Special Issue-"Natural Products That Might Change Society".

This Special Issue of Molecules gathers eight research papers and two review articles covering the isolation, identification, and biological activity of selected natural products, with the aim of discovering potential candidates that could change society and improve human health [...].

Unveiling the Antiviral Efficacy of Forskolin: A Multifaceted In Vitro and In Silico Approach.

Coleus forskohlii (Willd.) Briq. is a medicinal herb of the Lamiaceae family. It is native to India and widely present in the tropical and sub-tropical regions of Egypt, China, Ethiopia, and Pakistan. The roots of C. forskohlii are edible, rich with pharmaceutically bioactive compounds, and traditionally reported to treat a variety of diseases, including inflammation, respiratory disorders, obesity, and viral ailments. Notably, the emergence of viral diseases is expected to quickly spread; consequently, these data impose a need for various approaches to develop broad active therapeutics for utilization in the management of future viral infectious outbreaks. In this study, the naturally occurring labdane diterpenoid derivative, Forskolin, was obtained from Coleus forskohlii. Additionally, we evaluated the antiviral potential of Forskolin towards three viruses, namely the herpes simplex viruses 1 and 2 (HSV-1 and HSV-2), hepatitis A virus (HAV), and coxsackievirus B4 (COX-B4). We observed that Forskolin displayed antiviral activity against HAV, COX-B4, HSV-1, and HSV-2 with IC50 values of 62.9, 73.1, 99.0, and 106.0 µg/mL, respectively. Furthermore, we explored the Forskolin's potential antiviral target using PharmMapper, a pharmacophore-based virtual screening platform. Forskolin's modeled structure was analyzed to identify potential protein targets linked to its antiviral activity, with results ranked based on Fit scores. Cathepsin L (PDB ID: 3BC3) emerged as a top-scoring hit, prompting further exploration through molecular docking and MD simulations. Our analysis revealed that Forskolin's binding mode within Cathepsin L's active site, characterized by stable hydrogen bonding and hydrophobic interactions, mirrors that of a co-crystallized inhibitor. These findings, supported by consistent RMSD profiles and similar binding free energies, suggest Forskolin's potential in inhibiting Cathepsin L, highlighting its promise as an antiviral agent.

Anti-phototoxicity and anti-melanogenesis activities of eelgrass Zostera marina and its phenolic constituents.

The eelgrass Zostera marina L. has several economic roles, from its earlier usage in the insulation industry to protecting the earth from global warming. In this study, we aimed to discover the cosmetic potential of Z. marina. A methanolic extract of Z. marina showed anti-phototoxicity and anti-melanogenesis activity with an IC50 of 17.5 µM, followed by a phytochemical analysis of its phenolic constituents. Ten compounds (1-10) were isolated by several chromatographic techniques and identified by means of nuclear magnetic resonance spectroscopy (NMR) as well as high-resolution mass spectrometry (HR/MS). The identified compounds are caffeic acid (1), 3,4-dihydroxybenzoic acid (protocatechuic acid) (2), luteolin (3), diosmetin (4), 4-coumaroyl-4'-hydroxyl phenyllactic acid (5), rosmarinic acid (6), caffeoyl-4'-hydroxy-phenyllactic acid (isorinic acid) (7), apigenin 7-O-ß-D-glucopyranoside (8), luteolin 7-O-ß-D-glucopyranoside (9), and luteolin 7-sulfate (10). This is the first report to identify compounds 5 and 7 from the family Zosteraceae. The isolated compounds were assessed for their anti-aging abilities and were found to exhibit good anti-phototoxicity and anti-melanogenesis activities by increasing the viability of UVB-irradiated HaCaT cells by 6% to 34% and by inhibiting melanin synthesis in B16 melanoma cells by 44% to 65%.

Cytotoxicity evaluation of phytochemicals from stingless bee (Tetragonula biroi) propolis.

Three prenylated flavonoids (1-3) were isolated from Tetragonula biroi propolis. The structures of the isolated compounds were characterized by NMR, IR, and UV spectroscopic and mass spectrometric analyses. The cytotoxicity activity of the crude extracts, fractions and the isolated compounds were established against four cell lines such as Caco-2, HeLa, MCF-7, and OVK-18. Among the tested compounds, compound 1 showed cytotoxicity activity against MCF-7 cell lines, whereas compound 2 showed good activity against Caco-2 and OVK-18 cell lines with IC50 values of 14.73 and 14.44, respectively. Moreover, compound 3 exhibited strong activity against OVK-18 cell lines. These findings contribute to the phytochemical understanding of the T. biroi propolis, and their cytotoxicity effects for future pharmaceutical purposes.

Vanilla pompona Leaves and Stems as New Sources of Bioactive Compounds: The Therapeutic Potential for Skin Senescence.

A large variety of natural plants are widely produced and utilised because of their remarkable pharmacological effects. In this study, two phenolic glycosides were isolated for the first time from Vanilla pompona Schiede (Orchidaceae) from Kyushu, Japan: bis [4-(ß-D - O-glucopyranosyloxy)-benzyl] (S)-2-isopropylmalate (1: ) and bis 4-[ß-D-O-glucopyranosyloxy)-benzyl]-(2R,3S)-2-isopropyl tartrate (2: ). We have discovered that the crude extract of V. pompona leaves and stems and its two phenolic glycosides (compounds 1:  - 2: ) are highly effective in reversing skin senescence. V. pompona and compounds 1:  - 2: were found to promote the synthesis of collagen, hyaluronic acid, and elastin in skin fibroblasts in a normal skin cell model; in a replicative senescence model, V. pompona and compounds 1:  - 2: significantly reduced the ageing phenotype in skin fibroblasts. These compounds also demonstrated a significant protective effect in a UV-induced photo-senescence model; the possible mechanisms of this effect were investigated in this study. To the best of our knowledge, this study is the first to develop V. pompona leaves and stems as new sources of bioactive compounds and to examine their therapeutic potential for skin senescence. The development potential of V. pompona leaves and stems for use in the cosmetics, cosmeceutical, and pharmaceutical industries remains to be investigated.

Deacylated Derivative of Hericenone C Treated by Lipase Shows Enhanced Neuroprotective Properties Compared to Its Parent Compound.

Hericium erinaceus, a mushroom species commonly known as Yamabushitake in Japan, is known to have a stimulatory effect on neurotrophic factors, such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). Hericenone C, a meroterpenoid with palmitic acid as the fatty acid side chain, is reported to be one such stimulant. However, according to the structure of the compound, the fatty acid side chain seems highly susceptible to lipase decomposition, under in vivo metabolic conditions. To study this phenomenon, hericenone C from the ethanol extract of the fruiting body was subjected to lipase enzyme treatment and observed for changes in the chemical structure. The compound formed after the lipase enzyme digestion was isolated and identified using LC-QTOF-MS combined with 1H-NMR analysis. It was found to be a derivative of hericenone C without its fatty acid side chain and was named deacylhericenone. Interestingly, a comparative investigation of the neuroprotective properties of hericenone C and deacylhericenone showed that the BDNF mRNA expression in human astrocytoma cells (1321N1) and the protection against H2O2-induced oxidative stress was considerably higher in the case of deacylhericenone. These findings suggest that the stronger bioactive form of the hericenone C compound is in fact deacylhericenone.

Phytochemical, ethnomedicinal uses and pharmacological profile of Juncus decipiens (Buchenau) Nakai (common rush).

Juncus decipiens is a member of the Juncaceae family and has culinary, medicinal, and decorative properties. It is also used in traditional Chinese Medicines for many years that promotes diuresis for strangury and clears out heart fire. This species has recently gained medicinal attention as a source of phenanthrenes, phenolic compounds, glycerides, flavonoids, and cycloartane triterpenes. This plant was also shown to be active, and researchers explored its antioxidant, anti-inflammatory, antialgal, antibacterial, and psychological behaviour-boosting properties. Preliminary research suggests that this species might be used for skin protection and brain disorders if proper clinical trials are conducted. The ethnomedicinal, phytochemistry, biological potencies, dangers, and scopes of Juncus decipiens have been examined in this respect.

New benzaldehyde derivatives from the fruiting bodies of Hericium erinaceus with cytotoxic activity.

Four new natural compounds named hericenone O (1), hericenone P (2), hericenone Q (3), and hericenone R (4), two of them were reported synthetically (3-4), together with eleven known compounds were isolated from the fruiting bodies of Hericium erinaceus. The chemical structures of the isolated compounds were elucidated by using NMR analysis and mass spectrometry, as well as comparisons with the reported data in the literature. The bioactivity evaluation revealed that hericenone Q showed significant cytotoxic activity against Hep-G2 with IC50 values of 23.89 µM, and against HCT-116 with IC50 values of 65.64 µM.

Antioxidant, anti-inflammatory and anti-acne activities of stingless bee (Tetragonula biroi) propolis.

We collected stingless bee propolis Tetragonula biroi in order to find materials for medicine and cosmetics applications from tropical rainforest resources. Even though this bee has some biological functions including a cancer cell line, hair growth promotion, asthma remedy, α-glucosidase enzyme inhibition, and antiviral action, the investigation on anti-acne has not been reported yet. This study was to focus on propolis Tetragonula biroi extracts and leads us to isolate active compounds for antioxidant, anti-inflammatory, and anti-acne. We used methanol to obtain the extract from this propolis and assayed it with antioxidants, anti-inflammation, and anti-acne. The extract showed strong activity in antioxidants by DPPH radical scavenging activity (82.31% in 6.25 µg/ml). Via a column chromatography and Reveleris PREP purification system, we isolated 3'-O-methyldiplacone, nymphaeol A, and 5,7,3',4'-tetrahydroxy-6-geranyl flavonol. These compounds showed potential biological activity with IC50 for antioxidant 6.33, 15.49, 17.32 µM; and antiinflammatory 121.54, 121.20, 117.31 µM. The isolated compounds showed anti-acne properties with properties 0.00, 14.11, and 13.78 mm for the inhibition zone (at a concentration of 1 µg/well), respectively. The results indicated that the propolis extract of Tetragonula biroi has the potential to be developed as a cosmetic agent; however, further work needs to be done to clarify its application.

Acetylcholinesterase inhibitors from Conocarpus lancifolius Engl. (Combretaceae).

Conocarpus lancifolius Engl. (Combretaceae) has several potential health-promoting effects, such as antidiabetic, antimicrobial, antioxidant, and cytotoxic effects. Phytochemical study of the ethyl acetate fraction of the leaf extract of this plant led to the isolation and identification of eight compounds viz., gallic acid (1), dihydromyricetin (2), myricetin (3), daucosterol (4), syringetin 3-O-ß-D-glucopyranoside (5), quercetin 3-O-ß-D-glucoside (6), gallocatechin (7), and (-)-epigallocatechin-3-O-gallate (8). Their acetylcholinesterase (AChE) in vitro and in silico inhibitory activities were evaluated. Daucosterol (4) showed the highest activity (IC50 0.316 µM) which was further validated by the superimposed docking orientation with the co-crystallized inhibitor, donepezil.

Oligomeric Proanthocyanidin Complex from Avocado Seed as A Promising α-glucosidase Inhibitor: Characteristics and Mechanisms.

Although considered an abundant source of agricultural by-products, avocado (Persea americana Mill.) seed, with several biological activities and bioactive components, might become a promising resource for phytopharmaceutical development. In this study, through bioassay-guided isolation of the main α-glucosidase inhibitors in avocado seed, we discovered the major α-glucosidase inhibitor to be avocado seed oligomeric proanthocyanidin complex (ASOPC). Thiolysis and UPLC-DAD-HRESIMS showed the presence of A- and B-type procyanidins, and B-type propelargonidin with (epi)afzelechin as extension unit. Mean degree of polymerization (mDP) of ASOPC was calculated as 7.3 ± 1. Furthermore, ASOPC appeared to be a strong, reversible, competitive inhibitor of α-glucosidase, with IC50 value of 0.1 µg/mL, which was significantly lower than Acarbose (IC50 = 75.6 µg/mL), indicated that ASOPC is a potential natural α-glucosidase inhibitor. These findings would contribute to the direction of utilizing avocado seed bioactive components with the possibility to be used as natural anti-diabetic agents.

New Butyroside D from Argan Press Cake Possess Anti-Melanogenesis Effect via MITF Downregulation in B16F10 and HEM Cells.

Hyperpigmentation is a skin condition where patches of skin become darker in color due to excess melanin production upon UV exposure leading to melasma, which are lentigines or post inflammatory hyperpigmentation that psychologically affecting a great number of people. The present study investigates the anti-melanogenic effect of Butyroside D and the underling mechanism. After the confirmation of the non-cytotoxic effect of Butyroside D on B16F10 cells, we proceeded with analyzing the impact of the treatment at low and high concentration (i.e., 0.2 µM and 2 µM) using gene profiling analysis and examined the differentiation in gene expression. Our results identify cyclic adenosine monophosphate (cAMP), Wnt/ß-catenin and Mitogen-Activated Protein Kinase (MAPK) signaling pathways to be downregulated upon treatment with Butyroside D. These pathways were targeted to further validate the effect of Butyroside D on membrane receptors melanocortin 1 receptor (MC1R) and receptor tyrosine kinase (c-Kit), related microphthalmia-associated transcription factor (MITF) and consequently tyrosinase (TYR), and tyrosine-related protein-1 (TYRP-1) that were all shown to be downregulated and, therefore, leading to the repression of melanin biosynthesis. Finally, the anti-melanogenic effect of Butyroside D was confirmed on human epidermal melanocytes (HEM) cells by inhibiting the activation of cAMP pathway generally mediated through α-melanocyte-stimulating hormone (α-MSH) and MC1R. Overall, this study suggests the potential applicability of this purified compound for the prevention of hyperpigmentation conditions.

Screening of Selected Stingless Bee Honey Varieties for ACE2-Spike Protein-Binding Inhibition Activity: A Potential Preventive Medicine Against SARS-Cov-2 Infection.

The broader objective of this study is to identify natural materials that might inhibit the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We have focused on stingless bee honey, which has a unique taste that is both sweet and sour and sometimes bitter. We screened 12 samples of honey from 11 species of stingless bees using an angiotensin-converting enzyme 2 (ACE2)-spike protein-binding assay and phytochemical analysis. Ten of the samples showed inhibition above 50% in this assay system. Most of the honey contained tannins, alkaloids, flavonoids, triterpenoids, carotenoids and carbohydrates. Our findings in this in vitro study showed that honey from stingless bees may have a potent effect against SARS-CoV-2 infection by inhibiting the ACE2-spike protein-binding.

Anti-diabetic activities of phenolic compounds of Alternaria sp., an endophyte isolated from the leaves of desert plants growing in Egypt.

Six phenolic compounds (talaroflavone (1), alternarienoic acid (2), altenuene (3), altenusin (4), alternariol (5), and alternariol-5-O-methyl ether (6)) were isolated from the solid rice culture media of Alternaria sp., an endophyte isolated from the fresh leaves of three desert plants, Lycium schweinfurthii Dammer (Solanaceae), Pancratium maritimum L. (Amaryllidaceae) and Cynanchum acutum L. (Apocynaceae). Compounds 2, 3, and 4 exhibited potent α-glucosidase and lipase inhibitory activities suggesting that they might act as naturally occurring anti-diabetic candidates. The same compounds showed potent binding in the active site for both enzymes with desirable pharmacokinetic properties. The isolated bioactive compounds were not exclusive to a certain host plant which reveals the dominant ecological standpoints for consequent optimization. This could lead to a cost-effective and reproducible yield applicable to commercial scale-up.

Potential of Hibiscus sabdariffa L. and Hibiscus Acid to Reverse Skin Aging.

Hibiscus sabdariffa L. (HS) has a long history of edible and medicinal uses. In this study, the biological activities of the extracts, chromatographic fractions, and hibiscus acid obtained from HS were evaluated for their potential bioactivities. Their ability to promote extracellular matrix synthesis in skin fibroblasts was evaluated by enzyme-linked immunosorbent assays. Their anti-inflammatory activity was evaluated in a nitric oxide (NO)-Griess inflammatory experiment. Furthermore, hibiscus acid was found to have a strong anti-oxidative stress effect through the establishment of an oxidative stress model induced by hydrogen peroxide. Several assays indicated that hibiscus acid treatment can effectively reduce extracellular adenosine triphosphate (ATP) secretion and carbonyl protein production, as well as maintain a high level of reduced/oxidized glutathione (GSH/GSSG) in skin cells, thus providing a possible mechanism by which hibiscus acid can counter antioxidative stress. The present study is the first to explore the reversing skin aging potential and the contributory component of HS.

Possible neuroprotective effects of amide alkaloids from Bassia indica and Agathophora alopecuroides: in vitro and in silico investigations.

In Alzheimer's disease (AD), the accumulation of amyloid-ß plaques, overactivity of MAO-B, and phosphorylated tau protein in the central nervous system result in neuroinflammation and cognitive impairments. Therefore, the multi-targeting of these therapeutic targets has emerged as a promising strategy for the development of AD treatments. The current study reports the isolation and identification of seven amide alkaloids, namely, N-trans-feruloyl-3-methoxytyramine (1), N-trans-feruloyltyramine (2), S-(-)-N-trans-feruloylnormetanephrine (3), S-(-)-N-trans-feruloyloctopamine (4), R-(+)-N-trans-feruloyloctopamine (5), N-trans-caffeoyltyramine (6), and S-(-)-3-(4-hydroxy-3-methoxyphenyl)-N-[2-(4-hydroxyphenyl)-methoxyethyl]acrylamide (7), from B. indica and A. alopecuroides, which are halophytic plants that have been reported to contain diverse phytochemicals. Additionally, the study explores the potential inhibition effects of the isolates on ß-secretase, monoamine oxidase enzymes, and phosphorylated tau protein, and their anti-aggregation effects on amyloid-ß fibrils. Compounds 1, 2, and 7 showed potent inhibitory activity against BACE1, MAO-B, and phosphorylated tau protein, as well as anti-aggregation activity against Aß-peptides. Additionally, compound 6 displayed promising inhibition activity against MAO-B enzyme. Further in-depth in silico and modeling analyses (i.e., docking, absolute binding free energy calculations, and molecular dynamics simulations) were carried out to reveal the binding mode of each active compound inside the corresponding enzyme (i.e., MAO-B and BACE1). The results indicate that B. indica, A. alopecuroides, and the isolated amide alkaloids might be useful in the development of lead compounds for the prevention of neurodegenerative diseases, especially AD.

Undescribed glucosylceramide, flavonol triglycoside, and oleanane saponin from the halophyte Agathophora alopecuroides: Promising candidates for stimulating ceramide synthesis.

The phytochemical study of Agathophora alopecuroides (Chenopodiaceae) led to the isolation of previously undescribed glucosylceramide, flavonol triglycoside, and triterpene oleanane saponin, together with eight known compounds. Their structures were elucidated using NMR analysis and HR-MS as (2'R, 12E) N-[(2S, 3S, 4R)-1-(ß-D-glucopyranosyloxy)-3,4-dihydroxy-octadec-2-yl]-2-hydroxytetracos-12-enamide, namely Agathophamide A; isorhamnetin-3-O-[ß-D-xylopyranosyl-(1→3)-α-L-rhamnopyranosyl-(1→6)]-ß-D-galactopyranoside, namely Agathophoroside A; and 3-O-[4'-(ß-D-xylopyranosyl)-ß-D-glucuronopyranosyl]-28-O-ß-D-glucopyranosyl-olean-12-en-3ß-ol-28-oic acid, namely Solysaponin A. We evaluated the effect of extract and isolates on ceramide levels via the up-regulated expression of the enzyme for ceramide synthesis in HaCaT keratinocytes. Interestingly, the study results revealed that the methanol extract of A. alopecuroides, together with some isolated compounds significantly up-regulated the mRNA expression of ceramide synthase-3 by 1.2- to 4.3-fold compared with the control in HaCaT cells. These findings indicate that the halophyte A. alopecuroides is a promising source of candidate compounds that can contribute to ceramide synthesis via the up-regulated expression levels of ceramide synthase-3 in the ceramide synthesis pathway.

Anti-Phototoxicity Effect of Phenolic Compounds from Acetone Extract of Entada phaseoloides Leaves via Activation of COX-2 and iNOS in Human Epidermal Keratinocytes.

The extract from Entada phaseoloides was employed as active ingredients of natural origin into cosmetic products, while the components analysis was barely reported. Using LC-DAD-MS/qTOF analysis, eleven compounds (1-11) were proposed or identified from acetone extract of E. phaseoloides leaves (AE). Among them, six phenolic compounds, protocatechuic acid (2), 4-hydroxybenzoic acid (3), luteolin-7-O-ß-d-glucoside (5), cirsimaritin (6), dihydrokaempferol (9), and apigenin (10), were isolated by various chromatographic techniques. Protocatechuic acid (2), epicatechin (4), and kaempferol (11) at a concentration 100 µM increased the HaCaT cells viability of the UVB-irradiated cell without any cytotoxicity effect and reduced the expression of COX-2 and iNOS inflammation gene. Moreover, compounds 2 and 4 could have potent effects on cell migration during wound closure. These results suggest that compounds 2, 4, and 11 from AE have anti-photoaging properties and could be employed in pharmaceutical and cosmeceutical products.

A new cycloartane triterpene and other phytoconstituents from the aerial parts of Euphorbia dendroides.

New cycloartane-type triterpene 23 R/S-3ß-hydroxycycloart-24-ene-23-methyl ether 1a,b (as an C-23 epimeric mixture), along with ten known compounds, including 1 steroid, 3 fatty acids and 6 triterpenoids were isolated from the aerial parts of Euphorbia dendroides L. (Euphorbiaceae). The known compounds (2-11) were identified using 1 D & 2 D-NMR spectra and by comparison with data reported in the literature as well as using GC-MS for the isolated fatty acids. The new compound 1 (a,b) was elucidated by comprehensive 1 D & 2 D NMR experiments as well as LR & HR-FAB-MS. In addition, the isolated cycloartane-type triterpenoids have been tested for in vitro cytotoxicity against different cell lines. The new compound 1 (a,b) exhibited good to weak selective cytotoxic activities against HepG2, Huh-7, KLM-1, 1321N1 and HeLa cell lines with IC50 values of 20.67 ± 0.72, 16.24 ± 0.53, 22.59 ± 0.94, 25.99 ± 0.31 and 40.50 ± 3.14 µM, respectively.