Journal articles: 'Anti-amyloidogenic compounds'

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Porzoor, Afsaneh, Benjamin Alford, Helmut Hügel, Danilla Grando, Joanne Caine, and Ian Macreadie. "Anti-Amyloidogenic Properties of Some Phenolic Compounds." Biomolecules 5, no. 2 (April 17, 2015): 505–27. http://dx.doi.org/10.3390/biom5020505.

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Hirohata, Mie, Kenjiro Ono, and Masahito Yamada. "Non-Steroidal Anti-Inflammatory Drugs as Anti-Amyloidogenic Compounds." Current Pharmaceutical Design 14, no. 30 (October 1, 2008): 3280–94. http://dx.doi.org/10.2174/138161208786404173.

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Ziaunys, Mantas, and Vytautas Smirnovas. "Exploring Epigallocatechin-3-Gallate Autoxidation Products: Specific Incubation Times Required for Emergence of Anti-Amyloid Properties." Antioxidants 11, no. 10 (September 23, 2022): 1887. http://dx.doi.org/10.3390/antiox11101887.

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Amyloidogenic protein/peptide aggregation into fibrillar aggregates is associated with multiple amyloidoses, including widespread neurodegenerative disorders. Despite years of research and a well-understood mechanism, there are still very few treatments available for the increasing number of amyloid-related disorders. In recent years, the search for potential anti-aggregation compounds has shifted toward naturally occurring molecules, with one of the most promising being epigallocatechin-3-gallate (EGCG). This polyphenolic compound was shown to inhibit the aggregation of several amyloidogenic proteins/peptides, including amyloid-beta (related to Alzheimer’s disease) and alpha-synuclein (related to Parkinson’s disease). However, multiple reports have indicated its limited stability under physiological conditions and the possibility of EGCG autoxidation products being the actual inhibitory compounds. In this work, we explore how different EGCG autoxidation products associate with non-aggregated insulin, as well as how they affect its aggregation and resulting fibril structure. We also show that there is a specific incubation time required for the emergence of compounds, which alters the amyloid aggregation process.

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Skibiszewska and Jankowska. "Can Short Peptides Be Inhibitors of Serum Amyloid a Protein Aggregation?" Proceedings 22, no. 1 (August 7, 2019): 38. http://dx.doi.org/10.3390/proceedings2019022038.

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Tan, Mario A., Mark Wilson D. Lagamayo, Grecebio Jonathan D. Alejandro, and Seong Soo A. An. "Anti-Amyloidogenic and Cyclooxygenase Inhibitory Activity of Guettarda speciosa." Molecules 24, no. 22 (November 14, 2019): 4112. http://dx.doi.org/10.3390/molecules24224112.

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Guettarda speciosa is known in traditional folk medicine for treating cough, cold, sore throat, fever, wounds, epilepsy, and headaches. To discover the scientific pharmacological potential of G. speciosa, we explore its anti-inflammatory, cytotoxicity, and inhibition of amyloid-beta (Aβ) aggregation effects. Cyclooxygenase assay of the G. speciosa CHCl3 (GSC) extract and G. speciosa MeOH (GSM) extract are more selective to COX-1 inhibition with a 50% inhibitory concentration (IC50) of 3.56 μg/mL for the GSC extract and 4.98 μg/mL for the GSM extract. Neuroblastoma SH-SY5Y inhibition and thioflavin T assay amyloid-beta (Aβ) aggregate inhibition of the GSM and GSC extracts showed their potential therapeutic effects against Alzheimer’s disease. The putative compounds from the LC-MS analysis could be responsible for the observed activities. The results suggest that G. speciosa possesses anti-inflammatory and anti-neurodegenerative properties and a promising lead as a source of pharmacologically active compounds.

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Yeo, Ji-Yun, Seul Lee, Min Sung Ko, Chung Hyun Lee, Jee Yeon Choi, Kwang Woo Hwang, and So-Young Park. "Anti-Amyloidogenic Effects of Metasequoia glyptostroboides Fruits and Its Active Constituents." Molecules 28, no. 3 (January 19, 2023): 1017. http://dx.doi.org/10.3390/molecules28031017.

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Alzheimer’s disease (AD) is a serious neurodegenerative brain disease that interferes with daily life. The accumulation of beta-amyloid (Aβ), along with oxidative stress-inducing neurocellular apoptosis, has been considered one of the causes of AD. Thus, the purpose of this study is to find natural products that can reduce Aβ accumulation. The ethanol extract of Metasequoia glyptostroboides Hu & Cheng fruits (Cupressaceae) significantly reduced the aggregation of Aβ into oligomers and fibrils determined by Thioflavin T (ThT) assay. The solvent-partitioned ethyl acetate layer was further separated based on the bioassay-guided isolation method combined with the ThT assay. As a result, five compounds were isolated and elucidated as taxoquinone (1), sugiol (2), suginal (3), sandaracopimarinol (4), and sandaracopimaradien-19-ol (5) by comparing NMR data with references. All the compounds significantly reduced the aggregation of Aβ and enhanced the disaggregation of pre-formed Aβ aggregates in a dose-dependent manner. Furthermore, the inhibition of Aβ aggregation by the compounds protected PC12 cells from Aβ aggregate-induced toxicity. Among the five compounds, sandaracopimarinol (4) and sandaracopimaradien-19-ol (5) were the most effective. These results suggest that M. glyptostroboides and isolated five compounds have a potential for further study to be developed as anti-AD agents.

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Quiroz, Jose Paredes, Andi Zeng, Michelle Young, Patrick Gordon, Aadya Jaipuria, Kristi J. Reed, Greg M. Landry, et al. "Homotaurine and Curcumin Analogues as Potential Anti-Amyloidogenic Agents." Chemistry 5, no. 1 (February 7, 2023): 223–41. http://dx.doi.org/10.3390/chemistry5010018.

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Currently, there is neither a cure for Alzheimer’s disease (AD) nor a way to stop the progressive death of neuronal cells associated with this devastating aliment. To date, there are only medications that temporarily slow its progression, and do not interfere with its pathogenesis. One of the hallmarks of AD is the presence of amyloid-beta plaques derived from the metabolism of the amyloid precursor protein, via the cleavage by beta followed by gamma secretase. Homotaurine, a naturally occurring small molecule found in some seaweeds, and curcumin, a phenolic antioxidant found in Curcuma longa, have been extensively studied as potential compounds to prevent/reverse plaque formation. In this study, libraries of chalcones and extended chalcones based on curcumin, as well as aminopropylsulfonamides inspired by homotaurine, were synthesized. Using fluorescence spectroscopic analysis with Thioflavin T, the anti-aggregation effect on Aβ42 was determined. A select number of newly synthesized chalcones and extended chalcone analogs were revealed to be potential anti-amyloidogenic agents. These were further evaluated with regard to their neurotoxicity/neuroprotection. The extended chalcone analogs that displayed the most anti-aggregation effect on Aβ42 were further analyzed in an MTT assay. Although none of the compounds alone displayed any neurotoxicity, none were able to provide neuroprotection against Aβ42.

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Marvastizadeh, Narges, Bahareh Dabirmanesh, Reza H. Sajedi, and Khosro Khajeh. "Anti-amyloidogenic effect of artemin on α-synuclein." Biological Chemistry 401, no. 10 (September 25, 2020): 1143–51. http://dx.doi.org/10.1515/hsz-2019-0446.

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Abstractα-Synuclein fibrillation is now regarded as a major pathogenic process in Parkinson’s disease and its proteinaceous deposits are also detected in other neurological disorders including Alzheimer's disease. Therefore anti-amyloidegenic compounds may delay or prevent the progression of synucleinopathies disease. Molecular chaperones are group of proteins which mediate correct folding of proteins by preventing unsuitable interactions which may lead to aggregation. The objective of this study was to investigate the anti-amyloidogenic effect of molecular chaperone artemin on α-synuclein. As the concentration of artemin was increased up to 4 μg/ml, a decrease in fibril formation of α-synuclein was observed using thioflavin T (ThT) fluorescence and congo red (CR) assay. Transmission electron microscopy (TEM) images also demonstrated a reduction in fibrils in the presence of artemin. The secondary structure of α-synuclein was similar to its native form prior to fibrillation when incubated with artemin. A cell-based assay has shown that artemin inhibits α-synuclein aggregation and reduce cytotoxicity, apoptosis and reactive oxygen species (ROS) production. Our results revealed that artemin has efficient chaperon activity for preventing α-synuclein fibril formation and toxicity.

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Jiaranaikulwanitch, Jutamas, Hataichanok Pandith, Sarin Tadtong, Phanit Thammarat, Supat Jiranusornkul, Nattapong Chauthong, Supitcha Nilkosol, and Opa Vajragupta. "Novel Multifunctional Ascorbic Triazole Derivatives for Amyloidogenic Pathway Inhibition, Anti-Inflammation, and Neuroprotection." Molecules 26, no. 6 (March 12, 2021): 1562. http://dx.doi.org/10.3390/molecules26061562.

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Alzheimer’s disease (AD) is a common neurodegenerative disorder. The number of patients with AD is projected to reach 152 million by 2050. Donepezil, rivastigmine, galantamine, and memantine are the only four drugs currently approved by the United States Food and Drug Administration for AD treatment. However, these drugs can only alleviate AD symptoms. Thus, this research focuses on the discovery of novel lead compounds that possess multitarget regulation of AD etiopathology relating to amyloid cascade. The ascorbic acid structure has been designated as a core functional domain due to several characteristics, including antioxidant activities, amyloid aggregation inhibition, and the ability to be transported to the brain and neurons. Multifunctional ascorbic derivatives were synthesized by copper (I)-catalyzed azide–alkyne cycloaddition reaction (click chemistry). The in vitro and cell-based assays showed that compounds 2c and 5c exhibited prominent multifunctional activities as beta-secretase 1 inhibitors, amyloid aggregation inhibitors, and antioxidant, neuroprotectant, and anti-inflammatory agents. Significant changes in activities promoting neuroprotection and anti-inflammation were observed at a considerably low concentration at a nanomolar level. Moreover, an in silico study showed that compounds 2c and 5c were capable of being permeated across the blood–brain barrier by sodium-dependent vitamin C transporter-2.

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Ciaramelli, Carlotta, Alessandro Palmioli, Ada De Luigi, Laura Colombo, Gessica Sala, Chiara Riva, Chiara Paola Zoia, Mario Salmona, and Cristina Airoldi. "NMR-driven identification of anti-amyloidogenic compounds in green and roasted coffee extracts." Food Chemistry 252 (June 2018): 171–80. http://dx.doi.org/10.1016/j.foodchem.2018.01.075.

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Lakey-Beitia, Johant, Jagadeesh Kumar D., Muralidhar Hegde, and K. S. Rao. "Carotenoids as Novel Therapeutic Molecules Against Neurodegenerative Disorders: Chemistry and Molecular Docking Analysis." International Journal of Molecular Sciences 20, no. 22 (November 7, 2019): 5553. http://dx.doi.org/10.3390/ijms20225553.

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Alzheimer’s disease (AD) is the most devastating neurodegenerative disorder that affects the aging population worldwide. Endogenous and exogenous factors are involved in triggering this complex and multifactorial disease, whose hallmark is Amyloid-β (Aβ), formed by cleavage of amyloid precursor protein by β- and γ-secretase. While there is no definitive cure for AD to date, many neuroprotective natural products, such as polyphenol and carotenoid compounds, have shown promising preventive activity, as well as helping in slowing down disease progression. In this article, we focus on the chemistry as well as structure of carotenoid compounds and their neuroprotective activity against Aβ aggregation using molecular docking analysis. In addition to examining the most prevalent anti-amyloidogenic carotenoid lutein, we studied cryptocapsin, astaxanthin, fucoxanthin, and the apocarotenoid bixin. Our computational structure-based drug design analysis and molecular docking simulation revealed important interactions between carotenoids and Aβ via hydrogen bonding and van der Waals interactions, and shows that carotenoids are powerful anti-amyloidogenic molecules with a potential role in preventing AD, especially since most of them can cross the blood-brain barrier and are considered nutraceutical compounds. Our studies thus illuminate mechanistic insights on how carotenoids inhibit Aβ aggregation. The potential role of carotenoids as novel therapeutic molecules in treating AD and other neurodegenerative disorders are discussed.

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Nisha, Chaluveelaveedu Murleedharan, Ashwini Kumar, Prateek Nair, Nityasha Gupta, Chitrangda Silakari, Timir Tripathi, and Awanish Kumar. "Molecular Docking and In Silico ADMET Study Reveals Acylguanidine 7a as a Potential Inhibitor of β-Secretase." Advances in Bioinformatics 2016 (April 10, 2016): 1–6. http://dx.doi.org/10.1155/2016/9258578.

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Amyloidogenic pathway in Alzheimer’s disease (AD) involves breakdown of APP by β-secretase followed by γ-secretase and results in formation of amyloid beta plaque. β-secretase has been a promising target for developing novel anti-Alzheimer drugs. To test different molecules for this purpose, test ligands like acylguanidine 7a, rosiglitazone, pioglitazone, and tartaric acid were docked against our target protein β-secretase enzyme retrieved from Protein Data Bank, considering MK-8931 (phase III trial, Merck) as the positive control. Docking revealed that, with respect to their free binding energy, acylguanidine 7a has the lowest binding energy followed by MK-8931 and pioglitazone and binds significantly to β-secretase. In silico ADMET predictions revealed that except tartaric acid all other compounds had minimal toxic effects and had good absorption as well as solubility characteristics. These compounds may serve as potential lead compound for developing new anti-Alzheimer drug.

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Kleinrichert, Kody, and Bindhu Alappat. "Comparative Analysis of Antioxidant and Anti-Amyloidogenic Properties of Various Polyphenol Rich Phytoceutical Extracts." Antioxidants 8, no. 1 (January 1, 2019): 13. http://dx.doi.org/10.3390/antiox8010013.

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Though the pathogenesis of Alzheimer’s Disease (AD) is not completely elucidated, it is generally accepted that the aggregation of toxic amyloid-β (Aβ) protein fibrils plays a major role in the disease’s onset and progression. Various phytoceutical compounds have been shown to attenuate Aβ toxicity and disrupt its aggregation, including various types of polyphenolic compounds. These polyphenolic compounds have also been found to demonstrate potent antioxidant activity, which may contribute to their anti-amyloidogenic properties. This study compares three plants, traditionally used for numerous medicinal purposes in Asian countries, including: Curcuma longa (Turmeric), Camellia sinensis (Green Tea), and Scoparia dulcis (Sweet Broomweed). Antioxidant effects of the crude, polyphenol rich phytoceutical extracts from these plants were analyzed using a 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. The ability of these extracts to prevent Aβ fibril formation was then carried out in order to establish a relationship between antioxidant activity and Aβ aggregation. A positive correlation between antioxidant efficacy and prevention of Aβ aggregation was demonstrated, indicating that antioxidant activity may play some role in preventing Aβ aggregation.

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Vasarri, Marzia, Matteo Ramazzotti, Bruno Tiribilli, Emanuela Barletta, Carlo Pretti, Nadia Mulinacci, and Donatella Degl’Innocenti. "The In Vitro Anti-amyloidogenic Activity of the Mediterranean Red Seaweed Halopithys Incurva." Pharmaceuticals 13, no. 8 (August 7, 2020): 185. http://dx.doi.org/10.3390/ph13080185.

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Neurodegenerative diseases are generally characterized by the presence of neurotoxic amyloid aggregates underlying progressive neuronal death. Since ancient times, natural compounds have been used as curative agents for human health. Amyloid research is constantly looking for safe natural molecules capable of blocking toxic amyloid aggregates’ formation. From the marine environment, seaweeds are recognized as rich reservoirs of molecules with multiple bioactivities, including the anti-amyloidogenic activity. Here, hydroalcoholic extracts of two seasonal samples of the Mediterranean red seaweed Halophytis incurva (HIEs) were characterized by the HPLC-DAD-MS analysis. The H. incurva anti-amyloidogenic role was explored by incubating both HIEs with hen egg white lysozyme (HEWL), a well-known protein model widely used in amyloid aggregation experiments. The aggregation kinetics and morphological analysis of amyloid aggregates were performed by ThT and AFM analysis, respectively, while their cytotoxicity on SH-SY5Y human neuroblastoma cells was examined by MTT assay. HIEs showed a different efficacy, probably dependent on their metabolic composition, both in inhibiting amyloid fibrillation and in obtaining short and less toxic pre-fibrillary aggregates. Overall, this work sheds light, for the first time, on a Mediterranean red seaweed as a promising renewable resource of bioactive compounds, potentially useful in preventing the formation of toxic amyloid aggregates.

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Florio, Daniele, Maria Cuomo, Ilaria Iacobucci, Giarita Ferraro, Ahmed M. Mansour, Maria Monti, Antonello Merlino, and Daniela Marasco. "Modulation of Amyloidogenic Peptide Aggregation by Photoactivatable CO-Releasing Ruthenium(II) Complexes." Pharmaceuticals 13, no. 8 (July 29, 2020): 171. http://dx.doi.org/10.3390/ph13080171.

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Three Ru(II)-based CO-releasing molecules featuring bidentate benzimidazole and terpyridine derivatives as ligands were investigated for their ability to modulate the aggregation process of the second helix of the C-terminal domain of nucleophosmin 1, namely nucleophosmin 1 (NPM1)264–277, a model amyloidogenic system, before and after irradiation at 365 nm. Thioflavin T (ThT) binding assays and UV/Vis absorption spectra indicate that binding of the compounds to the peptide inhibits its aggregation and that the inhibitory effect increases upon irradiation (half maximal effective concentration (EC50) values in the high micromolar range). Electrospray ionization mass spectrometry data of the peptide in the presence of one of these compounds confirm that the modulation of amyloid aggregation relies on the formation of adducts obtained when the Ru compounds react with the peptide upon releasing of labile ligands, like chloride and carbon monoxide. This mechanism of action explains the subtle different behavior of the three compounds observed in ThT experiments. Overall, data support the hypothesis that metal-based CO releasing molecules can be used to develop metal-based drugs with potential application as anti-amyloidogenic agents.

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Poliseno, Viviana, Sílvia Chaves, Leonardo Brunetti, Fulvio Loiodice, Antonio Carrieri, Antonio Laghezza, Paolo Tortorella, et al. "Derivatives of Tenuazonic Acid as Potential New Multi-Target Anti-Alzheimer’s Disease Agents." Biomolecules 11, no. 1 (January 15, 2021): 111. http://dx.doi.org/10.3390/biom11010111.

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Alzheimer’s disease (AD) is generally recognized as a multifactorial neurodegenerative pathology with an increasing impact on society. Tenuazonic acid (TA) is a natural compound that was recently identified as a potential multitarget ligand with anti-cholinesterase, anti-amyloidogenic and antioxidant activities. Using its structure as a chemical scaffold, we synthesized and evaluated new derivatives (1–5), including tenuazonic-donepezil (TA-DNP) hybrids (4 and 5) due to the clinical importance of the anti-AD drug donepezil. These novel compounds all achieved activity in the micromolar range towards all selected targets and demonstrated to be potentially orally absorbed. Moreover, a selected compound (1) was further investigated as a chelating agent towards copper (II), zinc (II) and iron (III) and showed good chelating ability (pFe = 16.6, pCu = 11.6, pZn = 6.0 at pH 7.4). Therefore, the TA motif can be considered an interesting building block in the search for innovative multi-functional anti-neurodegenerative drugs, as exemplified by hybrid 5, a promising non-cytotoxic lead compound adequate for the early stages of AD, and capable of ameliorating the oxidative status of SH-SY5Y human neuroblastoma cells.

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Hengge, Regine. "Targeting Bacterial Biofilms by the Green Tea Polyphenol EGCG." Molecules 24, no. 13 (June 29, 2019): 2403. http://dx.doi.org/10.3390/molecules24132403.

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Bacterial biofilms are multicellular aggregates in which cells are embedded in an extracellular matrix of self-produced biopolymers. Being refractory to antibiotic treatment and host immune systems, biofilms are involved in most chronic infections, and anti-biofilm agents are being searched for urgently. Epigallocatechin-3-gallate (EGCG) was recently shown to act against biofilms by strongly interfering with the assembly of amyloid fibres and the production of phosphoethanolamin-modified cellulose fibrils. Mechanistically, this includes a direct inhibition of the fibre assembly, but also triggers a cell envelope stress response that down-regulates the synthesis of these widely occurring biofilm matrix polymers. Based on its anti-amyloidogenic properties, EGCG seems useful against biofilms involved in cariogenesis or chronic wound infection. However, EGCG seems inefficient against or may even sometimes promote biofilms which rely on other types of matrix polymers, suggesting that searching for ‘magic bullet’ anti-biofilm agents is an unrealistic goal. Combining molecular and ecophysiological aspects in this review also illustrates why plants control the formation of biofilms on their surfaces by producing anti-amyloidogenic compounds such as EGCG. These agents are not only helpful in combating certain biofilms in chronic infections but even seem effective against the toxic amyloids associated with neuropathological diseases.

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Galdeano, Carles, Elisabet Viayna, Irene Sola, Xavier Formosa, Pelayo Camps, Albert Badia, M. Victòria Clos, et al. "Huprine–Tacrine Heterodimers as Anti-Amyloidogenic Compounds of Potential Interest against Alzheimer’s and Prion Diseases." Journal of Medicinal Chemistry 55, no. 2 (January 10, 2012): 661–69. http://dx.doi.org/10.1021/jm200840c.

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Musteikyte, Greta, Mantas Ziaunys, and Vytautas Smirnovas. "Methylene blue inhibits nucleation and elongation of SOD1 amyloid fibrils." PeerJ 8 (August 14, 2020): e9719. http://dx.doi.org/10.7717/peerj.9719.

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Protein aggregation into highly-structured amyloid fibrils is linked to several neurodegenerative diseases. Such fibril formation by superoxide dismutase I (SOD1) is considered to be related to amyotrophic lateral sclerosis, a late-onset and fatal disorder. Despite much effort and the discovery of numerous anti-amyloid compounds, no effective cure or treatment is currently available. Methylene blue (MB), a phenothiazine dye, has been shown to modulate the aggregation of multiple amyloidogenic proteins. In this work we show its ability to inhibit both the spontaneous amyloid aggregation of SOD1 as well as elongation of preformed fibrils.

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Ramya, S., T. Loganathan, M. Chandran, R. Priyanka, K. Kavipriya, G. Grace Lydial Pushpalatha, Devaraj Aruna, L. Ramanathan, R. Jayakumararaj, and Vikrant Saluja. "Phytochemical Screening, GCMS, FTIR profile of Bioactive Natural Products in the methanolic extracts of Cuminum cyminum seeds and oil." Journal of Drug Delivery and Therapeutics 12, no. 2-S (April 15, 2022): 110–18. http://dx.doi.org/10.22270/jddt.v12i2-s.5280.

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Seeds of cumin (Cuminum cyminum L.) are widely used as a spice for their distinctive aroma. C. cyminum have been used in traditional medicine to treat a variety of diseases. Literature presents ample evidence for biomedical activities of cumin which is attributed to its bioactive secondary metabolites - terpenes, phenols, and flavonoids. Besides, health effects of cumin seeds have been experimentally validated through phytochemical analysis depicting the presence of a wide array of bioactive secondary metabolites (BASMs) viz., alkaloid, coumarin, anthraquinone, flavonoid, glycoside, protein, resin, saponin, tannin and steroid. Pharmacological studies indicate that BASMs in seeds of C. cyminum exert antimicrobial, insecticidal, anti-inflammatory, analgesic, antioxidant, anticancer, antidiabetic, anti-platelet-aggregation, hypotensive, bronchodilatory, immunological, contraceptive, anti-amyloidogenic, anti-osteoporotic, aldose reductase, α-glucosidase and tyrosinase inhibitory effects. In the present study phytochemical screening, GCMS, FTIR profile of bioactive natural products from C. cyminum has been envisaged. Phytochemical screening revealed the presence of alkaloids, anthraquinones, carbohydrates, coumarins, flavonoids, glycosides, proteins, quinones, saponins, steroids, tannins and terpenoids. GC-MS analysis revealed the presence of 21 compounds, of which Cuminaldehyde was prominent. FTIR analysis showed the presence of a strong peak value for 15 compounds and medium peak value for 6 compounds. Many of the compounds in the list could be ADMET bioprospected for biomedical applications as natural drug leads. Keywords: Cuminum cyminum; Cuminaldehyde; Bioactive Natural Products; GCMS; FTIR

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Ramya, S., T. Loganathan, M. Chandran, R. Priyanka, K. Kavipriya, G. Grace Lydial Pushpalatha, Devaraj Aruna, L. Ramanathan, R. Jayakumararaj, and Vikrant Saluja. "Phytochemical Screening, GCMS, FTIR profile of Bioactive Natural Products in the methanolic extracts of Cuminum cyminum seeds and oil." Journal of Drug Delivery and Therapeutics 12, no. 2-S (April 15, 2022): 110–18. http://dx.doi.org/10.22270/jddt.v12i2-s.5280.

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Seeds of cumin (Cuminum cyminum L.) are widely used as a spice for their distinctive aroma. C. cyminum have been used in traditional medicine to treat a variety of diseases. Literature presents ample evidence for biomedical activities of cumin which is attributed to its bioactive secondary metabolites - terpenes, phenols, and flavonoids. Besides, health effects of cumin seeds have been experimentally validated through phytochemical analysis depicting the presence of a wide array of bioactive secondary metabolites (BASMs) viz., alkaloid, coumarin, anthraquinone, flavonoid, glycoside, protein, resin, saponin, tannin and steroid. Pharmacological studies indicate that BASMs in seeds of C. cyminum exert antimicrobial, insecticidal, anti-inflammatory, analgesic, antioxidant, anticancer, antidiabetic, anti-platelet-aggregation, hypotensive, bronchodilatory, immunological, contraceptive, anti-amyloidogenic, anti-osteoporotic, aldose reductase, α-glucosidase and tyrosinase inhibitory effects. In the present study phytochemical screening, GCMS, FTIR profile of bioactive natural products from C. cyminum has been envisaged. Phytochemical screening revealed the presence of alkaloids, anthraquinones, carbohydrates, coumarins, flavonoids, glycosides, proteins, quinones, saponins, steroids, tannins and terpenoids. GC-MS analysis revealed the presence of 21 compounds, of which Cuminaldehyde was prominent. FTIR analysis showed the presence of a strong peak value for 15 compounds and medium peak value for 6 compounds. Many of the compounds in the list could be ADMET bioprospected for biomedical applications as natural drug leads. Keywords: Cuminum cyminum; Cuminaldehyde; Bioactive Natural Products; GCMS; FTIR

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Li, Hongyun, Genevieve Evin, Andrew F. Hill, Ya Hui Hung, Ashley I. Bush, and Brett Garner. "Dissociation of ERK signalling inhibition from the anti-amyloidogenic action of synthetic ceramide analogues." Clinical Science 122, no. 9 (January 16, 2012): 409–20. http://dx.doi.org/10.1042/cs20110257.

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Inhibition of GSL (glycosphingolipid) synthesis reduces Aβ (amyloid β-peptide) production in vitro. Previous studies indicate that GCS (glucosylceramide synthase) inhibitors modulate phosphorylation of ERK1/2 (extracellular-signal-regulated kinase 1/2) and that the ERK pathway may regulate some aspects of Aβ production. It is not clear whether there is a causative relationship linking GSL synthesis inhibition, ERK phosphorylation and Aβ production. In the present study, we treated CHO cells (Chinese-hamster ovary cells) and SH-SY5Y neuroblastoma cells, that both constitutively express human wild-type APP (amyloid precursor protein) and process this to produce Aβ, with GSL-modulating agents to explore this relationship. We found that three related ceramide analogue GSL inhibitors, based on the PDMP (D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol) structure, reduced cellular Aβ production and in all cases this was correlated with inhibition of pERK (phosphorylated ERK) formation. Importantly, the L-threo enantiomers of these compounds (that are inferior GSL synthesis inhibitors compared with the D-threo-enantiomers) also reduced ERK phosphorylation to a similar extent without altering Aβ production. Inhibition of ERK activation using either PD98059 [2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one] or U0126 (1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio] butadiene) had no impact on Aβ production, and knockdown of endogenous GCS using small interfering RNA reduced cellular GSL levels without suppressing Aβ production or pERK formation. Our data suggest that the alteration in pERK levels following treatment with these ceramide analogues is not the principal mechanism involved in the inhibition of Aβ generation and that the ERK signalling pathway does not play a crucial role in processing APP through the amyloidogenic pathway.

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Alattiya, Reem Halim, Farah Khalid Tarish, Lina Loai Hashim, and Saad Abdulrahman Hussain. "The Role of Polyphenols in the Treatment of Alzheimer's Disease: Narrative Review." Al-Rafidain Journal of Medical Sciences ( ISSN: 2789-3219 ) 1 (October 13, 2021): 53–61. http://dx.doi.org/10.54133/ajms.v1i.31.

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Many epidemiological studies have suggested that consuming a diet rich in polyphenols can help prevent Alzheimer's disease (AD). Based on well-known in vitro and in vivo models of cerebral Aβ amyloidosis, we examined the data on the effects of various natural polyphenols on the aggregation of amyloid-protein (Aβ). These polyphenols effectively prevent oligomerization and fibril formation of Aβ through differential binding patterns, lowering Aβ oligomer-induced synaptic and neuronal toxicity, according to in vitro investigations. Furthermore, in a transgenic mouse model fed orally with such polyphenolic compounds, soluble Aβ oligomers as well as insoluble Aβ deposits in the brain were significantly reduced. Natural polyphenols exhibit anti-amyloidogenic effects on Aβ, in addition to well-known anti-oxidative and anti-inflammatory activities, according to an updated assessment of the literature, implying their potential as therapeutic and/or preventive agents for AD treatment. To prove polyphenols' efficacy as disease-modifying agents, well-designed clinical trials or preventive treatments using various polyphenols are required.

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Coimbra, Judite R. M., Salete J. Baptista, Teresa C. P. Dinis, Maria M. C. Silva, Paula I. Moreira, Armanda E. Santos, and Jorge A. R. Salvador. "Combining Virtual Screening Protocol and In Vitro Evaluation towards the Discovery of BACE1 Inhibitors." Biomolecules 10, no. 4 (April 1, 2020): 535. http://dx.doi.org/10.3390/biom10040535.

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The treatment options for a patient diagnosed with Alzheimer’s disease (AD) are currently limited. The cerebral accumulation of amyloid-β (Aβ) is a critical molecular event in the pathogenesis of AD. When the amyloidogenic β-secretase (BACE1) is inhibited, the production of Aβ peptide is reduced. Henceforth, the main goal of this study is the discovery of new small bioactive molecules that potentially reach the brain and inhibit BACE1. The work was conducted by a customized molecular modelling protocol, including pharmacophore-based and molecular docking-based virtual screening (VS). Structure-based (SB) and ligand-based (LB) pharmacophore models were designed to accurately screen several drug-like compound databases. The retrieved hits were subjected to molecular docking and in silico filtered to predict their ability to cross the blood–brain barrier (BBB). Additionally, 34 high-scoring compounds structurally distinct from known BACE1 inhibitors were selected for in vitro screening assay, which resulted in 13 novel hit-compounds for this relevant therapeutic target. This study disclosed new BACE1 inhibitors, proving the utility of combining computational and in vitro approaches for effectively predicting anti-BACE1 agents in the early drug discovery process.

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Hosseinkhani, Ayda, Ali Sahragard, Aida Namdari, and Mohammad M. Zarshenas. "Botanical Sources for Alzheimer’s: A Review on Reports From Traditional Persian Medicine." American Journal of Alzheimer's Disease & Other Dementiasr 32, no. 7 (July 6, 2017): 429–37. http://dx.doi.org/10.1177/1533317517717013.

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Herbal medicines for the treatment of Alzheimer’s disease (AD) have attracted considerable attention nowadays. Alzheimer’s disease is described in traditional Persian medicine (TPM) by the term Nesyān. In this study, 5 main medicinal medieval Persian manuscripts were reviewed to filter plants reported for the treatment of Nesyān. Databases were searched for related possible mechanisms of action of these medicinal plants. Each herb was searched for along with these keywords: “acetyl and butyryl cholinesterase inhibition,” “antioxidant,” “anti-inflammatory,” and “anti-amyloidogenic.” In Total, 44 herbs were used for the treatment of Nesyān; 40 of those were authenticated. Also, 30 plants had at least one of the mechanisms of action that were searched for or related pharmacological functions known for the treatment of AD. In this work, we introduce promising candidates in TPM that could undergo further investigation for identification of their active compounds and clinical validation in the treatment of AD.

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Ramya, S., T. Loganathan, M. Chandran, R. Priyanka, K. Kavipriya, G. Lydial Grace Lydial Pushpalatha, Devaraj Aruna, GC Abraham, and R. Jayakumararaj. "ADME-Tox profile of Cuminaldehyde (4-Isopropylbenzaldehyde) from Cuminum cyminum seeds for potential biomedical applications." Journal of Drug Delivery and Therapeutics 12, no. 2-S (April 15, 2022): 127–41. http://dx.doi.org/10.22270/jddt.v12i2-s.5286.

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Cuminum cyminum L (Family: Apiaceae) is a small multipurpose herb. Seeds of cumin are widely used as a spice for its distinctive aroma, and more commonly in various indigenous traditional systems of medicine. Access through web literature provides ample evidence for biomedical activities of Cuminum cyminum seeds (CCS). CCS has been used in traditional medicine to treat variety of diseases, including hypolipidemia, cancer, and diabetes. Biomedical properties of CCS is attributed to its phytochemical class of compounds viz., terpenes, phenols and flavonoids. Health effects of CCS have been experimentally validated through phytochemical screening deciphering the fact that it contains a large number of bioactive secondary metabolites (BASMs) viz., alkaloid, coumarin, anthraquinones, flavonoid, glycoside, protein, resin, saponin, tannin and steroid. Furthermore, pharmacological studies indicate that BASMs in CCS exert antimicrobial, insecticidal, anti-inflammatory, analgesic, antioxidant, anticancer, antidiabetic, anti-platelet-aggregation, hypotensive, bronchodilatory, immunological, contraceptive, anti-amyloidogenic, anti-osteoporotic, aldose reductase, α-glucosidase and tyrosinase inhibitory effects. Cuminaldehyde is one of the major bioactive compounds in CCS that holds significant pharmacological prominence. However, in-depth studies are lacking henceforth warranted to elucidate and fill the gaps, particularly on phytocompound isolation, pre-clinical, clinical characterization, and evaluation of structure–activity relationship. The present study prospects ADMETox perspectives of cuminaldehyde (4-Isopropylbenzaldehyde). Keywords: Cuminaldehyde; Isopropylbenzaldehyde; Cuminum cyminum; ADMETox; Natural Product (NP)

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Ramya, S., T. Loganathan, M. Chandran, R. Priyanka, K. Kavipriya, G. Lydial Grace Lydial Pushpalatha, Devaraj Aruna, GC Abraham, and R. Jayakumararaj. "ADME-Tox profile of Cuminaldehyde (4-Isopropylbenzaldehyde) from Cuminum cyminum seeds for potential biomedical applications." Journal of Drug Delivery and Therapeutics 12, no. 2-S (April 15, 2022): 127–41. http://dx.doi.org/10.22270/jddt.v12i2-s.5286.

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Cuminum cyminum L (Family: Apiaceae) is a small multipurpose herb. Seeds of cumin are widely used as a spice for its distinctive aroma, and more commonly in various indigenous traditional systems of medicine. Access through web literature provides ample evidence for biomedical activities of Cuminum cyminum seeds (CCS). CCS has been used in traditional medicine to treat variety of diseases, including hypolipidemia, cancer, and diabetes. Biomedical properties of CCS is attributed to its phytochemical class of compounds viz., terpenes, phenols and flavonoids. Health effects of CCS have been experimentally validated through phytochemical screening deciphering the fact that it contains a large number of bioactive secondary metabolites (BASMs) viz., alkaloid, coumarin, anthraquinones, flavonoid, glycoside, protein, resin, saponin, tannin and steroid. Furthermore, pharmacological studies indicate that BASMs in CCS exert antimicrobial, insecticidal, anti-inflammatory, analgesic, antioxidant, anticancer, antidiabetic, anti-platelet-aggregation, hypotensive, bronchodilatory, immunological, contraceptive, anti-amyloidogenic, anti-osteoporotic, aldose reductase, α-glucosidase and tyrosinase inhibitory effects. Cuminaldehyde is one of the major bioactive compounds in CCS that holds significant pharmacological prominence. However, in-depth studies are lacking henceforth warranted to elucidate and fill the gaps, particularly on phytocompound isolation, pre-clinical, clinical characterization, and evaluation of structure–activity relationship. The present study prospects ADMETox perspectives of cuminaldehyde (4-Isopropylbenzaldehyde). Keywords: Cuminaldehyde; Isopropylbenzaldehyde; Cuminum cyminum; ADMETox; Natural Product (NP)

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Ramya, S., T. Loganathan, M. Chandran, R. Priyanka, K. Kavipriya, G. Lydial Grace Lydial Pushpalatha, Devaraj Aruna, GC Abraham, and R. Jayakumararaj. "ADME-Tox profile of Cuminaldehyde (4-Isopropylbenzaldehyde) from Cuminum cyminum seeds for potential biomedical applications." Journal of Drug Delivery and Therapeutics 12, no. 2-S (April 15, 2022): 127–41. http://dx.doi.org/10.22270/jddt.v12i2-s.5286.

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Abstract:

Cuminum cyminum L (Family: Apiaceae) is a small multipurpose herb. Seeds of cumin are widely used as a spice for its distinctive aroma, and more commonly in various indigenous traditional systems of medicine. Access through web literature provides ample evidence for biomedical activities of Cuminum cyminum seeds (CCS). CCS has been used in traditional medicine to treat variety of diseases, including hypolipidemia, cancer, and diabetes. Biomedical properties of CCS is attributed to its phytochemical class of compounds viz., terpenes, phenols and flavonoids. Health effects of CCS have been experimentally validated through phytochemical screening deciphering the fact that it contains a large number of bioactive secondary metabolites (BASMs) viz., alkaloid, coumarin, anthraquinones, flavonoid, glycoside, protein, resin, saponin, tannin and steroid. Furthermore, pharmacological studies indicate that BASMs in CCS exert antimicrobial, insecticidal, anti-inflammatory, analgesic, antioxidant, anticancer, antidiabetic, anti-platelet-aggregation, hypotensive, bronchodilatory, immunological, contraceptive, anti-amyloidogenic, anti-osteoporotic, aldose reductase, α-glucosidase and tyrosinase inhibitory effects. Cuminaldehyde is one of the major bioactive compounds in CCS that holds significant pharmacological prominence. However, in-depth studies are lacking henceforth warranted to elucidate and fill the gaps, particularly on phytocompound isolation, pre-clinical, clinical characterization, and evaluation of structure–activity relationship. The present study prospects ADMETox perspectives of cuminaldehyde (4-Isopropylbenzaldehyde). Keywords: Cuminaldehyde; Isopropylbenzaldehyde; Cuminum cyminum; ADMETox; Natural Product (NP)

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Quezada, Elías, Fernanda Rodríguez-Enríquez, Reyes Laguna, Elena Cutrín, Francisco Otero, Eugenio Uriarte, and Dolores Viña. "Curcumin–Coumarin Hybrid Analogues as Multitarget Agents in Neurodegenerative Disorders." Molecules 26, no. 15 (July 28, 2021): 4550. http://dx.doi.org/10.3390/molecules26154550.

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Neurodegenerative diseases have a complex nature which highlights the need for multitarget ligands to address the complementary pathways involved in these diseases. Over the last decade, many innovative curcumin-based compounds have been designed and synthesized, searching for new derivatives having anti-amyloidogenic, inhibitory of tau formation, as well as anti-neuroinflammation, antioxidative, and AChE inhibitory activities. Regarding our experience studying 3-substituted coumarins with interesting properties for neurodegenerative diseases, our aim was to synthesize a new series of curcumin–coumarin hybrid analogues and evaluate their activity. Most of the 3-(7-phenyl-3,5-dioxohepta-1,6-dien-1-yl)coumarin derivatives 11–18 resulted in moderated inhibitors of hMAO isoforms and AChE and BuChE activity. Some of them are also capable of scavenger the free radical DPPH. Furthermore, compounds 14 and 16 showed neuroprotective activity against H2O2 in SH-SY5Y cell line. Nanoparticles formulation of these derivatives improved this property increasing the neuroprotective activity to the nanomolar range. Results suggest that by modulating the substitution pattern on both coumarin moiety and phenyl ring, ChE and MAO-targeted derivatives or derivatives with activity in cell-based phenotypic assays can be obtained.

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Kashyap, Priya, Vivekanandan Kalaiselvan, Robin Kumar, and Suresh Kumar. "Ajmalicine and Reserpine: Indole Alkaloids as Multi-Target Directed Ligands Towards Factors Implicated in Alzheimer’s Disease." Molecules 25, no. 7 (April 1, 2020): 1609. http://dx.doi.org/10.3390/molecules25071609.

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Alzheimer’s disease (AD) is a multifactorial disorder characterized by exponential loss of memory and cognitive deficit involving several disease modifying targets (amyloid beta, beta-secretase, monoaminoxidase-B, and cholinesterase). The present study explores multi-target directed ligand approach using secondary metabolite reserpine (RES) and ajmalicine (AJM) obtained from Rauwolfia serpentina roots. Novel LCMS and HPLC methods were developed for identification and quantification of reserpine and ajmalicine. In vitro enzyme inhibition assays were performed to evaluate anti-cholinesterase, β-site amyloid cleaving enzyme (BACE-1) inhibition and monoamine oxidase-B (MAO-B) inhibition, further analyzed with in silico analysis. Anti-amyloidogenic potential was studied using anti-aggregation studies along with TEM and circular dichroism (CD) analysis. In vitro neuroprotective potential against Aβ toxicity and anti-oxidative stress was demonstrated using PC12 cell cultures. Reserpine is a more potent dual cholinesterase inhibitor than ajmalicine (IC50 values of 1.7 μM (AChE) and 2.8 μM (BuChE)). The anti-aggregation activity of reserpine (68%) was more than ajmalicine (56%). Both compounds demonstrated neuroprotective activity against Aβ42 (92%) and H2O2 (93%) induced toxicity in PC12 cells against controls. Phytocompounds also inhibited MAO-B and BACE-1 enzymes in concentration dependent manner. Molecular docking studies indicated the strong binding of compounds to the catalytic site of targets. This novel study demonstrated that reserpine and ajmalicine as a multi-target directed ligand that have disease modifying potential for amelioration of AD.

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Martinez Pomier, Karla, Rashik Ahmed, and Giuseppe Melacini. "Catechins as Tools to Understand the Molecular Basis of Neurodegeneration." Molecules 25, no. 16 (August 6, 2020): 3571. http://dx.doi.org/10.3390/molecules25163571.

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Protein misfolding as well as the subsequent self-association and deposition of amyloid aggregates is implicated in the progression of several neurodegenerative disorders including Alzheimer’s and Parkinson’s diseases. Modulators of amyloidogenic aggregation serve as essential tools to dissect the underlying molecular mechanisms and may offer insight on potential therapeutic solutions. These modulators include green tea catechins, which are potent inhibitors of amyloid aggregation. Although catechins often exhibit poor pharmacokinetic properties and bioavailability, they are still essential tools for identifying the drivers of amyloid aggregation and for developing other aggregation modulators through structural mimicry. As an illustration of such strategies, here we review how catechins have been used to map the toxic surfaces of oligomeric amyloid-like species and develop catechin-based phenolic compounds with enhanced anti-amyloid activity.

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Abdul Manap, Aimi Syamima, Priya Madhavan, Shantini Vijayabalan, Adeline Chia, and Koji Fukui. "Explicating anti-amyloidogenic role of curcumin and piperine via amyloid beta (Aβ) explicit pathway: recovery and reversal paradigm effects." PeerJ 8 (September 30, 2020): e10003. http://dx.doi.org/10.7717/peerj.10003.

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Previously, we reported the synergistic effects of curcumin and piperine in cell cultures as potential anti-cholinesterase and anti-amyloidogenic agents. Due to limited findings on the enrolment of these compounds on epigenetic events in AD, we aimed at elucidating the expression profiles of Aβ42-induced SH-SY5Y cells using microarray profiling. In this study, an optimized concentration of 35 µM of curcumin and piperine in combination was used to treat Aβ42 fibril and high-throughput microarray profiling was performed on the extracted RNA. This was then compared to curcumin and piperine used singularly at 49.11 µM and 25 µM, respectively. Our results demonstrated that in the curcumin treated group, from the top 10 upregulated and top 10 downregulated significantly differentially expressed genes (p < 0.05; fold change ≥ 2 or ≤ −2), there were five upregulated and three downregulated genes involved in the amyloidogenic pathway. While from top 10 upregulated and top 10 downregulated significantly differentially expressed genes (p < 0.05; fold change ≥ 2 or ≤ − 2) in the piperine treated group, there were four upregulated and three downregulated genes involved in the same pathway, whereas there were five upregulated and two downregulated genes involved (p < 0.05; fold change ≥ 2 or ≤ − 2) in the curcumin-piperine combined group. Four genes namely GABARAPL1, CTSB, RAB5 and AK5 were expressed significantly in all groups. Other genes such as ITPR1, GSK3B, PPP3CC, ERN1, APH1A, CYCS and CALM2 were novel putative genes that are involved in the pathogenesis of AD. We revealed that curcumin and piperine have displayed their actions against Aβ via the modulation of various mechanistic pathways. Alterations in expression profiles of genes in the neuronal cell model may explain Aβ pathology post-treatment and provide new insights for remedial approaches of a combined treatment using curcumin and piperine.

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Hannan, Md Abdul, Raju Dash, Md Nazmul Haque, Md Mohibbullah, Abdullah Al Mamun Sohag, Md Ataur Rahman, Md Jamal Uddin, Mahboob Alam, and Il Soo Moon. "Neuroprotective Potentials of Marine Algae and Their Bioactive Metabolites: Pharmacological Insights and Therapeutic Advances." Marine Drugs 18, no. 7 (July 1, 2020): 347. http://dx.doi.org/10.3390/md18070347.

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Beyond their significant contribution to the dietary and industrial supplies, marine algae are considered to be a potential source of some unique metabolites with diverse health benefits. The pharmacological properties, such as antioxidant, anti-inflammatory, cholesterol homeostasis, protein clearance and anti-amyloidogenic potentials of algal metabolites endorse their protective efficacy against oxidative stress, neuroinflammation, mitochondrial dysfunction, and impaired proteostasis which are known to be implicated in the pathophysiology of neurodegenerative disorders and the associated complications after cerebral ischemia and brain injuries. As was evident in various preclinical studies, algal compounds conferred neuroprotection against a wide range of neurotoxic stressors, such as oxygen/glucose deprivation, hydrogen peroxide, glutamate, amyloid β, or 1-methyl-4-phenylpyridinium (MPP+) and, therefore, hold therapeutic promise for brain disorders. While a significant number of algal compounds with promising neuroprotective capacity have been identified over the last decades, a few of them have had access to clinical trials. However, the recent approval of an algal oligosaccharide, sodium oligomannate, for the treatment of Alzheimer’s disease enlightened the future of marine algae-based drug discovery. In this review, we briefly outline the pathophysiology of neurodegenerative diseases and brain injuries for identifying the targets of pharmacological intervention, and then review the literature on the neuroprotective potentials of algal compounds along with the underlying pharmacological mechanism, and present an appraisal on the recent therapeutic advances. We also propose a rational strategy to facilitate algal metabolites-based drug development.

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Caruana, Mario, Angelique Camilleri, Maria Ylenia Farrugia, Stephanie Ghio, Michaela Jakubíčková, Ruben J. Cauchi, and Neville Vassallo. "Extract from the Marine Seaweed Padina pavonica Protects Mitochondrial Biomembranes from Damage by Amyloidogenic Peptides." Molecules 26, no. 5 (March 7, 2021): 1444. http://dx.doi.org/10.3390/molecules26051444.

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The identification of compounds which protect the double-membrane of mitochondrial organelles from disruption by toxic confomers of amyloid proteins may offer a therapeutic strategy to combat human neurodegenerative diseases. Here, we exploited an extract from the marine brown seaweed Padina pavonica (PPE) as a vital source of natural bioactive compounds to protect mitochondrial membranes against insult by oligomeric aggregates of the amyloidogenic proteins amyloid-β (Aβ), α-synuclein (α-syn) and tau, which are currently considered to be major targets for drug discovery in Alzheimer’s disease (AD) and Parkinson’s disease (PD). We show that PPE manifested a significant inhibitory effect against swelling of isolated mitochondria exposed to the amyloid oligomers, and attenuated the release of cytochrome c from the mitochondria. Using cardiolipin-enriched synthetic lipid membranes, we also show that dye leakage from fluorophore-loaded vesicles and formation of channel-like pores in planar bilayer membranes are largely prevented by incubating the oligomeric aggregates with PPE. Lastly, we demonstrate that PPE curtails the ability of Aβ42 and α-syn monomers to self-assemble into larger β-aggregate structures, as well as potently disrupts their respective amyloid fibrils. In conclusion, the mito-protective and anti-aggregator biological activities of Padina pavonica extract may be of therapeutic value in neurodegenerative proteinopathies, such as AD and PD.

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Dey, Arpita, Ran Chen, Feng Li, Subhamita Maitra, Jean-Francois Hernandez, Guo-Chun Zhou, and Bruno Vincent. "Synthesis and Characterization of Andrographolide Derivatives as Regulators of βAPP Processing in Human Cells." Molecules 26, no. 24 (December 17, 2021): 7660. http://dx.doi.org/10.3390/molecules26247660.

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Alzheimer’s disease (AD) is a devastating neurodegenerative disorder, one of the main characteristics of which is the abnormal accumulation of amyloid peptide (Aβ) in the brain. Whereas β-secretase supports Aβ formation along the amyloidogenic processing of the β-amyloid precursor protein (βAPP), α-secretase counterbalances this pathway by both preventing Aβ production and triggering the release of the neuroprotective sAPPα metabolite. Therefore, stimulating α-secretase and/or inhibiting β-secretase can be considered a promising anti-AD therapeutic track. In this context, we tested andrographolide, a labdane diterpene derived from the plant Andrographis paniculata, as well as 24 synthesized derivatives, for their ability to induce sAPPα production in cultured SH-SY5Y human neuroblastoma cells. Following several rounds of screening, we identified three hits that were subjected to full characterization. Interestingly, andrographolide (8,17-olefinic) and its close derivative 14α-(5′,7′-dichloro-8′-quinolyloxy)-3,19-acetonylidene (compound 9) behave as moderate α-secretase activators, while 14α-(2′-methyl-5′,7′-dichloro-8′-quinolyloxy)-8,9-olefinic compounds 31 (3,19-acetonylidene) and 37 (3,19-diol), whose two structures are quite similar although distant from that of andrographolide and 9, stand as β-secretase inhibitors. Importantly, these results were confirmed in human HEK293 cells and these compounds do not trigger toxicity in either cell line. Altogether, these findings may represent an encouraging starting point for the future development of andrographolide-based compounds aimed at both activating α-secretase and inhibiting β-secretase that could prove useful in our quest for the therapeutic treatment of AD.

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Corti, Roberta, Alysia Cox, Valeria Cassina, Luca Nardo, Domenico Salerno, Claudia Adriana Marrano, Natalia Missana, et al. "The Clustering of mApoE Anti-Amyloidogenic Peptide on Nanoparticle Surface Does Not Alter Its Performance in Controlling Beta-Amyloid Aggregation." International Journal of Molecular Sciences 21, no. 3 (February 5, 2020): 1066. http://dx.doi.org/10.3390/ijms21031066.

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The deposition of amyloid-β (Aβ) plaques in the brain is a significant pathological signature of Alzheimer’s disease, correlating with synaptic dysfunction and neurodegeneration. Several compounds, peptides, or drugs have been designed to redirect or stop Aβ aggregation. Among them, the trideca-peptide CWG-LRKLRKRLLR (mApoE), which is derived from the receptor binding sequence of apolipoprotein E, is effectively able to inhibit Aβ aggregation and to promote fibril disaggregation. Taking advantage of Atomic Force Microscopy (AFM) imaging and fluorescence techniques, we investigate if the clustering of mApoE on gold nanoparticles (AuNP) surface may affect its performance in controlling Aβ aggregation/disaggregation processes. The results showed that the ability of free mApoE to destroy preformed Aβ fibrils or to hinder the Aβ aggregation process is preserved after its clustering on AuNP. This allows the possibility to design multifunctional drug delivery systems with clustering of anti-amyloidogenic molecules on any NP surface without affecting their performance in controlling Aβ aggregation processes.

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Mikalauskaite, Kamile, Mantas Ziaunys, and Vytautas Smirnovas. "Lysozyme Amyloid Fibril Structural Variability Dependence on Initial Protein Folding State." International Journal of Molecular Sciences 23, no. 10 (May 12, 2022): 5421. http://dx.doi.org/10.3390/ijms23105421.

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Amyloid fibril formation is associated with several amyloidoses, including neurodegenerative Alzheimer’s or Parkinson’s diseases. The process of such fibrillar structure formation is still not fully understood, with new mechanistic insights appearing on a regular basis. This, in turn, has limited the development of potential anti-amyloid compounds, with only a handful of effective cures or treatment modalities available. One of the multiple amyloid aggregation factors that requires further examination is the ability of proteins to form multiple, structurally distinct aggregates, based on the environmental conditions. In this work, we examine how the initial folding state affects the fibrilization of lysozyme—an amyloidogenic protein, often used in protein aggregation studies. We show that there is a correlation between the initial state of the protein and the aggregate formation lag time, rate of elongation, resulting aggregate structural variability and dye-binding properties, as well as formation lag time and rate of elongation.

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Gijsen, Harrie J. M., and Marc Mercken. "-Secretase Modulators: Can We Combine Potency with Safety?" International Journal of Alzheimer's Disease 2012 (2012): 1–10. http://dx.doi.org/10.1155/2012/295207.

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-Secretase modulation has been proposed as a potential disease modifying anti-Alzheimer’s approach. -Secretase modulators (GSMs) cause a product shift from the longer amyloid-beta (Aβ) peptide isoforms to shorter, more soluble, and less amyloidogenic isoforms, without inhibiting APP or Notch proteolytic processing. As such, modulating -secretase may avoid some of the adverse effects observed with -secretase inhibitors. Since the termination of the GSM tarenfurbil in 2008 due to negative phase III trial results, a considerable progress has been made towards more potent and better brain penetrable compounds. However, an analysis of their lipophilic efficiency indices indicates that their increased potency can be largely attributed to their increased lipophilicity. The need for early and chronic dosing with GSMs will require high-safety margins. This will be a challenge to achieve with the current, highly lipophilic GSMs. We will demonstrate that by focusing on the drug-like properties of GSMs, a combination of highin vitropotency and reduced lipophilicity can be achieved and does result in better tolerated compounds. The next hurdle will be to translate this knowledge into GSMs which are highly efficacious and safein vivo.

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Dhahri, Manel, Mawadda Alghrably, Hamdoon A. Mohammed, Syed Lal Badshah, Noreen Noreen, Fouzi Mouffouk, Saleh Rayyan, et al. "Natural Polysaccharides as Preventive and Therapeutic Horizon for Neurodegenerative Diseases." Pharmaceutics 14, no. 1 (December 21, 2021): 1. http://dx.doi.org/10.3390/pharmaceutics14010001.

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Neurodegenerative diseases are a serious and widespread global public health burden amongst aging populations. The total estimated worldwide global cost of dementia was US$818 billion in 2015 and has been projected to rise to 2 trillion US$ by 2030. While advances have been made to understand different neurodegenerative disease mechanisms, effective therapeutic strategies do not generally exist. Several drugs have been proposed in the last two decades for the treatment of different types of neurodegenerative diseases, with little therapeutic benefit, and often with severe adverse and side effects. Thus, the search for novel drugs with higher efficacy and fewer drawbacks is an ongoing challenge in the treatment of neurodegenerative disease. Several natural compounds including polysaccharides have demonstrated neuroprotective and even therapeutic effects. Natural polysaccharides are widely distributed in plants, animals, algae, bacterial and fungal species, and have received considerable attention for their wide-ranging bioactivity, including their antioxidant, anti-neuroinflammatory, anticholinesterase and anti-amyloidogenic effects. In this review, we summarize different mechanisms involved in neurodegenerative diseases and the neuroprotective effects of natural polysaccharides, highlighting their potential role in the prevention and therapy of neurodegenerative disease.

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Kolstoe, Simon E., and Steve P. Wood. "Drug targets for amyloidosis." Biochemical Society Transactions 38, no. 2 (March 22, 2010): 466–70. http://dx.doi.org/10.1042/bst0380466.

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The amyloid hypothesis indicates that protein misfolding is at the root of many neurodegenerative disorders. Small molecules targeting the formation, clearance, aggregation to toxic oligomers or SOD (superoxide dismutase)-like activities of Aβ (amyloid β-peptide) 1–42 have provided encouraging candidates for AD (Alzheimer's disease) medicines in animal models, although none have yet proved to be effective in human trials. We have been investigating approaches to treat systemic amyloidoses, conditions that show common features with some CNS (central nervous system) disorders. For TTR (transthyretin) amyloidosis, we are seeking small molecule compounds that stabilize the amyloidogenic protein and either prevent its structural transition to the crossed β fibres deposited in diseased tissues, or promote its clearance from circulation. Effective stabilizer compounds that simultaneously bind to both thyroxine-binding sites have been developed. A more generic approach involves targeting the plasma glycoprotein SAP (serum amyloid P component). This protein recognizes the misfolded polypeptide structures of amyloid deposits wherever they occur, and acts as a powerful anti-opsonin. We have developed a bivalent drug called CPHPC {(R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]-pyrrolidine-2-carboxylic acid} that cross-links pairs of pentameric SAP molecules and causes their rapid elimination from the circulation. This strategy raises the prospect of encouraging natural mechanisms to clear amyloid and recent work suggests that this approach extends to the CNS.

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Costa, Alana C., Helena P. G. Joaquim, João F. C. Pedrazzi, Andreia de O. Pain, Gustavo Duque, and Ivan Aprahamian. "Cannabinoids in Late Life Parkinson’s Disease and Dementia: Biological Pathways and Clinical Challenges." Brain Sciences 12, no. 12 (November 22, 2022): 1596. http://dx.doi.org/10.3390/brainsci12121596.

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The use of cannabinoids as therapeutic drugs has increased among aging populations recently. Age-related changes in the endogenous cannabinoid system could influence the effects of therapies that target the cannabinoid system. At the preclinical level, cannabidiol (CBD) induces anti-amyloidogenic, antioxidative, anti-apoptotic, anti-inflammatory, and neuroprotective effects. These findings suggest a potential therapeutic role of cannabinoids to neurodegenerative disorders such as Parkinson’s disease (PD) and Alzheimer. Emerging evidence suggests that CBD and tetrahydrocannabinol have neuroprotective therapeutic-like effects on dementias. In clinical practice, cannabinoids are being used off-label to relieve symptoms of PD and AD. In fact, patients are using cannabis compounds for the treatment of tremor, non-motor symptoms, anxiety, and sleep assistance in PD, and managing responsive behaviors of dementia such as agitation. However, strong evidence from clinical trials is scarce for most indications. Some clinicians consider cannabinoids an alternative for older adults bearing Parkinson’s disease and Alzheimer’s dementia with a poor response to first-line treatments. In our concept and experience, cannabinoids should never be considered a first-line treatment but could be regarded as an adjuvant therapy in specific situations commonly seen in clinical practice. To mitigate the risk of adverse events, the traditional dogma of geriatric medicine, starting with a low dose and proceeding with a slow titration regime, should also be employed with cannabinoids. In this review, we aimed to address preclinical evidence of cannabinoids in neurodegenerative disorders such as PD and AD and discuss potential off-label use of cannabinoids in clinical practice of these disorders.

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Guzzi, Cinzia, Laura Colombo, Ada De Luigi, Mario Salmona, Francesco Nicotra, and Cristina Airoldi. "Flavonoids and Their Glycosides as Anti-amyloidogenic Compounds: Aβ1-42 Interaction Studies to Gain New Insights into Their Potential for Alzheimer's Disease Prevention and Therapy." Chemistry - An Asian Journal 12, no. 1 (December 5, 2016): 67–75. http://dx.doi.org/10.1002/asia.201601291.

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Silvestro, Serena, Luigi Chiricosta, Agnese Gugliandolo, Renato Iori, Patrick Rollin, Daniele Perenzoni, Fulvio Mattivi, Placido Bramanti, and Emanuela Mazzon. "The Moringin/α-CD Pretreatment Induces Neuroprotection in an In Vitro Model of Alzheimer’s Disease: A Transcriptomic Study." Current Issues in Molecular Biology 43, no. 1 (May 26, 2021): 197–214. http://dx.doi.org/10.3390/cimb43010017.

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Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and represents the most common form of senile dementia. Autophagy and mitophagy are cellular processes that play a key role in the aggregation of β-amyloid (Aβ) and tau phosphorylation. As a consequence, impairment of these processes leads to the progression of AD. Thus, interest is growing in the search for new natural compounds, such as Moringin (MOR), with neuroprotective, anti-amyloidogenic, antioxidative, and anti-inflammatory properties that could be used for AD prevention. However, MOR appears to be poorly soluble and stable in water. To increase its solubility MOR was conjugated with α-cyclodextrin (MOR/α-CD). In this work, it was evaluated if MOR/α-CD pretreatment was able to exert neuroprotective effects in an AD in vitro model through the evaluation of the transcriptional profile by next-generation sequencing (NGS). To induce the AD model, retinoic acid-differentiated SH-SY5Y cells were exposed to Aβ1-42. The MOR/α-CD pretreatment reduced the expression of the genes which encode proteins involved in senescence, autophagy, and mitophagy processes. Additionally, MOR/α-CD was able to induce neuronal remodeling modulating the axon guidance, principally downregulating the Slit/Robo signaling pathway. Noteworthy, MOR/α-CD, modulating these important pathways, may induce neuronal protection against Aβ1-42 toxicity as demonstrated also by the reduction of cleaved caspase 3. These data indicated that MOR/α-CD could attenuate the progression of the disease and promote neuronal repair.

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Kola, Arian, Stefania Lamponi, Francesco Currò, and Daniela Valensin. "A Comparative Study between Lycorine and Galantamine Abilities to Interact with AMYLOID β and Reduce In Vitro Neurotoxicity." International Journal of Molecular Sciences 24, no. 3 (January 28, 2023): 2500. http://dx.doi.org/10.3390/ijms24032500.

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Galantamine is a natural alkaloid extracted from the Amaryllidaceae plants and is used as the active ingredient of a drug approved for the treatment of the early stages of Alzheimer’s disease. It mainly acts as an acetylcholinesterase (AChE) inhibitor, increasing concentrations of the acetylcholine neurotransmitter. Recent cellular studies have also shown the ability of galantamine to protect SH-SY5Y cell lines against amyloid-β (Aβ)-induced toxicity. Such investigations have supported and validated further in-depth studies for understanding the chemical and molecular features associated with galantamine-protective abilities. In addition to galantamine, other natural alkaloids are known to possess AChE inhibitory activity; among them lycorine has been extensively investigated for its antibacterial, anti-inflammatory and antitumoral activities as well. Despite its interesting biological properties, lycorine’s neuroprotective functions against Aβ-induced damages have not been explored so far. In this research study, the ability of galantamine and lycorine to suppress Aβ-induced in vitro neuronal toxicity was evaluated by investigating the chemical interactions of the two alkaloids with Aβ peptide. A multi-technique spectroscopic analysis and cellular cytotoxicity assays were applied to obtain new insights on these molecular associations. The comparison between the behaviors exhibited by the two alkaloids indicates that both compounds possess analogue abilities to interact with the amyloidogenic peptide and protect cells.

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Omar, Syed, Christopher Scott, Adam Hamlin, and Hassan Obied. "Olive Biophenols Reduces Alzheimer’s Pathology in SH-SY5Y Cells and APPswe Mice." International Journal of Molecular Sciences 20, no. 1 (December 30, 2018): 125. http://dx.doi.org/10.3390/ijms20010125.

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Alzheimer’s disease (AD) is a major neurodegenerative disease, associated with the hallmark proteinacious constituent called amyloid beta (Aβ) of senile plaques. Moreover, it is already established that metals (particularly copper, zinc and iron) have a key role in the pathogenesis of AD. In order to reduce the Aβ plaque burden and overcome the side effects from the synthetic inhibitors, the current study was designed to focus on direct inhibition of with or without metal-induced Aβ fibril formation and aggregation by using olive biophenols. Exposure of neuroblastoma (SH-SY5Y) cells with Aβ42 resulted in decrease of cell viability and morphological changes might be due to severe increase in the reactive oxygen species (ROS). The pre-treated SH-SY5Y cells with olive biophenols were able to attenuate cell death caused by Aβ42, copper- Aβ42, and [laevodihydroxyphenylalanine (l-DOPA)] l-DOPA-Aβ42-induced toxicity after 24 h of treatment. Oleuropein, verbascoside and rutin were the major anti-amyloidogenic compounds. Transgenic mice (APPswe/PS1dE9) received 50 mg/kg of oleuropein containing olive leaf extracts (OLE) or control diet from 7 to 23 weeks of age. Treatment mice (OLE) were showed significantly reduced amyloid plaque deposition (p < 0.001) in cortex and hippocampus as compared to control mice. Our findings provide a basis for considering natural and low cost biophenols from olive as a promising candidate drug against AD. Further studies warrant to validate and determine the anti-amyloid mechanism, bioavailability as well as permeability of olive biophenols against blood brain barrier in AD.

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Windsor, Peter K., Stephen P. Plassmeyer, Dominic S. Mattock, Jonathan C. Bradfield, Erika Y. Choi, Bill R. Miller, and Byung Hee Han. "Biflavonoid-Induced Disruption of Hydrogen Bonds Leads to Amyloid-β Disaggregation." International Journal of Molecular Sciences 22, no. 6 (March 12, 2021): 2888. http://dx.doi.org/10.3390/ijms22062888.

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Deposition of amyloid β (Aβ) fibrils in the brain is a key pathologic hallmark of Alzheimer’s disease. A class of polyphenolic biflavonoids is known to have anti-amyloidogenic effects by inhibiting aggregation of Aβ and promoting disaggregation of Aβ fibrils. In the present study, we further sought to investigate the structural basis of the Aβ disaggregating activity of biflavonoids and their interactions at the atomic level. A thioflavin T (ThT) fluorescence assay revealed that amentoflavone-type biflavonoids promote disaggregation of Aβ fibrils with varying potency due to specific structural differences. The computational analysis herein provides the first atomistic details for the mechanism of Aβ disaggregation by biflavonoids. Molecular docking analysis showed that biflavonoids preferentially bind to the aromatic-rich, partially ordered N-termini of Aβ fibril via the π–π interactions. Moreover, docking scores correlate well with the ThT EC50 values. Molecular dynamic simulations revealed that biflavonoids decrease the content of β-sheet in Aβ fibril in a structure-dependent manner. Hydrogen bond analysis further supported that the substitution of hydroxyl groups capable of hydrogen bond formation at two positions on the biflavonoid scaffold leads to significantly disaggregation of Aβ fibrils. Taken together, our data indicate that biflavonoids promote disaggregation of Aβ fibrils due to their ability to disrupt the fibril structure, suggesting biflavonoids as a lead class of compounds to develop a therapeutic agent for Alzheimer’s disease.

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Banerjee, Sauradipta. "Effect of glyoxal and 1-methylisatin on stress-induced fibrillation of Hen Egg White Lysozyme: Insight into the anti-amyloidogenic property of the compounds with possible therapeutic implications." International Journal of Biological Macromolecules 165 (December 2020): 1552–61. http://dx.doi.org/10.1016/j.ijbiomac.2020.10.017.

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Dash, Debabrata, and Raj Kumar Koiri. "Alzheimer\'s disease and traditional medicinal plants: A review." IP Indian Journal of Neurosciences 8, no. 4 (January 15, 2023): 226–33. http://dx.doi.org/10.18231/j.ijn.2022.047.

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Alzheimer's disease (AD) is characterized by severe memory loss that affects one's ability to operate in social and professional contexts. More than 20 million individuals worldwide are affected by it, making it the most prevalent type of dementia. An elusive memory loss, corresponding functional deterioration, and behavioral abnormalities are hallmarks of AD. AD is the most common cause of disability in the elderly and patients may survive for more than ten years after receiving their diagnosis. From its lowest level at ages 65 to 70 to rates that may approach 6 percent for those over the age of 85, the incidence of AD ranges from 1 to 4 percent of the population per year. Over a hundred novel products are currently undergoing clinical trials thanks to ayurvedic medicinal plants, which have shown to be the most fruitful source of leads or medication development. Indeed, the use of several Ayurvedic medicinal plants and their ingredients for treating Alzheimer's disease has been detailed in a number of scientific research. Phytochemical analyses of the various plant parts have revealed the presence of numerous valuable compounds, including lignans, flavonoids, tannins, polyphenols, triterpenes, sterols, and alkaloids, that exhibit a wide range of pharmacological activities, including anti-inflammatory, anti-amyloidogenic, anticholinesterase, hypolipidemic, and antioxidant effects. However, the precise mechanism of their action is still unclear. This study compiles studies on several medicinal plants that have demonstrated potential for correcting the pathology of Alzheimer's disease. The report provides sufficient baseline data that could be used in drug discovery campaigns and development processes, thereby providing new functional leads for Alzheimer's disease. It does this by summarizing information regarding the phytochemistry, biological, and cellular activities, as well as the clinical applications, of these various plants.

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Najarzadeh, Zahra, Hossein Mohammad-Beigi, Jannik Nedergaard Pedersen, Gunna Christiansen, Thorbjørn Vincent Sønderby, Seyed Abbas Shojaosadati, Dina Morshedi, et al. "Plant Polyphenols Inhibit Functional Amyloid and Biofilm Formation in Pseudomonas Strains by Directing Monomers to Off-Pathway Oligomers." Biomolecules 9, no. 11 (October 26, 2019): 659. http://dx.doi.org/10.3390/biom9110659.

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Self-assembly of proteins to β-sheet rich amyloid fibrils is commonly observed in various neurodegenerative diseases. However, amyloid also occurs in the extracellular matrix of bacterial biofilm, which protects bacteria from environmental stress and antibiotics. Many Pseudomonas strains produce functional amyloid where the main component is the highly fibrillation-prone protein FapC. FapC fibrillation may be inhibited by small molecules such as plant polyphenols, which are already known to inhibit formation of pathogenic amyloid, but the mechanism and biological impact of inhibition is unclear. Here, we elucidate how polyphenols modify the self-assembly of functional amyloid, with particular focus on epigallocatechin gallate (EGCG), penta-O-galloyl-β-d-glucose (PGG), baicalein, oleuropein, and procyanidin B2. We find EGCG and PGG to be the best inhibitors. These compounds inhibit amyloid formation by redirecting the aggregation of FapC monomers into oligomeric species, which according to small-angle X-ray scattering (SAXS) measurements organize into core-shell complexes of short axis diameters 25–26 nm consisting of ~7 monomers. Using peptide arrays, we identify EGCG-binding sites in FapC’s linker regions, C and N-terminal parts, and high amyloidogenic sequences located in the R2 and R3 repeats. We correlate our biophysical observations to biological impact by demonstrating that the extent of amyloid inhibition by the different inhibitors correlated with their ability to reduce biofilm, highlighting the potential of anti-amyloid polyphenols as therapeutic agents against biofilm infections.

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Chainoglou, Eirini, and Dimitra Hadjipavlou-Litina. "Curcumin in Health and Diseases: Alzheimer’s Disease and Curcumin Analogues, Derivatives, and Hybrids." International Journal of Molecular Sciences 21, no. 6 (March 13, 2020): 1975. http://dx.doi.org/10.3390/ijms21061975.

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Worldwide, Alzheimer’s disease (AD) is the most common neurodegenerative multifactorial disease influencing the elderly population. Nowadays, several medications, among them curcumin, are used in the treatment of AD. Curcumin, which is the principal component of Curcuma longa, has shown favorable effects forsignificantly preventing or treating AD. During the last decade, the scientific community has focused their research on the optimization of therapeutic properties and on the improvement of pharmacokinetic properties of curcumin. This review summarizes bibliographical data from 2009 to 2019 on curcumin analogues, derivatives, and hybrids, as well as their therapeutic, preventic, and diagnostic applications in AD. Recent advances in the field have revealed that the phenolic hydroxyl group could contribute to the anti-amyloidogenic activity. Phenyl methoxy groups seem to contribute to the suppression of amyloid-β peptide (Aβ42) and to the suppression of amyloid precursor protein (APP) andhydrophobic interactions have also revealed a growing role. Furthermore, flexible moieties, at the linker, are crucial for the inhibition of Aβ aggregation. The inhibitory activity of derivatives is increased with the expansion of the aromatic rings. The promising role of curcumin-based compounds in diagnostic imaging is highlighted. The keto-enol tautomerism seems to be a novel modification for the design of amyloid-binding agents. Molecular docking results, (Q)SAR, as well as in vitro and in vivo tests highlight the structures and chemical moieties that are correlated with specific activity. As a result, the knowledge gained from the existing research should lead to the design and synthesis ofinnovative and multitargetedcurcumin analogues, derivatives, or curcumin hybrids, which would be very useful drug and tools in medicine for both diagnosis and treatment of AD.

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Journal articles on the topic 'Anti-amyloidogenic compounds'

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