Neuroprotective potentials of Lead phytochemicals against Alzheimer's disease with focus on oxidative stress-mediated signaling pathways: Pharmacokinetic challenges, target specificity, clinical trials and future perspectives.

BACKGROUND: Alzheimer's diseases (AD) and dementia are among the highly prevalent neurological disorders characterized by deposition of beta amyloid (Aß) plaques, dense deposits of highly phosphorylated tau proteins, insufficiency of acetylcholine (ACh) and imbalance in glutamatergic system. Patients typically experience cognitive, behavioral alterations and are unable to perform their routine activities. Evidence also suggests that inflammatory processes including excessive microglia activation, high expression of inflammatory cytokines and release of free radicals. Thus, targeting inflammatory pathways beside other targets might be the key factors to control- disease symptoms and progression. PURPOSE: This review is aimed to highlight the mechanisms and pathways involved in the neuroprotective potentials of lead phytochemicals. Further to provide updates regarding challenges associated with their use and their progress into clinical trials as potential lead compounds. METHODS: Most recent scientific literature on pre-clinical and clinical data published in quality journals especially on the lead phytochemicals including curcumin, catechins, quercetin, resveratrol, genistein and apigenin was collected using SciFinder, PubMed, Google Scholar, Web of Science, JSTOR, EBSCO, Scopus and other related web sources. RESULTS: Literature review indicated that the drug discovery against AD is insufficient and only few drugs are clinically approved which have limited efficacy. Among the therapeutic options, natural products have got tremendous attraction owing to their molecular diversity, their safety and efficacy. Research suggest that natural products can delay the disease onset, reduce its progression and regenerate the damage via their anti-amyloid, anti-inflammatory and antioxidant potentials. These agents regulate the pathways involved in the release of neurotrophins which are implicated in neuronal survival and function. Highly potential lead phytochemicals including curcumin, catechins, quercetin, resveratrol, genistein and apigenin regulate neuroprotective signaling pathways implicated in neurotrophins-mediated activation of tropomyosin receptor kinase (Trk) and p75 neurotrophins receptor (p75NTR) family receptors. CONCLUSIONS: Phytochemicals especially phenolic compounds were identified as highly potential molecules which ameliorate oxidative stress induced neurodegeneration, reduce Aß load and inhibit vital enzymes. Yet their clinical efficacy and bioavailability are the major challenges which need further interventions for more effective therapeutic outcomes.

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.

In-Vitro, In-Vivo, Molecular Docking and ADMET Studies of 2-Substituted 3,7-Dihydroxy-4H-chromen-4-one for Oxidative Stress, Inflammation and Alzheimer's Disease.

Plants' bioactives are well-known safe drugs for vital diseases. Flavones and Flavonoid-rich dietary supplements are known to exhibit neuroprotective potential. In this study, we isolated a flavone 2-(3,4-dimethoxyphenyl)-3,7-dihydroxy-4H-chromen-4-one from Notholirion thomsonianum and it was evaluated against various targets of the oxidative stress-related neurological disorders. The compound showed excellent acetyl and butyrylcholinesterase inhibitions in its profile, giving IC50 values of 1.37 and 0.95 µM, respectively. Similarly, in in-vitro MAO-B assay, our flavone exhibited an IC50 value of 0.14 µM in comparison to the standard safinamide (IC50 0.025 µM). In in-vitro anti-inflammatory assay, our isolated compound exhibited IC50 values of 7.09, 0.38 and 0.84 µM against COX-1, COX-2 and 5-LOX, respectively. The COX-2 selectivity (SI) of the compound was 18.70. The compound was found safe in animals and was very effective in carrageenan-induced inflammation. Due to the polar groups in the structure, a very excellent antioxidant profile was observed in both in-vitro and in-vivo models. The compound was docked into the target proteins of the respective activities and the binding energies confirmed the potency of our compound. Furthermore, absorption, distribution, metabolism, excretion, and toxicity (ADMET) results showed that the isolated flavone has a good GIT absorption ability and comes with no hepatic and cardiotoxicity. In addition, the skin sensitization test, in-vitro human cell line activation test (h-CLAT) and KeratinoSens have revealed that isolated flavone is not skin sensitive with a confidence score of 59.6% and 91.6%. Herein, we have isolated a natural flavone with an effective profile against Alzheimer's, inflammation and oxidative stress. The exploration of this natural flavone will provide a baseline for future research in the field of drug development.

Succinimide Derivatives as Antioxidant Anticholinesterases, Anti-α-Amylase, and Anti-α-Glucosidase: In Vitro and In Silico Approaches.

Based on the diverse pharmacological potency and the structural features of succinimide, this research considered to synthesize succinimide derivatives. Moreover, these compounds were estimated for their biological potential in terms of anti-diabetic, anti-cholinesterase, and anti-oxidant capacities. The compounds were synthesized through Michael addition of various ketones to N-aryl maleimides. Similarly, the MOE software was used for the molecular docking study to explore the binding mode of the potent compounds against different enzymes. In the anti-cholinesterase activity, the compounds MSJ2 and MSJ10 exhibited outstanding activity against acetylcholinesterase (AChE), i.e., 91.90, 93.20%, and against butyrylcholinesterase (BChE), i.e., 97.30, 91.36% inhibitory potentials, respectively. The compounds MSJ9 and MSJ10 exhibited prominent α-glucosidase inhibitory potentials, i.e., 87.63 and 89.37 with IC50 value of 32 and 28.04 µM, respectively. Moreover, the compounds MSJ2 and MSJ10 revealed significant scavenging activity against DPPH free radicals with IC50 values of 2.59 and 2.52, while against ABTS displayed excellent scavenging potential with IC50 values 7.32 and 3.29 µM, respectively. The tentative results are added with molecular docking studies in the active sites of enzymes to predict the theoretical protein-ligand binding modes. Further detailed mechanism-based studies in animal models are essential for the in vivo evaluation of the potent compound.

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.

α-Glucosidase, α-Amylase and Antioxidant Evaluations of Isolated Bioactives from Wild Strawberry.

Diabetes mellitus is a metabolic disorder and is a global challenge to the current medicinal chemists and pharmacologists. This research has been designed to isolate and evaluate antidiabetic bioactives from Fragaria indica. The crude extracts, semi-purified and pure bioactives have been used in all in vitro assays. The in vitro α-glucosidase, α-amylase and DPPH free radical activities have been performed on all plant samples. The initial activities showed that ethyl acetate (Fi.EtAc) was the potent fraction in all the assays. This fraction was initially semi-purified to obtain Fi.EtAc 1-3. Among the semi-purified fractions, Fi.EtAc 2 was dominant, exhibiting potent IC50 values in all the in vitro assays. Based on the potency and availability of materials, Fi.EtAc 2 was subjected to further purification to obtain compounds 1 (2,4-dichloro-6-hydroxy-3,5-dimethoxytoluene) and 2 (2-methyl-6-(4-methylphenyl)-2-hepten-4-one). The two isolated compounds were characterized by mass and NMR analyses. The compounds 1 and 2 showed excellent inhibitions against α-glucosidase (21.45 for 1 and 15.03 for 2 µg/mL), α-amylase (17.65 and 16.56 µg/mL) and DPPH free radicals (7.62 and 14.30 µg/mL). Our study provides baseline research for the antidiabetic bioactives exploration from Fragaria indica. The bioactive compounds can be evaluated in animals-based antidiabetic activity in future.

Antioxidant, Enzyme Inhibitory, and Molecular Docking Approaches to the Antidiabetic Potentials of Bioactive Compounds from Persicaria hydropiper L.

Introduction: Natural products are among the most useful sources for the discovery of new drugs against various diseases. Keeping in view the ethnobotanical relevance ethnopharmacological significance of Polygonaceae family in diabetes, the current study was designed to isolate pure compounds from Persicaria hydropiper L. leaves and evaluate their in vitro and in silico antidiabetic potentials. Methods: Six compounds were isolated from the chloroform-ethyl acetate fractions using gravity column chromatography and were subjected to structure elucidation process. Structures were confirmed using 1H-NMR, 13C-NMR, and mass spectrometry techniques. Isolated phytochemicals were subjected to in vitro antidiabetic studies, including α-glucosidase, α-amylase inhibition, and DPPH, and ABTS antioxidant studies. Furthermore, the in silico binding mode of these compounds in the target enzymes was elucidated via MOE-Dock software. Results: The isolated compounds revealed concentration-dependent inhibitions against α-glucosidase enzyme. Ph-1 and Ph-2 were most potent with 81.84 and 78.79% enzyme inhibitions at 1000 µg·mL-1, respectively. Ph-1 and Ph-2 exhibited IC50s of 85 and 170 µg·mL-1 correspondingly. Likewise, test compounds showed considerable α-amylase inhibitions with Ph-1 and Ph-2 being the most potent. Tested compounds exhibited considerable antioxidant potentials in both DPPH and ABTS assays. Molecular simulation studies also revealed top-ranked confirmations for the majority of the compounds in the target enzymes. Highest observed potent compound was Ph-1 with docking score of -12.4286 and formed eight hydrogen bonds and three H-pi linkages with the Asp 68, Phe 157, Phe 177, Asn 241, Glu 276, His 279, Phe 300, Glu 304, Ser 308, Pro 309, Phe 310, Asp 349, and Arg 439 residues of α-glucosidase binding packets. Asp 68, Glu 276, Asp 349, and Arg 439 formed polar bonds with the 3-ethyl-2-methylpentane moiety of the ligand. Conclusions: The isolated compounds exhibited considerable antioxidant and inhibitory potentials against vital enzymes implicated in T2DM. The docking scores of the compounds revealed that they exhibit affinity for binding with target ligands. The enzyme inhibition and antioxidant potential of the compounds might contribute to the hypoglycemic effects of the plant and need further studies.

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.

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.

Pollen morphology and its taxonomic potential in some selected taxa of Caesalpiniaceae observed under light microscopy and scanning electron microscopy.

Pollen micromorphology is not only used to check the functional and structural evolution in plants but also to solve the taxonomic problem related to the classification of plants. Therefore, keeping in view the significance of pollen traits, selected taxa of the subfamily Caesalpiniaceae was collected from different geographical regions of Pakistan. The species were then analyzed under both light microscopy and scanning electron microscopy techniques to investigate the importance of micromorphological characters of pollen in the identification and classification of species. Great variation was recorded in equatorial shape, surface ornamentation, tectum, polar diameter, equatorial diameter, and exine thickness. However, little variation was observed in pollen type, polar shape, and fertility of pollen. The equatorial shape of five types was observed: prolate, prolate-spheroidal, spheroidal-subprolate, subspheroidal-prolate, and subspheroidal. Four types of surface ornamentation, psilate, granulate, clavate, and perforate, were recorded. Tectum of five types, intactate, reticulate regulate, medium reticulate, tactate, and striate, was observed. Sexine was thicker than nexine in all studied species. The largest polar diameter was observed in Caesalpinia pulcherrima 64.1 µm while the smallest in Parkinsonia aculeata 26.1 µm. The largest equatorial diameter was found in C. pulcherrima of 70.25 µm whereas the smallest in P. aculeata 27.57 µm. All the pollens analyzed were tricolporate. All studied species have a fertility ratio of more than 90%. A taxonomic key was developed to show the variation in pollen features and delimit species for the correct identification. In conclusion, the pollen traits were found useful to define species boundaries at various taxonomic ranks and will strengthen the taxonomy of this subfamily. Besides, this study also explored the palynological traits and their implication in the taxonomy of the subfamily Caesalpiniaceae.

Neuroprotective potentials of selected natural edible oils using enzyme inhibitory, kinetic and simulation approaches.

BACKGROUND: Edible oils have proven health benefits in the prevention and treatment of various disorders since the establishment of human era. This study was aimed to appraise neuropharmacological studies on the commonly used edible oils including Cinnamomum verum (CV), Zingiber officinale (ZO) and Cuminum cyminum (CC). METHODS: The oils were analyzed via GC-MS for identifications of bioactive compounds. Anti-radicals capacity of the oils were evaluated via 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS) radicals scavenging assays. The samples were also tested against two important acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) which are among the important drug targets in Alzheimer's disease. Lineweaver-Burk plots were constructed for enzyme inhibition studies which correspond to velocity of enzymes (Vmax) against the reciprocal of substrate concentration (Km) in the presence of test samples and control drugs following Michaelis-Menten kinetics. Docking studies on AChE target were also carried out using Molecular Operating Environment (MOE 2016.0802) software. RESULTS: (Gas chromatography-mass spectrometry GC-MS) analysis revealed the presence of thirty-four compounds in Cinnamon oil (Cv.Eo), fourteen in ginger oil (Zo.Eo) and fifty-six in cumin oil (Cc.Eo). In the antioxidant assays, Cv.Eo, Zo.Eo and Cc.Eo exhibited IC50 values of 85, 121, 280 µg/ml sequentially against DPPH radicals. Whereas, in ABTS assay, Cv.Eo, Zo.Eo and Cc.Eo showed considerable anti-radicals potentials with IC50 values of 93, 77 and 271 µg/ml respectively. Furthermore, Cv.Eo was highly active against AChE enzyme with IC50 of 21 µg/ml. Zo.Eo and Cc.Eo exhibited considerable inhibitory activities against AChE with IC50 values of 88 and 198 µg/ml respectively. In BChE assay, Cv.Eo, Zo.Eo and Cc.Eo exhibited IC50 values of 106, 101 and 37 µg/ml respectively. Our results revealed that these oils possess considerable antioxidant and cholinesterase inhibitory potentials. As functional foods these oils can be effective remedy for the prevention and management of neurological disorders including AD. Synergistic effect of all the identified compounds was determined via binding energy values computed through docking simulations. Binding orientations showed that all the compounds interact with amino acid residues present in the peripheral anionic site (PAS) and catalytic anionic site (CAS) amino acid residues, oxyanion hole and acyl pocket via π-π stacking interactions and hydrogen bond interactions.

Crude extract and isolated bioactive compounds from Notholirion thomsonianum (Royale) Stapf as multitargets antidiabetic agents: in-vitro and molecular docking approaches.

BACKGROUND: Diabetes mellitus is a common disease effecting the lifestyles of majority world population. In this research work, we have embarked the potential role of crude extracts and isolated compounds of Notholirion thomsonianum for the management diabetes mellitus. METHODS: The crude extracts of N. thomsonianum were initially evaluated for α-glucosidase, α-amylase and antioxidant activities. The compounds were isolated from the activity based potent solvent fraction. The structures of isolated compounds were confirmed with NMR and MS analyses. The isolated compounds were tested for α-glucosidase, α-amylase, protein tyrosine phosphatase 1B (PTP1B) and DPPH activities. The molecular docking studies were carried out to find the binding interactions of isolated compounds for α-glucosidase, α-amylase and PTP1B. RESULTS: Initially, we screened out crude extracts and subfractions of N. thomsonianum against different in-vitro targets. Among all, Nt.EtAc was observed a potent fraction among all giving IC50 values of 67, 70, < 0.1, 89 and 16 µg/mL against α-glucosidase, α-amylase, DPPH, ABTS and H2O2 respectively. Three compounds (Nt01, Nt02 and Nt03) were isolated from Nt.EtAc of N. thomsonianum. The isolated compounds Nt01, Nt02 and Nt03 exhibited IC50 values of 58.93, 114.93 and 19.54 µM against α-glucosidase, while 56.25, 96.54 and 24.39 µM against α-amylase respectively. Comparatively, the standard acarbose observed IC50 values were 10.60 and 12.71 µM against α-glucosidase, α-amylase respectively. In PTP1B assay, the compounds Nt01, Nt02 and Nt03 demonstrated IC50 values of 12.96, 36.22 and 3.57 µM in comparison to the standard ursolic acid (IC50 of 3.63 µM). The isolated compounds also gave overwhelming results in DPPH assay. Molecular docking based binding interactions for α-glucosidase, α-amylase and PTP1B were also encouraging. CONCLUSIONS: In the light of current results, it is obvious that N. thomsonianum is potential medicinal plant for the treatment of hyperglycemia. Overall, Nt.EtAc was dominant fraction in all in-vitro activities. Three compounds Nt01, Nt02 and Nt03 were isolated from ethyl acetate fraction. The Nt03 specifically was most potent in all in-vitro assays. The molecular docking studies supported our in-vitro results. It is concluded that N. thomsonianum is a rich source of bioactive antidiabetic compounds which can be further extended to in-vivo based experiments.

Zinc metal carboxylates as potential anti-Alzheimer's candidate: in vitro anticholinesterase, antioxidant and molecular docking studies.

In search of suitable therapy for the management of Alzheimer's disease, this study was designed to evaluate metal complexes against its biochemical targets. Zinc metal carboxylates (AAZ1-AAZ6) were evaluated against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The antioxidant in combination with anticholinesterase activity can be considered as an important target in the management of Alzheimer's disease. Therefore, these compounds were also screened for ABTS and DPPH free radical scavenging activity. In AChE inhibition assay, we noticed encouraging IC50 values of 33.07 and 59.52 µM for compounds AAZ5 and AAZ3, respectively. However, when we tested BChE activity, we observed an outstanding IC50 of 0.056 µM for compound AAZ6. Amazingly all of our compounds (AAZ1-AAZ6) were proved to be strong antioxidants which actively supplement the anti-Alzheimer's activity. The majority of our compounds exhibited lower IC50 values than the standard ascorbic acid in both DPPH and ABTS assays. We also correlated our results with molecular docking studies. Results elaborated that AAZ1 and AAZ5 exhibit strong interactions with amino acids HIS 362, HIS 398, GLU 306 ARG 289 and SER 237 inside binding pocket of targeted protein. In remarks, we can claim that our synthesized zinc metal carboxylates have strong potency to manage Alzheimer's disease on both anticholinesterase and antioxidant targets. Communicated by Ramaswamy H. Sarma.

Persicaria hydropiper (L.) Delarbre: A review on traditional uses, bioactive chemical constituents and pharmacological and toxicological activities.

ETHNOPHARMACOLOGICAL RELEVANCE: Various plant parts of Persicaria hydropiper (L.) Delarbre (Syn.: Polygonum hydropiper L., Family: Polygonaceae) are used in traditional medicine systems as astringent, sedative, antiseptic and also for the treatment of respiratory disorders, edema and snake bites. It is also used as a spice in many Asian countries. AIM OF THE REVIEW: The main aim of this review is to critically analyze the reported traditional uses, bioactive chemical constituents and pharmacological activities of P. hydropiper. MATERIALS AND METHODS: Scientific database including PubMed, Scopus, SciFinder and secondary resources including books and proceedings were searched using relevant terminologies related to P. hydropiper and available scientific information was critically analyzed. RESULTS: Analysis of the scientific literature regarding the traditional uses revealed that P. hydropiper is used as a medicine and as spice in food preparations in various parts of the world. Various compounds including flavonoids, phenylpropanoid derivatives, and sesquiterpenoids among others were reported as active compounds. The extracts and compounds from P. hydropiper showed diverse biological activities including anti-inflammatory, antioxidant, cytotoxic, antimicrobial activities, etc. CONCLUSION: Although various research reports showed diverse biological activities for extracts and compounds obtained from P. hydropiper, very few studies were performed using animal models. Many of these studies also lacked proper experimental setting such as use of positive and negative controls and selection of dose as in most of these studies very high doses of extracts were administered. Further, as P. hydropiper is widely used in the treatment of snake bites and insect bites, such effects of extracts and/or compounds are not well explored. Future studies on P. hydropiper should be focused to establish the links between the traditional uses, active compounds and reported pharmacological activities.

Evaluation of crude saponins, methanolic extract and subsequent fractions from Isodon rugosus Wall. ex Benth: Potentials of anti-angiogenesis in egg and anti-tumorigenesis in potato.

Based on the ethnomedicinal use of Isodon rugosus the current study was designed to evaluate its crude saponins (Ir.Sp), and subsequent fractions for anti-angiogenic and anti-tumor potentials. Chorioallantoic membrane (CAM) assay was used in anti-angiogenic potentials with Dexamethasone as positive control. The antitumor activity was evaluated with potato disk method using Vincristine sulfate as positive control. Moreover, antibacterial activity was also conducted against A. tumefaciens. The highest anti-angiogenic effect was observed with Ir.Sp, i.e., 79.00±0.58% at concentration of 1000 µg/ml which drop drown to 48.67±1.20% at lowest tested concentration of 31.25 µg/ml with IC50 of 41 µg/ml. Similarly, in the anti-tumor activity the Ir. Chf revealed excellent inhibition of tumor with IC50 value of 60 µg/ml. All the samples (excluding Ir. Sp and Ir. Cr) were inactive against A. tumefaciens, which demonstrates that the samples which did not show any antibacterial activity are rich in certain bioactive principles which may be responsible for the anti-tumor and anti-angiogenic potentials. Our results conclude that the Ir.Sp, Ir.Chfmay be good targets for isolation of bioactive compounds responsible for the inhibition of excessive proliferation of cells and angiogenesis.

In Silico, Cytotoxic and Antioxidant Potential of Novel Ester, 3-hydroxyoctyl -5- trans-docosenoate Isolated from Anchusa arvensis (L.) M.Bieb. Against HepG-2 Cancer Cells.

BACKGROUND: Cancer is one of the chronic health conditions worldwide. Various therapeutically active compounds from medicinal plants were the current focus of this research in order to uncover a treatment regimen for cancer. Anchusa arvensis (A. anchusa) (L.) M.Bieb. contains many biologically active compounds. METHODS: In the current study, new ester 3-hydroxyoctyl -5- trans-docosenoate (compound-1) was isolated from the chloroform soluble fraction of A. anchusa using column chromatography. Using MTT assay, the anticancer effect of the compound was determined in human hepatocellular carcinoma cells (HepG-2) compared with normal epithelial cell line (Vero). DPPH and ABTS radical scavenging assays were performed to assess the antioxidant potential. The Molecular Operating Environment (MOE-2016) tool was used against tyrosine kinase. RESULTS: The structure of the compound was elucidated based on IR, EI, and NMR spectroscopy technique. It exhibited a considerable cytotoxic effect against HepG-2 cell lines with IC50 value of 6.50 ± 0.70 µg/mL in comparison to positive control (doxorubicin) which showed IC50 value of 1.3±0.21 µg/mL. The compound did not show a cytotoxic effect against normal epithelial cell line (Vero). The compound also exhibited significant DPHH scavenging ability with IC50 value of 12 ± 0.80 µg/mL, whereas ascorbic acid, used as positive control, demonstrated activity with IC50 = 05 ± 0.15 µg/mL. Similarly, it showed ABTS radical scavenging ability (IC50 = 130 ± 0.20 µg/mL) compared with the value obtained for ascorbic acid (06 ± 0.85 µg/mL). In docking studies using MOE-2016 tool, it was observed that compound-1 was highly bound to tyrosine kinase by having two hydrogen bonds at the hinge region. This good bonding network by the compound might be one of the reasons for showing significant activity against this enzyme. CONCLUSION: Our findings led to the isolation of a new compound from A. anchusa which has significant cytotoxic activity against HepG-2 cell lines with marked antioxidant potential.

Cytotoxicity of Anchusa arvensis Against HepG-2 Cell Lines: Mechanistic and Computational Approaches.

BACKGROUND: Liver cancer is a devastating cancer with increasing incidence and mortality rates worldwide. Plants possess numerous therapeutic properties, therefore the search for novel, naturally occurring cytotoxic compounds is urgently needed. METHODS: The anticancer activity of plant extracts and isolated compounds from Anchusa arvensis (A. arvensis) were studied against the cell culture of HepG-2 (human hepatocellular carcinoma cell lines) using 3-(4,5-Dimethylthiazol-yl)-diphenyl tetrazoliumbromide (MTT) assay. Apoptosis was investigated by performing Acridine orange -ethidium bromide staining, styox green assay and DNA interaction study. We also used tools for computational chemistry studies of isolated compounds with the tyrosine kinase. RESULTS: In MTT assay, the crude extract caused a significant cytotoxic effect with IC50 of 34.14 ± 0.9 µg/ml against HepG-2 cell lines. Upon fractionation, chloroform fraction (Aa.Chm) exhibited the highest antiproliferative activity with IC50 6.55 ± 1.2 µg/ml followed by ethyl acetate (Aa.Et) fraction (IC50, 24.59 ± 0.85 µg/ml) and n-hexane (Aa.Hex) fraction (IC50 29.53 ± 1.5µg/ml). However, the aqueous (Aa.Aq) fraction did not show any anti-proliferative activity. Bioactivity-guided isolation led to the isolation of two compounds which were characterized as para-methoxycatechol (1) and decane (2) through various spectroscopic techniques. Against HepG-2 cells, compound 1 showed marked potency with IC50 6.03 ± 0.75 µg/ml followed by 2 with IC50 18.52 ± 1.9 µg/ml. DMSO was used as a negative control and doxorubicin as a reference standard (IC50 1.3 ± 0.21 µg/ml). It was observed that compounds 1-2 caused apoptotic cell death evaluated by Acridine orange -ethidium bromide staining, styox green assay and DNA interaction study, therefore both compounds were tested for molecular docking studies against tyrosine kinase to support cytotoxic activity. CONCLUSION: This study revealed that the plant extracts and isolated compounds possess promising antiproliferative activity against HepG-2 cell lines via apoptotic cell death.

Flavonoids as Prospective Neuroprotectants and Their Therapeutic Propensity in Aging Associated Neurological Disorders.

Modern research has revealed that dietary consumption of flavonoids and flavonoids-rich foods significantly improve cognitive capabilities, inhibit or delay the senescence process and related neurodegenerative disorders including Alzheimer's disease (AD). The flavonoids rich foods such as green tea, cocoa, blue berry and other foods improve the various states of cognitive dysfunction, AD and dementia-like pathological alterations in different animal models. The mechanisms of flavonoids have been shown to be mediated through the inhibition of cholinesterases including acetylcholinesterase (AChE), and butyrylcholinesterase (BChE), ß-secretase (BACE1), free radicals and modulation of signaling pathways, that are implicated in cognitive and neuroprotective functions. Flavonoids interact with various signaling protein pathways like ERK and PI3-kinase/Akt and modulate their actions, thereby leading to beneficial neuroprotective effects. Moreover, they enhance vascular blood flow and instigate neurogenesis particularly in the hippocampus. Flavonoids also hamper the progression of pathological symptoms of neurodegenerative diseases by inhibiting neuronal apoptosis induced by neurotoxic substances including free radicals and ß-amyloid proteins (Aß). All these protective mechanisms contribute to the maintenance of number, quality of neurons and their synaptic connectivity in the brain. Thus flavonoids can thwart the progression of age-related disorders and can be a potential source for the design and development of new drugs effective in cognitive disorders.

Pollen micromorphological analysis of tribe Acacieae (Mimosaceae) with LM and SEM techniques.

The morphology of pollen grains of the 06 species of tribe Acacieae (Mimosaceae) belonging to one genus were investigated using scanning electron microscopic (SEM) and light microscopic (LM) approach. Lactic acid acetolysis method was used for (LM) while non-acetolysis for (SEM). The species were examined for the both qualitative and quantitative palynological features. Qualitatively the pollen was studied for the shape, exine sculpturing, pollen shape, and pollen type. Oblate spheroidal shape of pollen was observed in Accacia modesta. Subprolate shape in Accaca nilotica. In Accacia farnesiana, prolate pollen was examined while prolate spheroidal in Acacia tortilis and spheroidal pollen grains were studied in Acacia catechu, respectively. Pollen exine sculpturing of the studied tribe possesses novel variation. Foveolate, reticulate, foveolate-psilate, faint reticulate, fossulate, perforate, and scrabate exine sculpturing were noticed. Colpi were absent in all species. Excessive variation was observed in both qualitative and quantitative character of pollen. SPSS software was use for the quantitative measurement of the pollen grains. The current study will be helpful for the identification of the problematic species and phylogenetic studies of family Mimosaceae.