Methylene blue-assisted molecularly-imprinted film modified nitrogen and sulfur co-doped molybdenum carbide for simultaneous electrochemical determination of two hepatotoxic drugs.

A novel electrochemical sensor with a dual-template molecular imprinting technology was fabricated for the simultaneous detection of paracetamol (PAR) and isoniazid (INZ). The sensor was constructed using nitrogen and sulfur co-doped molybdenum carbide (N, S@Mo2C) and a thin layer of electro-polymerized methylene blue was applied onto the surface of the N, S@Mo2C. The electrochemical sensor demonstrated remarkable analytical efficiency for the concurrent PAR and INZ quantification under optimal circumstances. The system achieved an exceptionally low limit of detection (S/N = 3) of  3.7 nM for PAR, with a concentration range  of  0.013 and 140 µM.  A LOD of 7.6 nM was attained for INZ, with a linear range  between 0.025 and 140 µM. Furthermore, the platform's selectivity was evaluated using differential pulse voltammetry  (DPV). The designed platform successfully detected PAR and INZ in authentic samples with recoveries varying between 98.3% and 104.9%. The relative standard deviations (RSD) for these measurements ranged from 2.7 to 4.0%, demonstrating that the proposed sensor is extremely stable, repeatable, and reproducible. These promising results suggest that the sensor holds potential for the detection of various (bio) molecules, paving the way for future applications in sensing fields.

Ratiometric fluorometric determination of sulfide using graphene quantum dots and self-assembled thiolate-capped gold nanoclusters triggered by aluminum.

A ratiometric-based fluorescence emission system was proposed for the determination of sulfide. It consists of blue emissive graphene quantum dots (GQDs) and self-assembled thiolate-protected gold nanoclusters driven by aluminum ion (Al3+@GSH-AuNCs). The two types of fluorophores are combined to form a ratiometric emission probe. The orange emission of Al3+ @GSH-AuNCs at 624 nm was quenched in the presence of sulfide ion owing to the strong affinity between sulfide and Au(I), while the blue GQDs fluorescence at 470 nm remained unaffected. Interestingly, the Al3+@GSH-AuNCs and GQDs were excited under the same excitation wavelength (335 nm). The response ratios (F470/F624) are linearly proportional to the sulfide concentration within the linear range of 0.02-200 µM under the optimal settings, with a limit of detection (S/N = 3) of 0.0064 µM. The proposed emission probe was applied to detect sulfide ions in tap water and wastewater specimens, with recoveries ranging from 95.3% to 103.3% and RSD% ranging from 2.3% to 3.4%, supporting the proposed method's accuracy.

Juglone from Walnut Produces Cardioprotective Effects against Isoproterenol-Induced Myocardial Injury in SD Rats.

Therapeutic and/or preventive interventions using phytochemical constituents for ischemic heart disease have gained considerable attention worldwide, mainly due to their antioxidant activity. This study investigated the cardioprotective effect and possible mechanism of juglone, a major constituent of the walnut tree, using an isoproterenol (ISO)-induced myocardial infarction (MI) model in rats. Rats were pretreated for five (5) days with juglone (1, 3 mg/kg, i.p) and atenolol (1 mg/kg, i.p) in separate experiments before inducing myocardial injury by administration of ISO (80 mg/kg, s.c) at an interval of 24 h for 2 consecutive days (4th and 5th day). The cardioprotective effect of juglone was confirmed through a lead II electrocardiograph (ECG), cardiac biomarkers (cTnI, CPK, CK-MB, LDH, ALT and AST) and histopathological study. The results of our present study suggest that prior administration of juglone (1 and 3 mg/kg) proved to be effective as a cardioprotective therapeutic agent in reducing the extent of myocardial damage (induced by ISO) by fortifying the myocardial cell membrane, preventing elevated T-waves, deep Q-waves in the ECG, heart to body weight ratio, infarction and also by normalizing cardiac marker enzymes (cTnI, CPK, CK-MB, LDH, ALT and AST) and histopathological changes, such as inflammation, edema and necrosis. In conclusion, this study has identified phytochemical constituents, in particular juglone, as a potential cardioprotective agent.

Tailoring the substitution pattern of Pyrrolidine-2,5-dione for discovery of new structural template for dual COX/LOX inhibition.

Dual inhibition of the enzymatic pathways of cyclooxygenases (COX-1/COX-2) and lipoxygenase (LOX) is a rational approach for developing more efficient and safe anti-inflammatory agents. Herein, dual inhibitors of COX and LOX for the management of inflammation are reported. The structural modifications of starting pyrrolidine-2,5-dione aldehyde derivatives resulted in two structurally diverse families (Family A & B). Synthesized derivatives from both Families displayed preferential COX-2 affinity in submicromolar to nanomolar ranges. Disubstitution pattern of the most active series of compounds having N-(benzyl(4-methoxyphenyl)amino moiety presents a new template that is mimic to the diaryl pattern of traditional COX-2 inhibitors. Compound 78 with IC50 value of 0.051 ± 0.001 µM emerged as the most active compound. Highly potent COX-2/5-LOX inhibitors have also demonstrated appreciable in-vivo anti-inflammatory activity through carrageenan induced paw edema test. Moreover, the involvement of histamine, bradykinin, prostaglandin, and leukotriene mediators to adjust the inflammatory response were also studied. Apart from COX inhibition, sulfonamide is considered an important template for carbonic anhydrase inhibition. Hence, we also evaluated six sulfonamide derivatives for off-target in-vitro bovine carbonic anhydrase-II inhibition. Biological results were finally rationalized by docking simulations. Typically, most active COX-2 inhibitors interact with the amino acid residues responsible for the COX-2 selectivity.

Cardiotonic potential of Carissa opaca Stapf ex Haines: A study on isolated rabbit heart.

Carissa opaca (C.O) is a wild shrub, belonging to the family Apocynaceae. The medicinal virtues of this plant have long been known. The present study demonstrates the effects of aqueous-methanolic extract and various fractions (n-butanolic and aqueous) of Carissa opaca on cardiovascular parameters. The perfusion pressure (PP), force of contraction (FC) and heart rate (HR) were assessed on isolated heart of rabbit using Langendroff's technique for crude extract and fractions of C.O, followed by the elucidation of the mechanism of action after estimating toxicity of the plant. Negative ionotropic and positive chronotropic effects, with an increase in PP in isolated perfused rabbit heart were observed the with plant extract and fractions. The aqueous-methanolic extract exhibited maximum response at 1mg/ml while the n-butanolic and aqueous fractions showed a maximum response at 1mg/ml and 10µg/ml respectively. Both fractions produced the same response when treated with atropine (10-5 M), however the actions of adrenaline (10-5 M) and calcium chloride (10-5 M) remained unblocked. Acute toxicity studies indicated that the plant was safe up to 2000 mg/kg and sub-chronic studies demonstrated that no significant change in haematological and biochemical parameters observed. In conclusion, this study supports the folkloric claim of C.O extract.

Quantitative-HPLC-DAD polyphenols analysis, anxiolytic and cognition enhancing potentials of Sorbaria tomentosa Lindl. Rehder.

ETHNOPHARMACOLOGICAL RELEVANCE: Medicinal plants of the family Rosaceae have a long history of traditional uses in the management of neurological disorders. Sorbaria tomentosa Lindl. Rehder is composed of antioxidant and neuroprotective polyphenolics. AIMS OF THE STUDY: The current study was designed to explore phenolics profile via high performance liquid chromatography-photodiode array detector (HPLC-DAD) and validated the neuroprotective and anxiolytic potentials of S. tomentosa by applying in vitro and in vivo approaches. MATERIALS AND METHODS: The plant crude methanolic extract (St.Crm) and fractions were subjected to HPLC-DAD analysis for qualitative and quantitative assessment of phytochemicals. Samples were screened for in vitro free radicals scavenging assays by using 2,2-diphenylpicrylhydrazyl (DPPH), 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) along with acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes inhibition assays. For cognitive and anxiolytic studies, mice were subjected to open field, elevated plus maze (EPM), light-dark model, Y-maze, shallow water maze (SWM), and novel object recognition (NOR) tests. RESULTS: HPLC-DAD analysis revealed the presence of high concentrations of phenolic compounds. For instance, in St.Cr, 21 phenolics were quantified, among which apigenin-7-glucoside (291.6 mg/g), quercetin (122.1 mg/g), quercetin-3-feruloylsophoroside-7-glucoside (52.6 mg/g), quercetin-7-glucoside (51.8 mg/g), ellagic acid (42.7 mg/g), luteolin (45.0 mg/g), kaempferol (40.5 mg/g), 5-feruloylquinic acid (43.7 mg/g) were present in higher concentrations. Likewise, in ethyl acetate fraction (St.Et.Ac), 21 phenolics were identified as 3,5-di-caffeoylquinic acid (177.4 mg/g) and 5-hydroxybenzoylquinic acid (46.9 mg/g) were most abundant phytochemicals. Highly valuable phenolics were also identified in other fractions including butanol (St.Bt), chloroform (St.Chf), and n-hexane (St.Hex). The various fractions exhibited concentration dependent inhibition of free radicals in DPPH and ABTS assays. Potent AChE inhibitory potentials were revealed by the test samples with St.Chf, St.Bt and St.EtAc being the most active having an IC50 of 298.1, 580.1, and 606.47 µg mL-1, respectively. Similarly, St.Chf, St.Bt, St.EtAc and St.Cr exhibited potent BChE inhibitory activity and was observed as 59.14, 54.73, 51.35 and 49.44%, respectively. A significant improvement in the exploratory behavior was observed in open field test and stress/anxiety was relieved effectively at 50-100 mg/kg. Likewise, EPM, light-dark and NOR tests revealed an anxiolytic and memory enhancing behaviors. These effects were further corroborated from the Y-maze and SWM transgenic studies that showed considerable improvement in cognition retention. CONCLUSIONS: These findings concluded that S. tomentosa possessed potential anxiolytic and nootropic efficacies and may have therapeutic potential in neurodegenerative disorders.

Phytochemicals-based ß-amyloid cleaving enzyme-1 and MAO-B inhibitors for the treatment of Alzheimer's disease: molecular simulations-based predictions.

Alzheimer's disease (AD) is among the highly prevalent neurodegenerative disorder of the aging brain and is allied with cognitive and behavioral abnormalities. Unfortunately, there is very limited drug discovery for the effective management of AD, and the clinically approved drugs have limited efficacy. Consequently, there is an immediate demand for the development of new compounds that have the ability to act as multitarget-directed ligands (MTDLs). As major pathological targets of the disease, the current study aimed to investigate lead natural bioactive compounds including apigenin, epigallocatechin-3-gallate, berberine, curcumin, genistein, luteolin, quercetin, resveratrol for their inhibitory potentials against ß-amyloid cleaving enzyme-1 (BACE1) and monoamine oxidase-B (MAO-B) enzymes. The study compounds were docked against the target enzymes (MAO-B and BACE1) using MOE software and subsequent molecular dynamics simulations (MDS) studies. The molecular docking analysis revealed that these phytochemicals (MTDLs) showed good interactions with the target enzymes as compared to the reference inhibitors. Among these eight phytocompounds, the epigallocatechin-3-gallate compound was an active inhibitor against both drug targets, with the highest docking scores and good interactions with the active residues of the enzymes. Furthermore, the docking result of the active one inhibitor in complex with the target enzymes (epigallocatechin-3-gallate/BACE1, epigallocatechin-3-gallate/MAO-B, reference/BACE1 and reference/MAO-B) were further validated by MDS. According to the findings of our study, epigallocatechin-3-gallate has the potential to be a candidate for use in the treatment of neurological illnesses like AD. This compound has MTDL potential and may be exploited to create new compounds with disease-modifying features.Communicated by Ramaswamy H. Sarma.

Case Report of an Elderly Woman Who Presented with Hypothermia and an Electrocardiographic Finding of a J Wave.

BACKGROUND This report is of a 92-year-old woman who presented with hypothermia and an electrocardiogram (ECG) finding of a J wave, or Osborn wave. On ECG, the J wave had an elevation of the J point at the junction of the QRS complex and ST segment, which usually appears at a body temperature below 32°C. CASE REPORT A 92-year-old woman presented to our hospital with an altered mental status. On evaluation, the vital signs were significant for low temperature (34.7°C), and she looked dehydrated. An ECG was performed as a part of the initial assessment and displayed normal sinus rhythm with an elevation of the J point (Osborn wave). Empiric antibiotic coverage was initiated for possible sepsis, in addition to supportive measures including hydration and passive external warming. By the next day, the patient's hypothermia was resolved, with improvement in her mental status, and a repeated ECG showed disappearance of the Osborn waves after appropriate warming. CONCLUSIONS This case highlights the importance of recognizing the J wave, or Osborn wave, and distinguishing it from ST-segment elevation seen in ischemic cardiac injury. Identification of the J wave is neither a specific finding nor predictive of patient outcome from hypothermia; however, an ECG should be performed in all patients with hypothermia as it serves a pivotal role in preventing progression to ventricular arrhythmia by prompt intervention and management.

Cardiac Metastasis of Neuroendocrine Tumor Without Cardiovascular Symptoms.

A 72-year-old man with a stage IV small intestinal neuroendocrine tumor presented to our cardiology clinic as a referral for an abnormal positron emission tomography-computed tomography scan with an intense gallium uptake in the heart. Follow-up cardiac magnetic resonance was suggestive of myocardium infiltration by the neuroendocrine tumor with late gadolinium enhancement and T1 time elevation. (Level of Difficulty: Intermediate.).

Design, synthesis, antiproliferative activity, estrogen receptors binding affinity of C-3 pregnenolone-dihydropyrimidine derivatives for the treatment of breast cancer.

Breast cancer (BCa) is very common malignancy and globally, has become the second leading cause of cancer death among women. For the treatment of BCa, estrogen receptors-alpha (ERα) has proven to be a therapeutic target. In continuation of our previous reported dihydropyrimidine-based pregnenolone derivatives, we modified at C-3 hydroxyl group. Structural architecture of estrogen receptors (ER) with excellent ER binding affinity was used for modification. MTT assay was used to evaluate the synthesized steroidal analogs for their antiproliferative activities against ER-positive MCF-7, ER-negative MDA-MB-231 (ER-) breast cancer cells and non-cancerous HEK-293 cells. Structure activity relationship (SAR) studies revealed that diethanolamine containing pregnenolone derivatives showed significant cytotoxicity against ER + MCF-7 and also showed good binding affinity with ERα and are relatively safe against HEK-293 cell model. Docking studies demonstrated that high binding affinity of diethanolamine analogs is due to their binding interaction with key amino acid residues present in the binding site of Erα.

Cephalosporin as Potent Urease and Tyrosinase Inhibitor: Exploration through Enzyme Inhibition, Kinetic Mechanism, and Molecular Docking Studies.

In present study, eleven cephalosporin drugs were selected to explore their new medically important enzyme targets with inherited safety advantage. To this end, selected drugs with active ingredient, cefpodoxime proxetil, ceftazidime, cefepime, ceftriaxone sodium, cefaclor, cefotaxime sodium, cefixime trihydrate, cephalexin, cefadroxil, cephradine, and cefuroxime, were evaluated and found to have significant activity against urease (IC50 = 0.06 ± 0.004 to 0.37 ± 0.046 mM) and tyrosinase (IC50 = 0.01 ± 0.0005 to 0.12 ± 0.017 mM) enzymes. Urease activity was lower than standard thiourea; however, tyrosinase activity of all drugs outperforms (ranging 6 to 18 times) the positive control: hydroquinone (IC50 = 0.18 ± 0.02 mM). Moreover, the kinetic analysis of the most active drugs, ceftriaxone sodium and cefotaxime sodium, revealed that they bind irreversibly with both the enzymes; however, their mode of action was competitive for urease and mixed-type, preferentially competitive for tyrosinase enzyme. Like in vitro activity, ceftriaxone sodium and cefotaxime sodium docking analysis showed their considerable binding affinity and significant interactions with both urease and tyrosinase enzymes sufficient for downstream signaling responsible for observed enzyme inhibition in vitro, purposing them as potent candidates to control enzyme-rooted obstructions in future.

Antioxidant Molecules Isolated from Edible Prostrate Knotweed: Rational Derivatization to Produce More Potent Molecules.

Prostrate knotweed also called Polygonum aviculare is an important edible plant. The polygonum is majorly known for the phenolics and antioxidants. The antioxidants combat the excessive free radicals within the body. The excessive free radicals are implicated in various other diseases like diabetes, Alzheimer's, and inflammation. This study was aimed at exploring the antioxidant bioactives and their derivatizations to produce new molecules with advanced pharmacological features. We have isolated six compounds (1-6) from Polygonum aviculare. Furthermore, rational-based chemical derivatives for compound 5 have been formed for the management of diabetes, Alzheimer's, and inflammation. In preliminary antioxidant studies, all the isolated compounds (1-6) showed potential results against DPPH and ABTS free radicals. Based on the IC50 and chemical nature of the compounds, compound 5 was subjected to derivatization. Keeping the phenolic part of compound 5 unaffected, hydroxy succinimide (5A) and thiazolidinedione (5B) were synthesized. The compound 5A was found to be a potent inhibitor of AChE, BChE, COX-1, COX-2, 5-LOX, and DPPH giving IC50 values of 10.60, 15.10, 13.91, 1.08, 0.71, and 1.05 µM, respectively. The COX-2 selectivity of compound 5A was found at 12.9. The compound 5B was found to be a potent multitarget antidiabetic agent giving IC50 values of 15.34, 21.83, 53.28, and 1.94 µM against α-glucosidase, α-amylase, protein tyrosine phosphatase 1B, and DPPH. Docking studies were performed to manipulate the binding interactions. The docking pose of all the tested compounds was found to have increased binding affinity against all tested targets that supported the in vitro results. Our results showed that Polygonum aviculare is a rich source of antioxidant compounds. The two new derivatives have enhanced pharmacological features to treat diabetes, inflammation, and Alzheimer's disease.

Phytochemistry, anti-diabetic and antioxidant potentials of Allium consanguineum Kunth.

AIM: The study was planned to investigate the phytochemicals, antidiabetic and antioxidant studies of A. consanguineum. METHODS: The preliminary studies were performed on crude extract and different solvent fractions. Based on the potency, the chloroform fraction was semi-purified to phyto-fractions CHF-1 - 5. Furthermore, CHF-3 was subjected to isolation of pure compounds using column chromatography. The α-glucosidase, α-amylase and antioxidant assays (DPPH, ABTS, H2O2) were performed on all samples. The in-vivo experiments on compounds 1 and 2 were also performed using oral glucose tolerance test. Docking studies were performed on α-glucosidase and α-amylase targets. RESULTS: Among all fractions, the chloroform fraction exhibited excellent activities profile giving IC50 values of 824, 55, 117, 58 and 85 µg/ml against α-glucosidase, α-amylase, DPPH, ABTS and H2O2 targets respectively. Among the five semi-purified chloroform phyto-fractions (CHF-1-5), CHF-3 was the leading fraction in activities giving IC50 values of 85.54, 61.19 and 26.58 µg/ml against α-glucosidase, α-amylase and DPPH respectively. Based on the overall potency and physical amount of CHF-3, it was subjected to purification to get compounds 1 and 2. The two compounds were also found potent in in-vitro activities. The observed IC50 values for compound 1 were 7.93, 28.01 and 6.19 µg/ml against α-glucosidase, α-amylase and DPPH respectively. Similarly, the compound 2 exhibited IC50 of 14.63, 24.82 and 7.654 µg/ml against α-glucosidase, α-amylase and DPPH respectively. Compounds 1 and 2 were potent in decreasing the blood glucose levels in experimental animals. Compounds 1 and 2 also showed interactions with the respective enzymes with molecular docking. CONCLUSIONS: We can conclude that A. Consanguineum is a rich source of natural antidiabetic agents. Bioguided isolation of compound 1 and 2 showed potential inhibitions in all tested in-vitro antidiabetic targets. Further, both the compounds were also able to decrease the blood glucose levels in experimental animals.

Phytochemical Analysis, α-Glucosidase and Amylase Inhibitory, and Molecular Docking Studies on Persicaria hydropiper L. Leaves Essential Oils.

OBJECTIVE: Medicinal plants and essentials oils are well known for diverse biological activities including antidiabetic potential. This study was designed to isolate essential oils from the leaves of Persicaria hydropiper L. (P. hydropiper), perform its phytochemical analysis, and explore its in vitro antidiabetic effects. MATERIALS AND METHODS: P. hydropiper leaves essential oils (Ph.Los) were extracted using a hydrodistillation apparatus and were subjected to phytochemical analysis using the gas chromatography mass spectrometry (GC-MS) technique. Ph.Lo was tested against two vital enzymes including α-glucosidase and α-amylase which are important targets in type-2 diabetes. The identified compounds were tested using in silico approaches for their binding affinities against the enzyme targets using MOE-Dock software. RESULTS: GC-MS analysis revealed the presence of 141 compounds among which dihydro-alpha-ionone, cis-geranylacetone, α-bulnesene, nerolidol, ß-caryophyllene epoxide, and decahydronaphthalene were the most abundant compounds. Ph.Lo exhibited considerable inhibitory potential against α-glucosidase enzyme with 70% inhibition at 1000 µg mL-1 which was the highest tested concentration. The inhibitory activity of positive control acarbose was 77.30 ± 0.61% at the same tested concentration. Ph.Lo and acarbose exhibited IC50 of 170 and 18 µg mL-1 correspondingly. Furthermore, dose-dependent inhibitions were observed for Ph.Lo against α-amylase enzyme with an IC50 of 890 µg mL-1. The top-ranked docking conformation was observed for ß-caryophyllene epoxide with a docking score of -8.3182 against α-glucosidase, and it has established seven hydrogen bonds and one H-pi interaction at the active site residues (Phe 177, Glu 276, Arg 312, Asp 349, Gln 350, Asp 408, and Arg 439). Majority of the identified compounds fit well in the binding pocket of Tyr 62, Asp 197, Glu 233, Asp 300, His 305, and Ala 307 active residues of α-amylase. ß-Caryophyllene epoxide was found to be the most active inhibitor with a docking score of -8.3050 and formed five hydrogen bonds at the active site residues of α-amylase. Asp 197, Glu 233, and Asp 300 active residues were observed to be making polar interactions with the ligand. CONCLUSIONS: The current study revealed that Ph.Lo is rich in bioactive metabolites which might contribute to its enzyme inhibitory potential. Inhibition of these enzymes is the key target in reducing postprandial hyperglycemia. However, further detailed in vivo studies are required for their biological and therapeutic activities.

GC-MS Analysis and Various In Vitro and In Vivo Pharmacological Potential of Habenaria plantaginea Lindl.

Background. The current study aims to give a scientific origin for employing Habenaria plantaginea Lindl. as a potential candidate against nociception, inflammation, and pyrexia. The pharmacological studies were performed on crude extract and subfractions. In the gas chromatography-mass spectroscopy analysis, a total of 21 compounds were identified. The plant samples were displayed for in vitro anti-inflammatory potentials. The observed IC50 for chloroform against cyclooxygenase-2 and 5-lipoxygenase enzymes was 33.81 and 26.74 µg/mL, respectively. The in vivo activities were prerequisites with the acute toxicity studies. In carrageenan-induced inflammation, the chloroform fraction exhibited 46.15% inhibition similar to that of standard drug diclofenac sodium 47.15%. Likewise, in the acetic acid-induced writhing test, the ethyl acetate fraction displayed 71.42% activity, which was dose-dependent as that of standard drug. In Brewer's yeast-induced antipyretic activity, a significant decrease in rectal volume was observed after 30, 60, and 90 minutes. Moreover, the results of this study indicated that the chloroform and ethyl acetate fractions inhibited nociception, inflammation, and pyrexia dose dependently. Likewise, mechanistic insights indicated that naloxone antagonized the antinociceptive effect of chloroform and ethyl acetate fractions, thereby signifying the involvement of opioidergic mechanisms respectively. These results suggest that these molecules present in this plant have synergistically beneficial potential for the cure and management of analgesia, inflammation, and pyrexia.

HPLC-DAD phenolics analysis, α-glucosidase, α-amylase inhibitory, molecular docking and nutritional profiles of Persicaria hydropiper L.

BACKGROUND: Natural phenolic compounds and Phenolics-rich medicinal plants are also of great interest in the management of diabetes. The current study was aimed to analyze phenolics in P. hydropiepr L extracts via HPLC-DAD analysis and assess their anti-diabetic potentials using in-vitro and in-silico approaches. METHODS: Plant crude methanolic extract (Ph.Cme) was evaluated for the presence of phenolic compounds using HPLC-DAD analysis. Subsequently, samples including crude (Ph.Cr), hexane (Ph.Hex), chloroform (Ph.Chf), ethyl acetate (Ph.EtAc), butanol (Ph.Bt), aqueous (Ph.Aq) and saponins (Ph.Sp) were tested for α-glucsidase and α-amylase inhibitory potentials and identified compounds were docked against these target enzymes using Molecular Operating Environment (MOE) software. Fractions were also analyzed for the nutritional contents and acute toxicity was performed in animals. RESULTS: In HPLC-DAD analysis of Ph.Cme, 24 compounds were indentfied and quantified. Among these, Kaemferol-3-(p-coumaroyl-diglucoside)-7-glucoside (275.4 mg g- 1), p-Coumaroylhexose-4-hexoside (96.5 mg g- 1), Quercetin-3-glucoronide (76.0 mg g- 1), 4-Caffeoylquinic acid (58.1 mg g- 1), Quercetin (57.9 mg g- 1), 5,7,3'-Trihydroxy-3,6,4',5'-tetramethoxyflavone (55.5 mg g- 1), 5-Feruloylquinic acid (45.8 mg g- 1), Cyanidin-3-glucoside (26.8 mg g- 1), Delphinidin-3-glucoside (24 mg g- 1), Quercetin-3-hexoside (20.7 mg g- 1) were highly abundant compounds. In α-glucosidase inhibition assay, Ph.Sp were most effective with IC50 value of 100 µg mL-1. Likewise in α-amylase inhibition assay, Ph.Chf, Ph.Sp and Ph.Cme were most potent fractions displayed IC50 values of 90, 100 and 200 µg mL-1 respectively. Docking with the α-glucosidase enzyme revealed top ranked conformations for majority of the compounds with Kaemferol-3-(p-coumaroyl-diglucoside)-7-glucoside as the most active compound with docking score of - 19.80899, forming 14 hydrogen bonds, two pi-H and two pi-pi linkages with the Tyr 71, Phe 158, Phe 177, Gln 181, Arg 212, Asp 214, Glu 276, Phe 300, Val 303, Tyr 344, Asp 349, Gln 350, Arg 439, and Asp 408 residues of the enzyme. Likewise, docking with α-amylase revealed that most of the compounds are well accommodated in the active site residues (Trp 59, Tyr 62, Thr 163, Leu 165, Arg 195, Asp 197, Glu 240, Asp 300, His 305, Asp 356) of the enzyme and Cyanidin-3-rutinoside displayed most active compound with docking score of - 15.03757. CONCLUSIONS: Phytochemical studies revealed the presence of highly valuable phenolic compounds, which might be responsible for the anti-diabetic potentials of the plant samples.

Human Lung Cancer (A549) Cell Line Cytotoxicity and Anti-Leishmania major Activity of Carissa macrocarpa Leaves: A Study Supported by UPLC-ESI-MS/MS Metabolites Profiling and Molecular Docking.

Lung cancer and cutaneous leishmaniasis are critical diseases with a relatively higher incidence in developing countries. In this research, the activity of Carissa macrocarpa leaf hydromethanolic extract and its solvent-fractions (n-hexane, EtOAc, n-butanol, and MeOH) against the lung adenocarcinoma cell line (A549) and Leishmania major was investigated. The MeOH fraction exhibited higher cytotoxic activity (IC50 1.57 ± 0.04 µg/mL) than the standard drug, etoposide (IC50 50.8 ± 3.16 µg/mL). The anti-L. major results revealed strong growth inhibitory effects of the EtOAc fraction against L. major promastigotes (IC50 27.52 ± 0.7 µg/mL) and axenic amastigotes (29.33 ± 4.86% growth inhibition at 100 µg/mL), while the butanol fraction exerted moderate activity against promastigotes (IC50 73.17 ± 1.62), as compared with miltefosine against promastigotes (IC50 6.39 ± 0.29 µg/mL) and sodium stibogluconate against axenic amastigotes (IC50 22.45 ± 2.22 µg/mL). A total of 102 compounds were tentatively identified using UPLC-ESI-MS/MS analysis of the total extract and its fractions. The MeOH fraction was found to contain several flavonoids and flavan-3-ol derivatives with known cytotoxic properties, whereas the EtOAc fractions contained triterpene, hydroxycinnamoyl, sterol, and flavanol derivatives with known antileishmanial activity. Molecular docking of various polyphenolics of the MeOH fraction with HDAC6 and PDK3 enzymes demonstrates high binding affinity of the epicatechin 3-O-ß-D-glucopyranoside and catechin-7-O-ß-D-glucopyranoside toward HDAC6, and procyanidin C2, procyanidin B5 toward PDK3. These results are promising and encourage the pursuit of preclinical research using C. macrocarpa's MeOH fraction as anti-lung cancer and the EtOAc fraction as an anti-L. major drug candidates.

Preparation of Spice Extracts: Evaluation of Their Phytochemical, Antioxidant, Antityrosinase, and Anti-α-Glucosidase Properties Exploring Their Mechanism of Enzyme Inhibition with Antibrowning and Antidiabetic Studies In Vivo.

Tyrosinase and α-glucosidase enzymes are known as promising target candidates for inhibitors to control unwanted pigmentation and type II diabetics mellitus. Therefore, twenty extracts as enzyme inhibitors were prepared from edible spices: nutmeg, mace, star anise, fenugreek, and coriander aiming to explore their antioxidant, antibrowning, and antidiabetic potential. Results confirmed that all extracts showed potent antioxidant activity ranging from IC50 = 0.14 ± 0.03 to 3.69 ± 0.37 µg/mL. In addition, all extracts exhibited excellent antityrosinase (IC50 = 1.16 ± 0.06 to 71.32 ± 4.63 µg/mL) and anti-α-glucosidase (IC504.76 ± 0.71 to 42.57 ± 2.13 µg/mL) activities outperforming the corresponding standards, hydroquinone, and acarbose, respectively. Among all extracts, star anise ethyl acetate (Star anise ETAC) was found most potent inhibitor for both tyrosinase and α-glucosidase enzymes and was further studied to explore the mechanism of enzyme inhibition. Kinetic analysis revealed its irreversible but mixed-type tyrosinase inhibition with preferentially competitive mode of action. However, it binds reversibly with α-glucosidase through competitive mode of action. Further, star anise ETAC extract showed concentration dependent and posttreatment time-dependent antibrowning effect on potato slices and antidiabetic effect on diabetic rabbits in vivo proposing it promising candidate for tyrosinase-rooted antibrowning and α-glucosidase-associated diabetes management for future studies.

NiFe2O4 nanospheres functionalized with 2-(2, 4-Dihydroxyphenyl)-3, 5, 7-trihydroxychromen-4-one for selective solid-phase microextraction of aluminium.

Herein, a rational combination of dispersive solid-phase sorbent and 2-(2, 4-Dihydroxyphenyl)-3, 5, 7-trihydroxychromen-4-one (morin) was proposed for sensitive and selective determination of Al3+ ion. Nickel ferrite nanospheres (NiFe2O4 NS) functionalized with morin was used to preconcentrate and estimate Al3+ via the formation of fluorescent complex at pH 7.0. The functionalization was assisted by anionic surfactant sodium dodecyl sulphate (SDS) and ultrasonication. The results revealed that the fluorescence intensity of Al-morin/SDS@ NiFe2O4 NS is higher than Al-morin. Functionalization of NiFe2O4 NS with morin was confirmed by scanning electron microscopy (SEM), transmission electron microscopy (TEM), energy-dispersive X-ray spectroscopy (EDX), Fourier transform infrared spectroscopy (FTIR), powder X-ray diffractometer (PXRD), and fluorescence spectroscopy. Under the optimum conditions, the fluorescence intensity increased with increasing of Al3+ concentrations in the range of 0.28-500.0 ng mL-1 with LOD (S/N = 3) of 0.09 ng mL-1. The method was applied for the determination of Al3+ in natural waters and human serum samples with recoveries % of 97-104% and RSDs % of 2-4%.

Synthesis of Michael Adducts as Key Building Blocks for Potential Analgesic Drugs: In vitro, in vivo and in silico Explorations.

BACKGROUND: Organocatalytic asymmetric Michael addition is a strong approach for C-C bond formation. The objective of the study is to design molecules by exploiting the efficiency of Michael Adducts. We proceeded with the synthesis of Michael adducts by tailoring the substitution pattern on maleimide and trans-ß-nitro styrene as Michael acceptors. The synthesized compounds were evaluated for dual cyclooxygenases (COX) and lipoxygenase (LOX) inhibition. METHODS: The compounds (4, 9-11) were synthesized through Michael additions. The cyclooxygenases (COX-1 and 2) and lipoxygenase (5-LOX) assays were used for in vitro evaluations of compounds. After the acute toxicity studies, the in vivo analgesic potential was determined with acetic acid induced writhing, tail immersion, and formalin tests. Furthermore, the possible roles of adrenergic and dopaminergic receptors were also studied. Extensive computational studies were performed to get a better understanding regarding the binding of this compound with protein target. RESULTS: Four Michael adducts (4, 9-11) were synthesized. Compound 4 was obtained in enantio- and diastereopure form. The stereopure compound 4 showed encouraging COX-1 and-2 inhibitions with IC50 values of 128 and 65 µM with SI of 1.94. Benzyl derivative 11 showed excellent COX-2 inhibition with the IC50 value of 5.79 µM and SI value 7.96. Compounds 4 and 11 showed good results in in vivo models of analgesia like acetic acid test, tail immersion, and formalin tests. Our compounds were not active in dopaminergic and adrenergic pathways and so were acting centrally. Through extensive computational studies, we computed binding energies, and pharmacokinetic predictions. CONCLUSION: Our findings conclude that our synthesized Michael products (pyrrolidinedione 4 and nitroalkane 11) can be potent centrally acting analgesics. Our in silico predictions suggested that the compounds have excellent pharmacokinetic properties. It is concluded here that dual inhibition of COX/LOX pathways provides a convincing step towards the discovery of safe lead analgesic molecules.