SSGraphCPI: A Novel Model for Predicting Compound-Protein Interactions Based on Deep Learning.

Identifying compound-protein (drug-target, DTI) interactions (CPI) accurately is a key step in drug discovery. Including virtual screening and drug reuse, it can significantly reduce the time it takes to identify drug candidates and provide patients with timely and effective treatment. Recently, more and more researchers have developed CPI's deep learning model, including feature representation of a 2D molecular graph of a compound using a graph convolutional neural network, but this method loses much important information about the compound. In this paper, we propose a novel three-channel deep learning framework, named SSGraphCPI, for CPI prediction, which is composed of recurrent neural networks with an attentional mechanism and graph convolutional neural network. In our model, the characteristics of compounds are extracted from 1D SMILES string and 2D molecular graph. Using both the 1D SMILES string sequence and the 2D molecular graph can provide both sequential and structural features for CPI predictions. Additionally, we select the 1D CNN module to learn the hidden data patterns in the sequence to mine deeper information. Our model is much more suitable for collecting more effective information of compounds. Experimental results show that our method achieves significant performances with RMSE (Root Mean Square Error) = 2.24 and R2 (degree of linear fitting of the model) = 0.039 on the GPCR (G Protein-Coupled Receptors) dataset, and with RMSE = 2.64 and R2 = 0.018 on the GPCR dataset RMSE, which preforms better than some classical deep learning models, including RNN/GCNN-CNN, GCNNet and GATNet.

Growth inhibitory effects of standard pro- and antioxidants on the human malaria parasite Plasmodium falciparum.

The redox metabolism of the malaria parasite Plasmodium falciparum and its human host has been suggested to play a central role for parasite survival and clearance. A common approach to test hypotheses in redox research is to challenge or rescue cells with pro- and antioxidants. However, quantitative data on the susceptibility of infected erythrocytes towards standard redox agents is surprisingly scarce. Here we determined the IC50 values of P. falciparum strains 3D7 and Dd2 for a set of redox agents using a SYBR green-based growth assay. Parasite killing in this assay required extremely high concentrations of hydrogen peroxide with a millimolar IC50 value, whereas IC50 values for tert-butyl hydroperoxide and diamide were between 67 and 121 µM. Thus, in contrast to tert-butyl hydroperoxide and the disulfide-inducing agent diamide, the host-parasite unit appears to be very robust against challenges with hydrogen peroxide with implications for host defense mechanisms. N-acetylcysteine, ascorbate, and dithiothreitol also had antiproliferative instead of growth-promoting effects with IC50 values around 12, 3 and 0.4 mM, respectively. So-called antioxidants can therefore also inhibit parasite growth with implications for clinical trials and studies on 'oxidative stress'. Furthermore, the addition of reductants to parasite cultures resulted in the gelation of albumin, the formation of methemoglobin and hemolysis. These effects can alter the fluorescence in SYBR green assays and have to be taken into account for the determination of IC50 values. In summary, standard oxidants and reductants both inhibit the growth of P. falciparum with IC50 values differing by three orders of magnitude.

In vitro cytochrome P450 inhibition potential of methylenedioxy-derived designer drugs studied with a two-cocktail approach.

In vitro cytochrome P450 (CYP) inhibition assays are common approaches for testing the inhibition potential of drugs for predicting potential interactions. In contrast to marketed medicaments, drugs of abuse, particularly the so-called novel psychoactive substances, were not tested before distribution and consumption. Therefore, the inhibition potential of methylenedioxy-derived designer drugs (MDD) of different drug classes such as aminoindanes, amphetamines, benzofurans, cathinones, piperazines, pyrrolidinophenones, and tryptamines should be elucidated. The FDA-preferred test substrates, split in two cocktails, were incubated with pooled human liver microsomes and analysed after protein precipitation using LC-high-resolution-MS/MS. IC50 values were determined of MDD showing more than 50 % inhibition in the prescreening. Values were calculated by plotting the relative metabolite concentration formed over the logarithm of the inhibitor concentration. All MDD showed inhibition against CYP2D6 activity and most of them in the range of the clinically relevant CYP2D6 inhibitors quinidine and fluoxetine. In addition, the beta-keto compounds showed inhibition of the activity of CYP2B6, 5,6-MD-DALT of CYP1A2 and CYP3A, and MDAI of CYP2A6, all in the range of clinically relevant inhibitors. In summary, all MDD showed inhibition of the activity of CYP2D6, six of CYP1A2, three of CYP2A6, 13 of CYP2B6, two of CYP2C9, six of CYP2C19, one of CYP2E1, and six of CYP3A. These results showed that the CYP inhibition by MDD might be clinically relevant, but further studies are needed for final conclusions.

Preparation of bioactive peptides with high angiotensin converting enzyme inhibitory activity from winged bean [Psophocarpus tetragonolobus (L.) DC.] seed.

Winged bean [Psophocarpus tetragonolobus (L.) DC.] seed is a potential underexploited source of vegetable protein due to its high protein content. In the present work, undefatted and defatted winged bean seed hydrolysates, designated as UWBSH and DWBSH, respectively were produced separately by four proteolytic enzymes namely Flavourzyme, Alcalase, Bromelain, and Papain using pH-stat method in a batch reactor. Enzymatic hydrolysis was carried out over a period of 0.5 to 5 h. UWBSH and DWBSH produced were tested for their ACE inhibitory activity in relation to the hydrolysis time and degree of hydrolysis (DH). Maximum ACE inhibitory activity, both for UWBSH and DWBSH, were observed during 3 to 5 h of hydrolysis. Both, UWBSH (DH 91.84 %), and DWSBH (DH 18.72 %), produced by Papain at 5 h hydrolysis, exhibited exceptionally high ACE inhibitory activity with IC50 value 0.064 and 0.249 mg mL(-1), respectively. Besides, papain-produced UWBSH and DWBSH were further fractionated into three fractions based on molecular weight (UWBSH-I, <10 kDa; UWBSH-II, <5 kDa; UWBSH-III, <2 kDa) and (DWBSH-I, <10 kDa; DWBSH-II, <5 kDa; DWBSH-III, <2 kDa). UWBSH-III revealed the highest ACE inhibitory activity (IC50 0.003 mg mL(-1)) compared with DWBSH-III (IC50 0.130 mg mL(-1)). The results of the present investigation revealed that winged bean seed hydrolysates can be explored as a potential source of ACE inhibitory peptides suggesting their uses for physiological benefits as well as for other functional food applications.

Pharmaceutical characterization and exploration of Arkeshwara rasa in MDA-MB-231 cells.

BACKGROUND: The diverse specificity mode of cancer treatment targets and chemo resistance demands the necessity of drug entities which can address the devastating dynamicity of the disease. OBJECTIVES: To check the anti-tumour potential of traditional medicine rich in polyherbal components and metal nanoparticle namely Arkeshwara rasa (AR). MATERIAL METHODS: The AR was prepared in a modified version with reference from Rasaratna Samuchaya and characterized using sophisticated instrumental analysis including XRD, SEM-EDAX, TEM, TGA-DSC, and LC-MS and tested against the MDA-MB-231 cell line to screen cell viability and the cytotoxicity with MTT, SRB and the AO assay. RESULTS: XRD pattern shows cubic tetrahedrite structure with Sb, Cu, S peaks and trace elements like Fe, Mg, etc. The particle size of AR ranges between 20 and 30 nm. The TGA points thermal decomposition at 210 °C and the metal sulphide peaks in DSC. LC-MS analysis reveals the components of the formulation more on the flavonoid portion. The IC50 value of MTT and SRB are 25.28 µg/mL and 31.7 µg/mL respectively. The AO colorimeter substantiated the cell viability and the apoptosis figures of the same cell line. The AR exhibits cytotoxicity and reaffirms the apoptosis fraction with SRB assay. CONCLUSIONS: The Hesperidine, Neohesperidin, Rutin components in the phytochemical pool can synergize the anti-tumour potential with either influencing cellular pathways or decreasing chemo resistance to conventional treatment. AR need to be further experimented with reverse transcription, flow cytometry, western blotting, etc.

Challenges and Recent Advances of Novel Chemical Inhibitors in Medulloblastoma Therapy.

Medulloblastoma is a common term used for the juvenile malignant brain tumor, and its treatment is exciting due to different genetic origins, improper transportation of drug across the blood-brain barrier, and chemo-resistance with various side effects. Currently, medulloblastoma divided into four significant subsections (Wnt, Shh, Group 3, and Group 4) is based on their hereditary modulation and histopathological advancement. In this chapter, we tried to combine several novel chemical therapeutic agents active toward medulloblastoma therapy. All these compounds have potent activity to inhibit the medulloblastoma.

Phytochemical Screening, Antioxidant and Antifungal Activities of Aconitum chasmanthum Stapf ex Holmes Wild Rhizome Extracts.

Aconitum chasmanthum Stapf ex Holmes, an essential and critically endangered medicinal plant from Kashmir Himalayas, was studied for its antioxidant and antifungal properties. The shade-dried powdered rhizome was extracted sequentially with hexane, ethyl acetate, and methanol. These subsequent fractions were evaluated for total phenolic content (TPC); total flavonoid content (TFC); antioxidant assays, such as 1,1-diphenyl 1-2-picryl-hydrazyl (DPPH); ferric-reducing antioxidant power (FRAP); superoxide radical scavenging (SOR); hydroxyl radical scavenging (OH) and antifungal activity using the poisoned food technique. Highest TPC (5.26 ± 0.01 mg/g) and TFC (2.92 ± 0.04 mg/g) were reported from methanolic extracts. The highest values of radical scavenging activities were also observed in methanolic extracts with IC50 values of 163.71 ± 2.69 µg/mL in DPPH, 173.69 ± 4.91 µg/mL in SOR and 159.64 ± 2.43 µg/mL in OH. The chemical profile of ethyl acetate extract was tested using HR-LCMS. Methanolic extracts also showed a promising inhibition against Aspergillus niger (66.18 ± 1.03), Aspergillus flavus (78.91 ± 1.19) and Penicillium notatum (83.14 ± 0.97) at a 15% culture filtrate concentration with minimum inhibitory concentration (MIC) values of 230 µg/mL, 200 µg/mL and 190 µg/mL, respectively. Overall, the methanolic fractions showed significant biological potential, and its pure isolates might be used to construct a potential new medicinal source.

DL-SMILES#: A Novel Encoding Scheme for Predicting Compound Protein Affinity Using Deep Learning.

INTRODUCTION: Drug repositioning aims to screen drugs and therapeutic goals from approved drugs and abandoned compounds that have been identified as safe. This trend is changing the landscape of drug development and creating a model of drug repositioning for new drug development. In the recent decade, machine learning methods have been applied to predict the binding affinity of compound proteins, while deep learning is recently becoming prominent and achieving significant performances. Among the models, the way of representing the compounds is usually simple, which is the molecular fingerprints, i.e., a single SMILES string. METHODS: In this study, we improve previous work by proposing a novel representing manner, named SMILES#, to recode the SMILES string. This approach takes into account the properties of compounds and achieves superior performance. After that, we propose a deep learning model that combines recurrent neural networks with a convolutional neural network with an attention mechanism, using unlabeled data and labeled data to jointly encode molecules and predict binding affinity. RESULTS: Experimental results show that SMILES# with compound properties can effectively improve the accuracy of the model and reduce the RMS error on most data sets. CONCLUSION: We used the method to verify the related and unrelated compounds with the same target, and the experimental results show the effectiveness of the method.

Calculating Half Maximal Inhibitory Concentration (IC50) Values from Glycomics Microarray Data Using GraphPad Prism.

Half maximal inhibitory concentration (IC50) is a measurement often used to compare the efficiency of various carbohydrates and their derivatives for inhibition of lectin binding to particular ligands. IC50 values can be calculated using experimental data from various platforms including enzyme-linked immunosorbent assay- (ELISA-)type microtiter plate assays, isothermal titration calorimetry (ITC), or glycan microarrays. In this chapter, we describe methods to fluorescently label a lectin, to carry out a lectin binding inhibition experiment on glycan microarrays, and to calculate the IC50 value of a binding inhibitory molecule using GraphPad Prism software. In the example used to illustrate the method in this chapter, IC50 calculation is demonstrated for inhibition of Maackia amurensis agglutinin (MAA) binding to 3'sialyl-N-acetyllactosamine (3SLN) using free lactose.

Reversible Mechanisms of Enzyme Inhibition and Resulting Clinical Significance.

Inhibition of a drug-metabolizing enzyme by the reversible interaction of a drug with the enzyme, thus decreasing the metabolism of another drug, is a major cause of clinically significant drug-drug interactions. This chapter defines the four reversible mechanisms of inhibition exhibited by drugs: competitive, noncompetitive, uncompetitive, and mixed competitive/noncompetitive. An in vitro procedure to determine the potential of a drug to be a reversible inhibitor is also provided. Finally, a number of examples of clinically significant drug-drug interactions resulting from reversible inhibition are described.

Anti-EGFR-mAb and 5-Fluorouracil Conjugated Polymeric Nanoparticles for Colorectal Cancer.

BACKGROUND: Due to the higher intake of junk food and unhealthy lifestyle, the percentage of U.S. adults aged 50 to 75 years who were up-to-date with colorectal cancer screening increased 1.4 percentage points, from 67.4% in 2016 to 68.8% in 2018. This represents an additional 3.5 million adults screened for colorectal cancer. This is a severe concern of this research, and an attempt was made to prepare a target-specific formulation that could circumvent chemotherapy-related compilation and improvise higher cellular uptake. The fundamental agenda of this research was to prepare and develop Anti-EGFR mAb and 5-Fluorouracil (5-FU) fabricated polymeric nanoparticles for colorectal cancer. OBJECTIVE: The main objective of this research was to prepare and evaluate more target specific formulation for the treatment of colorectal cancer. PLGA and PEG-based polymeric nanoparticles are capable of preventing opsonization via the reticuloendothelial system. Hence, prepared polymeric nanoparticles are capable of higher cellular uptake. METHODS: The Poly(d,1-lactide-co-glycolide) (PLGA) and Polyethylene Glycol (PEG) were combined utilizing the ring-opening polymerization method. The presence of PEG prevents opsonization and distinguished blood concentration along with enhanced targeting. The presence of PLGA benefits in the sustained release of polymeric formulations. The optimized formulation (5-FU-PLGA- PEG-NP) was lyophilized using 4% trehalose (cryoprotectants) and conjugated with Anti- EGFR mAb on its surface to produce Anti-EGFR-5-FU-PLGA-PEG-NP; the final formulation, which increases target specificity and drug delivery system of nanoparticles. RESULTS: The spherical shaped optimized formulation, 5-FU-PLGA-PEG-NP-3 was found to have higher percentage drug entrapment efficacy (71.23%), higher percentage drug content (1.98 ± 0.34%) with minimum particles size (252.3nm) and anionic zeta potential (-31.23mV). The IC50 value of Anti-EGFR-5-FU-PLGA-PEG-NP was 1.01µg/mL after 48 hours incubation period in the HCT 116 cell line, indicating higher anticancer effects of the final formulation. CONCLUSION: From the outcomes of various experiments, it was concluded that Anti-EGFR-5-FUPLGA- PEG-NP has biphasic drug release kinetics, higher cellular uptake and higher cytotoxicity. Therefore, anti-EGFR-5-FU-PLGA-PEG-NP holds excellent potential for drug delivery to EGFR positive colorectal cancer cells.

The Effect of Methylselenocysteine and Sodium Selenite Treatment on microRNA Expression in Liver Cancer Cell Lines.

The unique character of selenium compounds, including sodium selenite and Se-methylselenocysteine (MSC), is that they exert cytotoxic effects on neoplastic cells, providing a great potential for treating cancer cells being highly resistant to cytostatic drugs. However, selenium treatment may affect microRNA (miRNA) expression as the pattern of circulating miRNAs changed in a placebo-controlled selenium supplement study. This necessitates exploring possible changes in the expression profiles of miRNAs. For this, miRNAs being critical for liver function were selected and their expression was measured in hepatocellular carcinoma (HLE and HLF) and cholangiocarcinoma cell lines (TFK-1 and HuH-28) using individual TaqMan MicroRNA Assays following selenite or MSC treatments. For establishing tolerable concentrations, IC50 values were determined by performing SRB proliferation assays. The results revealed much lower IC50 values for selenite (from 2.7 to 11.3 µM) compared to MSC (from 79.5 to 322.6 µM). The treatments resulted in cell line-dependent miRNA expression patterns, with all miRNAs found to show fold change differences; however, only a few of these changes were statistically different in treated cells compared to untreated cells below IC50. Namely, miR-199a in HLF, miR-143 in TFK-1 upon MSC treatment, miR-210 in HLF and TFK-1, miR-22, -24, -122, -143 in HLF upon selenite treatment. Fold change differences revealed that miR-122 with both selenium compounds, miR-199a with MSC and miR-22 with selenite were affected. The miRNAs showing minimal alterations included miR-125b and miR-194. In conclusion, our results revealed moderately altered miRNA expression in the cell lines (less alterations following MSC treatment), being miR-122, -199a the most affected and miR-125b, -194 the least altered miRNAs upon selenium treatment.

Identification of novel class I and class IIb histone deacetylase inhibitor for Alzheimer's disease therapeutics.

Histone deacetylase enzymes were prominent chromatin remodeling drug that targets in the pathophysiology of Alzheimer's disease associated with transcriptional dysregulation. In vitro and in vivo models of AD have demonstrated overexpression of HDAC activity. Non-specificity and non-selectivity of HDAC are the major problems of existing HDAC inhibitors. Hence, we aim to set up a methodology describing the rational development of isoform-selective HDAC inhibitor targeting class, I and class IIb. A convenient multistage virtual screening followed by machine learning and IC50 screenings were used to classify the 5064 compounds into inhibitors and non-inhibitors classes retrieved from the ChEMBL database. ADMET analysis identified the pharmacokinetics and pharmacodynamics properties of selected compounds. Molecular docking, along with mutational analysis of eleven compounds, characterized the inhibiting potency. Herein, for the first time, we reported ChEMBL1834473 (2-[[5-(4-chlorophenyl)-1,3,4-thiadiazol-2-yl]amino]-N-hydroxypyrimidine-5-carboxamide) as the isoform-selective HDAC inhibitor, which interact central Zn2+ atom. The negative energy and interacting residue of the ChEMBL1834473 with six HDAC isoform has also been tabulated and mapped. Moreover, our findings concluded histidine, glycine, phenylalanine, and aspartic acid as key residues in protein-ligand interaction and classify 2347 compounds as HDAC inhibitors. Later, a protein-protein interaction network of six HDAC with the key proteins involved in the progression of an AD and signaling pathway, which describes the relationship between ChEMBL1834473 and AD, has been demonstrated using PPI network where the chosen inhibitor will work. Altogether, we conclude that the compound ChEMBL1834473 may be capable of inhibiting all isoforms of class I and class IIb HDAC based on computational analysis for AD therapeutics.

High-performance liquid chromatographic analysis explores the potential antioxidative agents of Argyreia argentea ARN. EX CHOISY extract.

BACKGROUND: Antioxidative properties of medicinal plants play the key role in plant defense mechanism. Argyreia argentea is an evergreen shrub which is used in the treatment of boils, gastric ulcers, tumor, marasmus, paralysis and spermatorrhea, rheumatoid arthritis, cold, painful sensation, and fever. AIMS: This research investigates the phytochemical contents and antioxidative effects of optimized crude methanol extract of A. argentea. MATERIALS AND METHODS: Crude methanol extract of A. argentea prepared in an optimized procedure has been analyzed by high-performance liquid chromatography to quantitatively determine the phytochemical contents. Tannin content of the extract was determined by established method. The extract was also analyzed for in vitro antioxidative actions by spectrophotometric analysis using 2,2'-azino-bis(3-ethylbenzo-thiazoline-6-sulfonic acid) diammonium salt (ABTS) method, N, N-dimethyl-1,4-diaminobenzene (DMPD) free radical scavenging method, superoxide radical scavenging method, and nitric oxide scavenging method. RESULTS: The experimental results showed a high amount of catechin hydrate (348.62 mg/100 g of dry extract) and moderate amount of gallic acid, p-coumaric acid, and rutin hydrate in the methanol extract of A. argentea. Tannin content was found to be 29.66 mg/g tannic acid equivalent. Scavenging effects expressed as inhibition concentrations (IC50) for ABTS assay, DMPD assay, superoxide assay, and NO assay were 1148.3 µg/mL ± 7.32 µmol ascorbic acid/g, 1017.68 µg/mL, 1116.89 µg/mL, 1835.23 µg/mL, respectively. All the values were compared with their respective standards. No ß-carotene was detected in the extract. CONCLUSIONS: Use of A. argentea extract as a source of functional food as well as an antioxidative agent could be considered with further confirmation.

Interactions of phenethylamine-derived psychoactive substances of the 2C-series with human monoamine oxidases.

Psychoactive substances of the 2C-series (2Cs) are phenethylamine-derived designer drugs that can induce psychostimulant and hallucinogenic effects. Chemically, the classic 2Cs contain two methoxy groups in positions 2 and 5 of the phenyl ring, whereas substances of the so-called FLY series contain rigidified methoxy groups integrated in a 2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b']difuran core. One of the pharmacological features that has not been investigated in detail is the inhibition of monoamine oxidase (MAO). Inhibition of this enzyme can cause elevated monoamine levels that have been associated with adverse events such as agitation, nausea, vomiting, tachycardia, hypertension, or seizures. The aim of this study was to extend the knowledge surrounding the potential of MAO inhibition for 17 test drugs, which consisted of 12 2Cs (2C-B, 2C-D, 2C-E, 2C-H, 2C-I, 2C-N, 2C-P, 2C-T-2, 2C-T-7, 2C-T-21, bk-2C-B, and bk-2C-I) and five FLY analogs (2C-B-FLY, 2C-E-FLY, 2C-EF-FLY, 2C-I-FLY, and 2C-T-7-FLY). The extent of MAO inhibition was assessed using an established in vitro procedure based on heterologously expressed enzymes and analysis by hydrophilic interaction liquid chromatography-high resolution tandem mass spectrometry. Thirteen test drugs showed inhibition potential for MAO-A and 11 showed inhibition of MAO-B. In cases where MAO-A IC50 values were determined, values ranged from 10 to 125 µM (7 drugs) and from 1.7 to 180 µM for MAO-B (9 drugs). In the absence of detailed clinical information on most test drugs, it is concluded that a pharmacological contribution of MAO inhibition cannot be excluded and that further studies are warranted.

Antioxidant Activity of Crude Bromelain of Pineapple (Ananas comosus (L.) Merr) Crown from Subang District, Indonesia.

BACKGROUND: Antioxidants are chemical compounds that can donate one or more electrons to free radicals to prevent degenerative diseases. The crown of pineapple (Ananas comosus (L.) Merr.) contains bromelain, that is, a proteolytic enzyme, which can act as an antioxidant. AIMS AND OBJECTIVES: The aim of this study was to determine the antioxidant activity of crude bromelain from pineapple crowns that were collected from Subang district, West Java, Indonesia. MATERIALS AND METHODS: Antioxidant activity was determined by the method of 2,2-diphenyl-1-picrylhydrazyl (DPPH) with vitamin C as a standard and measured with visible spectrophotometer. RESULTS: The pineapple crown was produced 0.26% of dried crude bromelain with total protein content 44.10% and IC50 value 3624 µg/mL of crude bromelain, which was equivalent to 1590.18 µg/mL of total protein. CONCLUSION: Crude bromelain has medium antioxidant activity.

Effects of Curcumin on Squamous Cell Carcinoma of Tongue: An In Vitro Study.

BACKGROUND: The Squamous Cell Carcinoma of the Tongue (TSCC) is the most frequent cancer of oral cavity often characterized by poor prognosis. Conventional therapies are not very efficient and often may cause serious side effects. In this context, introduction of natural substances as possible adjuvant in the treatment and prevention of cancer is becoming a relevant topic. In fact, curcumin has been used for decades in Chinese traditional medicine for its beneficial effects. Curcumin has anticancer properties in many tumors however, its action on the tongue carcinoma is not entirely clear and many other investigations are necessary. OBJECTIVE: Curcumin seems to be a good adjuvant in the treatment of head and neck tumors. However, these studies are generic and there are not many specific studies on TSCC, the most frequent and most aggressive cancer of the head-neck region. Our goal is to demonstrate its effectiveness also for TSCC. METHODS: In this study, we evaluated the effects of curcumin on TSCC cells using different concentrations (1, 5, 10, 20 and 50 µM) and 3 different treatment times (24, 48 and 72 hours). The inhibition of adhesion, proliferation, viability, migration and apoptosis was studied. RESULTS: IC50 value of curcumin is about 10 µM and there have been inhibitory effects even for treatments at low concentrations. Curcumin reduces migration and progression of TSCC cells and it promotes apoptosis and inhibits tumorigenesis. CONCLUSIONS: These results suggest the possible use of curcumin as an anti-cancer agent in TSCC. However, in vivo studies are needed to confirm these effects and overcome its low bioavailability.

In vitro and in silico interaction of porcine α-amylase with Vicia faba crude seed extract and evaluation of antidiabetic activity.

Diabetes mellitus is a group of metabolic disorder of glucose metabolism. The proper management of blood glucose level is an indicator in the treatment of this complex pathology. The aim of the present study was to evaluate the inhibitory potential of Vicia faba crude seed extracts on the activities of α-amylase. Phytochemical screening, FTIR and HPLC analysis confirmed the presence of a phenolic compound with percentage yield of 9.87% in the acetone extract. Acetone extract of seed had highest inhibitory potential against porcine α-amylase (IC50 value of 2.94 mg/mL). Kinetic analysis revealed that the acetone and methanol extract displayed mixed mode of inhibition toward α-amylase. In-silico analysis was agreement with in-vitro studies in which phenolic compounds (catechin, epicatechin, gallic acid, and proanthocyanidin) showed more negative free energy against standard drug (acarbose) and bound with catalytic residues of α-amylase. These results might be due to the synergistic action of constituents present in seed extract or acting separately.

Hydrolyzable tannins from the fruits of Terminalia chebula Retz and their α-glucosidase inhibitory activities.

Nine hydrolyzable tannins, including three previously unknown and six artifacts, were isolated, together with thirty-nine known ones, from the fruits of Terminalia chebula Retz. (Combretaceae). They were identified as 1,2,3-tri-O-galloyl-6-O-cinnamoyl-ß-d-glucose, 1,2,3,6-tetra-O-galloyl-4-O-cinnamoyl-ß-d-glucose, 4-O-(2″,4″-di-O-galloyl-α-l-rhamnosyl)ellagic acid, 1'-O-methyl neochebulanin, dimethyl neochebulinate, 6'-O-methyl neochebulagate, dimethyl neochebulagate, dimethyl 4'-epi-neochebulagate, and methyl chebulagate by the spectroscopic interpretation. After evaluation for α-glucosidase inhibition of all isolated compounds, 1,2,3,6-tetra-O-galloyl-4-O-cinnamoyl-ß-d-glucose and 4-O-(2″,4″-di-O-galloyl-α-l-rhamnosyl)ellagic acid showed significant inhibitory activities with IC50 values of 2.9 and 6.4 µM, respectively. In addition, inhibition kinetic studies showed that both compounds have mixed-type inhibitory activities with the inhibition constants (Ki) of 1.9 and 4.0 µM, respectively.

In vitro monoamine oxidase inhibition potential of alpha-methyltryptamine analog new psychoactive substances for assessing possible toxic risks.

Tryptamines have emerged as new psychoactive substances (NPS), which are distributed and consumed recreationally without preclinical studies or safety tests. Within the alpha-methylated tryptamines, some of the psychoactive effects of the prototypical alpha-methyltryptamine (AMT) have been described decades ago and a contributing factor of its acute toxicity appears to involve the inhibition of monoamine oxidase (MAO). However, detailed information about analogs is scarce. Therefore, thirteen AMT analogs were investigated for their potential to inhibit MAO. An in vitro assay analyzed using hydrophilic interaction liquid chromatography-high resolution-tandem mass spectrometry was developed and validated. The AMT analogs were incubated with recombinant human MAO-A or B and kynuramine, a non-selective MAO substrate to determine the IC50 values. The known MAO-A inhibitors 5-(2-aminopropyl)indole (5-IT), harmine, harmaline, yohimbine, and the MAO-B inhibitor selegiline were tested for comparison. AMT and all analogs showed MAO-A inhibition properties with IC50 values between 0.049 and 166µM, whereas four analogs inhibited also MAO-B with IC50 values between 82 and 376µM. 7-Me-AMT provided the lowest IC50 value against MAO-A comparable to harmine and harmaline and was identified as a competitive MAO-A inhibitor. Furthermore, AMT, 7-Me-AMT, and nine further analogs inhibited MAO activity in human hepatic S9 fraction used as model for the human liver which expresses both isoforms. The obtained results suggested that MAO inhibition induced by alpha-methylated tryptamines might be clinically relevant concerning possible serotonergic and adrenergic effects and interactions with drugs (of abuse) particularly acting as monoamine reuptake inhibitors. However, as in vitro assays have only limited conclusiveness, further studies are needed.