS/MS spectra revealed different fragmentation pathways for different classes of limonoids which further aided dereplication.

Synthesis and evaluation of anti-plasmodial and cytotoxic activities of epoxyazadiradione derivatives.

Epoxyazadiradione (1), a major compound derived from Neem oil, showed modest anti-plasmodial activity against CQ-resistant and CQ-sensitive strains of the most virulent human malaria parasite P. falciparum. A series of analogues were synthesized by modification of the key structural moieties of this high yield natural product. Out of the library of all compounds tested, compounds 3c and 3g have showed modest anti-plasmodial activity against CQ-sensitive (IC50 2.8 ± 0.29 µM and 1.5 ± 0.01 µM) and CQ-resistant strains (IC50 1.3 ± 1.08 µM and 1.2 ± 0.14), while compounds 3k, 3l and 3m showed modest activity against CQ-sensitive strain of P. falciparum with IC50 values of 2.3 ± 0.4 µM, 2.9 ± 0.1 µM and 1.7 ± 0.06 µM, respectively. Additionally, cytotoxic properties of these derivatives against SIHA, PANC 1, MDA-MB-231, and IMR-3 cancer cell lines were also studied and the results indicated that low cytotoxic potentials of all the derivatives which indicating the high selectivity index of the compounds.

"Click" reaction mediated synthesis of costunolide and dehydrocostuslactone derivatives and evaluation of their cytotoxic activity.

As part of pharmacological-phytochemical integrated studies on medicinal plants from Indian flora, costunolide (1) and dehydrocostus lactone (2), were isolated as major phytochemicals from Saussurea lappa, a plant traditionally used in different Asian systems of medicine. A series of 1,4-disubstituted-1,2,3-triazoles conjugates were synthesized through diastereo selective Michael addition followed by regioselective Huisgen 1,3-dipolar cycloaddition reactions. All these triazolyl derivatives (5a-5j) & (7a-7j) were well characterized using modern spectroscopic techniques and evaluated for their anticancer activity against a panel of five human cancerous celllines. The results indicated that all the analogs displayed moderate cytotoxic activity.

New cytotoxic clerodane diterpenes from the leaves of Premna tomentosa.

Bio-activity directed investigation of hexane extract from the leaves of Premna tomentosa led to the isolation of three new clerodane diterpenes (1-3) along with four known compounds (4-7). The structures of new compounds were established using IR, MS, 1D, and 2D NMR techniques. The in vitro cytotoxicity of the crude hexane extract and the isolated compounds were evaluated against seven human cancer cell lines and results indicated that compounds 2 and 4 depicted significant cytotoxicity against hepatocellular carcinoma cell line.

Novel cycloartane triterpenoids from the Nepal native plant Caragana sukiensis.

A phytochemical study on the arial part of Caragana sukiensis resulted in the isolation of three new cycloartane triterpenoids 1-3 and their structures were fully established on the basis of detailed spectroscopic (especially 2D NMR and Mass) analysis. These new compounds possessed hemiacetal fused tetrahydropyran rings at C-15/C-16, while 2 and 3 also contains d-xylose moiety.

Isolation, semi-synthesis and bio-evaluation of spatane derivatives from the brown algae Stoechospermum marginatum.

A comprehensive investigation of chemical constituents from brown algae Stoechospermum marginatum yielded ten known spatane compounds (1-10). To develop the compound libraries on these scaffolds, a series of semi synthetic derivatives was prepared (1a-1d, 2a, 4a, 11 and 12) and investigated for their anti-microbial and anticancer activities. The results indicated that compounds 2a, 4, 1b and 4a exhibited potent cytotoxic activities against B16F10 cancer cell line with IC50 values of 3.28, 3.45, 3.62 and 4.11 µg/ml respectively, which are comparable to the standard drug (etoposide IC50=4.12 µg/ml). In addition, 4 and 1b were also manifested potent antimicrobial activities against tested bacterial and fungal strains. This is the first Letter on the synthesis and biological activities of these novel derivatives.

Role of long term antibiotics in chronic respiratory diseases.

Antibiotics are commonly used in the management of respiratory disorders such as cystic fibrosis (CF), non-CF bronchiectasis, asthma and COPD. In those conditions long-term antibiotics can be delivered as nebulised aerosols or administered orally. In CF, nebulised colomycin or tobramycin improve lung function, reduce number of exacerbations and improve quality of life (QoL). Oral antibiotics, such as macrolides, have acquired wide use not only as anti-microbial agents but also due to their anti-inflammatory and pro-kinetic properties. In CF, macrolides such as azithromycin have been shown to improve the lung function and reduce frequency of infective exacerbations. Similarly macrolides have been shown to have some benefits in COPD including reduction in a number of exacerbations. In asthma, macrolides have been reported to improve some subjective parameters, bronchial hyperresponsiveness and airway inflammation; however have no benefits on lung function or overall asthma control. Macrolides have also been used with beneficial effects in less common disorders such as diffuse panbronchiolitis or post-transplant bronchiolitis obliterans syndrome. In this review we describe our current knowledge the use of long-term antibiotics in conditions such as CF, non-CF bronchiectasis, asthma and COPD together with up-to-date clinical and scientific evidence to support our understanding of the use of antibiotics in those conditions.