Molecular networking-guided investigation of the secondary metabolome of four Morus species and their in vivo neuroprotective potential for the mitigation of Alzheimer's disease.

Alzheimer's Disease (AD) is a fatal age-related neurodegenerative condition with a multifactorial etiology contributing to 70% of dementia globally. The search for a multi-target agent to hit different targets involved in the pathogenesis of AD is crucial. In the present study, the neuroprotective effects of four Morus extracts were assessed in LPS-induced AD in mice. Among the studied species, M. macroura exhibited a profound effect on alleviating the loss of cognitive function, improved the learning ability, restored the acetylcholine esterase (AChE) levels to normal, and significantly reduced the tumor necrosis factor alpha (TNF-α) brain content in LPS-treated mice. To investigate the secondary metabolome of the studied Morus species, ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-HRMS/MS), aided with feature-based molecular networking, was employed. Among the annotated features, aryl benzofurans and prenylated flavonoids were suggested as being responsible for the observed neuroprotective effect. Furthermore, some of the detected metabolites were proposed as new natural products such as moranoline di-O-hexoside (1), isomers of trimethoxy-dihydrochalcone-O-dihexoside (59 & 76), (hydroxy-dimethoxyphenyl)butenone-O-hexoside (82), and O-methylpreglabridin-O-sulphate (105). In conclusion, our findings advocate the potential usage of M. macroura leaves for the management of AD, yet after considering further clinical trials.

Feature-Based Molecular Networking for the Exploration of the Metabolome Diversity of Common Egyptian Centaurea Species in Relation to Their Cytotoxic Activity.

Centaurea is a genus compromising over 250 herbaceous flowering species and is used traditionally to treat several ailments. Among the Egyptian Centaurea species, C. lipii was reported to be cytotoxic against multidrug-resistant cancer cells. In this context, we aimed to explore the metabolome of C. lipii and compare it to other members of the genus in pursuance of identifying its bioactive principles. An LC-MS/MS analysis approach synchronized with feature-based molecular networks was adopted to offer a holistic overview of the metabolome diversity of the Egyptian Centaurea species. The studied plants included C. alexandrina, C. calcitrapa, C. eryngioides, C. glomerata, C. lipii, C. pallescens, C. pumilio, and C. scoparia. Their constitutive metabolome showed diverse chemical classes such as cinnamic acids, sesquiterpene lactones, flavonoids, and lignans. Linking the recorded metabolome to the previously reported cytotoxicity identified sesquiterpene lactones as the major contributors to this activity. To confirm our findings, bioassay-guided fractionation of C. lipii was adopted and led to the isolation of the sesquiterpene lactone cynaropicrin with an IC50 of 1.817 µM against the CCRF-CEM leukemia cell line. The adopted methodology highlighted the uniqueness of the constitutive metabolome of C. lipii and determined the sesquiterpene lactones to be the responsible cytotoxic metabolites.

Plant cell cultures: An enzymatic tool for polyphenolic and flavonoid transformations.

BACKGROUND: In the pharmaceutical sector, tissue culture techniques for large-scale production of natural chemicals can be a less expensive alternative to large-scale synthesis. Although recent biotransformation research have used plant cell cultures to target a wide range of bioactive compounds, more compiled information and synopses are needed to better understand metabolic pathways and improve biotransformation efficiencies. PURPOSE: This report reviews the biochemical transformation of phenolic natural products by plant cell cultures in order to identify potential novel biotechnological approaches for ensuring more homogeneous and stable phenolic production year-round under controlled environmental conditions. METHODS: Articles on the use of plant cell culture for polyphenolic and flavonoid transformations (1988 - 2021) were retrieved from SciFinder, PubMed, Scopus, and Web of Science through electronic and manual search in English. Following that, the authors chose the required papers based on the criteria they defined. The following keywords were used for the online search: biotransformation, Plant cell cultures, flavonoids, phenolics, and pharmaceutical products. RESULTS: The initial search found a total of 96 articles. However, only 70 of them were selected as they met the inclusion criteria defined by the authors. The analysis of these studies revealed that plant tissue culture is applicable for the large-scale production of plant secondary metabolites including the phenolics, which have high therapeutic value. CONCLUSION: Plant tissue cultures could be employed as an efficient technique for producing secondary metabolites including phenolics. Phenolics possess a wide range of therapeutic benefits, as anti-oxidant, anti-cancer, and anti-inflammatory properties. Callus culture, suspension cultures, transformation, and other procedures have been used to improve the synthesis of phenolics. Their production on a large scale is now achievable. More breakthroughs will lead to newer insights and, without a doubt, to a new era of phenolics-based pharmacological agents for the treatment of a variety of infectious and degenerative disorders.

Anti-Viral and Immunomodulatory Properties of Propolis: Chemical Diversity, Pharmacological Properties, Preclinical and Clinical Applications, and In Silico Potential against SARS-CoV-2.

Propolis, a resin produced by honeybees, has long been used as a dietary supplement and folk remedy, and more recent preclinical investigations have demonstrated a large spectrum of potential therapeutic bioactivities, including antioxidant, antibacterial, anti-inflammatory, neuroprotective, immunomodulatory, anticancer, and antiviral properties. As an antiviral agent, propolis and various constituents have shown promising preclinical efficacy against adenoviruses, influenza viruses, respiratory tract viruses, herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), human immunodeficiency virus (HIV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Over 300 chemical components have been identified in propolis, including terpenes, flavonoids, and phenolic acids, with the specific constituent profile varying widely according to geographic origin and regional flora. Propolis and its constituents have demonstrated potential efficacy against SARS-CoV-2 by modulating multiple pathogenic and antiviral pathways. Molecular docking studies have demonstrated high binding affinities of propolis derivatives to multiple SARS-CoV-2 proteins, including 3C-like protease (3CLpro), papain-like protease (PLpro), RNA-dependent RNA polymerase (RdRp), the receptor-binding domain (RBD) of the spike protein (S-protein), and helicase (NSP13), as well as to the viral target angiotensin-converting enzyme 2 (ACE2). Among these compounds, retusapurpurin A has shown high affinity to 3CLpro (ΔG = -9.4 kcal/mol), RdRp (-7.5), RBD (-7.2), NSP13 (-9.4), and ACE2 (-10.4) and potent inhibition of viral entry by forming hydrogen bonds with amino acid residues within viral and human target proteins. In addition, propolis-derived baccharin demonstrated even higher binding affinity towards PLpro (-8.2 kcal/mol). Measures of drug-likeness parameters, including metabolism, distribution, absorption, excretion, and toxicity (ADMET) characteristics, also support the potential of propolis as an effective agent to combat COVID-19.

Kaemgalangol A: Unusual seco-isopimarane diterpenoid from aromatic ginger Kaempferia galanga.

A new unusual seco-isopimarane, kaemgalangol A (1) and 12 usual analogs (2-13) were isolated from the rhizomes of Kaempferia galanga (Family: Zingiberaceae). KaemgalangolA (1) represented a rarely isolated 9,10-seco-isopimarane skeleton. The chemical structures of the isolated compounds were mainlyinvestigated by spectroscopic techniques such as 1D, 2D NMR, and HRMS. The absolute configuration of 1-3 was studied by X-ray diffraction analysis as well as experimental and TDDFT-calculated electronic circular dichroism. Among the isolated diterpenoids, 5, 6 and 9 exhibited cytotoxic activity against HeLa (IC50 75.1, 74.2 and 76.5 µM, respectively) and HSC-2 (IC50 69.9, 53.3 and 58.2 µM, respectively) cancer cells.