Hericenone C attenuates the second phase of formalin-induced nociceptive behavior by suppressing the accumulation of CD11c-positive cells in the paw epidermis via phosphorylated P65.

Hericenone C is one of the most abundant secondary metabolites derived from Hericium erinaceus, under investigation for medicinal properties. Here, we report that Hericenone C inhibits the second phase of formalin-induced nociceptive behavior in mice. As the second phase is involved in inflammation, in a mechanistic analysis on cultured cells targeting NF-κB response element (NRE): luciferase (Luc)-expressing cells, lipopolysaccharide (LPS)-induced NRE::Luc luciferase activity was found to be significantly inhibited by Hericenone C. Phosphorylation of p65, which is involved in the inflammatory responses of the NF-κB signaling pathway, was also induced by LPS and significantly reduced by Hericenone C. Additionally, in mice, the number of CD11c-positive cells increased in the paw during the peak of the second phase of the formalin test, which decreased upon Hericenone C intake. Our findings confirm the possibility of Hericenone C as a novel therapeutic target for pain-associated inflammation.

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 [...].

Chemical composition and studying the possible neuroprotective effect of iridoids-rich fraction from Pentas lanceolata leaves using rotenone model of Parkinson's disease in mice.

Parkinsonism is an age-related neurodegenerative illness that affects motor coordination leading to loss of dopaminergic neurons. Many medications are used for the treatment of Parkinson's disease but are only symptomatic and have a limited effect on the progression of this ailment. Therefore, bioactive compounds which derived from plants have been examined for their ability to improve the neuronal damage and cell death happened in parkinsonian patients. In this study the iridoids-rich fraction isolated from Pentas lanceolata (PIRF) leaves was investigated for its phytoconstituents. Seven iridoids (1-7) and one flavonol diglycoside (8) were isolated, and their chemical structures were achieved by 1H and 13C nuclear magnetic resonance and ESI-MS spectral data. Compound 1 (6ß,7ß-epoxy-8-epi-splendoside) and 5 (gaertneroside) were isolated for the first time from Pentas genus as well as compound 8 (kaempferol-3-O-robinobioside). The current study aims to investigate the possible anti-parkinsonian effect of PIRF using a rotenone model of Parkinsonism in mice. Behavioural tests (wirehanging, stair and wooden-walking tests) were done to examine the motor coordination in mice after treatment. Biochemical and histopathological examinations for brain striatum in different groups were also evaluated. Results revealed that rotenone-treated mice had poor motor functions described by depletion of dopamine and Ach levels, a significant increase in proinflammatory cytokines, IL-1B, TNF-α and Mcp-1 and oxidative biomarkers with subsequent reduction in antioxidant mediators. Disorganization of striatum, degenerated neurocytes, slight vacuolation, shrunken neurons with pyknotic nuclei and apoptotic cells are displayed by histopathological examinations. Treatment with PIRF ameliorates the neurodegeneration-induced by rotenone in the brain of mice. The anti-parkinsonian effect of PIRF could be attributed to their bioactive constituents of iridoids.

Miniaturized ternary deep eutectic solvent-based matrix solid-phase dispersion: A green sample preparation method for the determination of chlorophenols in river sediment.

New ternary deep eutectic solvents were prepared and applied as efficient green dispersing solvents in miniaturized matrix solid-phase dispersion to extract chlorophenols from river sediments for the first time. High-performance liquid chromatography coupled with a photodiode array detector was used to analyze the target analytes. The significant factors affecting the extraction were optimized as follows: dispersant (100 mg), sample (100 mg), ternary eutectic solvents (150 µl), grinding for 1 min, 450 µl of acetonitrile as the elution solvent, and vortex mixing for 20 s. Under the optimal conditions, the method exhibited excellent linearity (correlation coefficient > 0.9980), low limits of detection between 1.039-2.478 µg/g, and extraction recoveries between 93.9% and 99.2%. Furthermore, the method demonstrated excellent precision in the intra- and inter-day analysis with a relative standard deviation below 6%. When compared to conventional extraction techniques, the miniaturized matrix solid-phase dispersion considerably reduced samples and solvent usag, offering important environmental benefits. The green profile of the method was assessed using the complementary green analytical procedure index tool confirming its eco-friendship. The technique was finally employed to evaluate sediment samples from three distinct locations along the Zuibaiji River, indicating its applicability for monitoring environmental samples.

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.

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.

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.

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.

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.

Conducting the RBD of SARS-CoV-2 Omicron Variant with Phytoconstituents from Euphorbia dendroides to Repudiate the Binding of Spike Glycoprotein Using Computational Molecular Search and Simulation Approach.

(1) Background: Natural constituents are still a preferred route for counteracting the outbreak of COVID-19. Essentially, flavonoids have been found to be among the most promising molecules identified as coronavirus inhibitors. Recently, a new SARS-CoV-2 B.1.1.529 variant has spread in many countries, which has raised awareness of the role of natural constituents in attempts to contribute to therapeutic protocols. (2) Methods: Using various chromatographic techniques, triterpenes (1-7), phenolics (8-11), and flavonoids (12-17) were isolated from Euphorbia dendroides and computationally screened against the receptor-binding domain (RBD) of the SARS-CoV-2 Omicron variant. As a first step, molecular docking calculations were performed for all investigated compounds. Promising compounds were subjected to molecular dynamics simulations (MD) for 200 ns, in addition to molecular mechanics Poisson-Boltzmann surface area calculations (MM/PBSA) to determine binding energy. (3) Results: MM/PBSA binding energy calculations showed that compound 14 (quercetin-3-O-ß-D-glucuronopyranoside) and compound 15 (quercetin-3-O-glucuronide 6″-O-methyl ester) exhibited strong inhibition of Omicron, with ΔGbinding of -41.0 and -32.4 kcal/mol, respectively. Finally, drug likeness evaluations based on Lipinski's rule of five also showed that the discovered compounds exhibited good oral bioavailability. (4) Conclusions: It is foreseeable that these results provide a novel intellectual contribution in light of the decreasing prevalence of SARS-CoV-2 B.1.1.529 and could be a good addition to the therapeutic protocol.

Anti-Obesity Evaluation of Averrhoa carambola L. Leaves and Assessment of Its Polyphenols as Potential α-Glucosidase Inhibitors.

Averrhoa carambola L. is reported for its anti-obese and anti-diabetic activities. The present study aimed to investigate its aqueous methanol leaf extract (CLL) in vivo anti-obese activity along with the isolation and identification of bioactive compounds and their in vitro α-glucosidase inhibition assessment. CLL improved all obesity complications and exhibited significant activity in an obese rat model. Fourteen compounds, including four flavone glycosides (1-4) and ten dihydrochalcone glycosides (5-12), were isolated and identified using spectroscopic techniques. New compounds identified in planta included (1) apigenin 6-C-(2-deoxy-ß-D-galactopyranoside)-7-O-ß-D-quinovopyranoside, (8) phloretin 3'-C-(2-O-(E)-cinnamoyl-3-O-ß-D-fucopyranosyl-4-O-acetyl)-ß-D-fucopyranosyl-6'-O-ß-D fucopyranosyl-(1/2)-α-L arabinofuranoside, (11a) phloretin3'-C-(2-O-(E)-p-coumaroyl-3-O-ß-D-fucosyl-4-O-acetyl)-ß-D-fucosyl-6'-O-(2-O-ß-D-fucosyl)-α-L-arabinofuranoside, (11b) phloretin3'-C-(2-O-(Z)-p-coumaroyl-3-O-ß-D-fucosyl-4-O-acetyl)-ß-D-fucosyl-6'-O-(2-O-ß-D-fucosyl)-α-L-arabinofuranoside. Carambolaside M (5), carambolaside Ia (6), carambolaside J (7), carambolaside I (9), carambolaside P (10a), carambolaside O (10b), and carambolaside Q (12), which are reported for the first time from A. carambola L. leaves, whereas luteolin 6-C-α-L-rhamnopyranosyl-(1-2)-ß-D-fucopyranoside (2), apigenin 6-C-ß-D-galactopyranoside (3), and apigenin 6-C-α-L-rhamnopyranosyl-(1-2)-ß-L-fucopyranoside (4) are isolated for the first time from Family. Oxalidaceae. In vitro α-glucosidase inhibitory activity revealed the potential efficacy of flavone glycosides, viz., 1, 2, 3, and 4 as antidiabetic agents. In contrast, dihydrochalcone glycosides (5-11) showed weak activity, except for compound 12, which showed relatively strong activity.

Melanin Synthesis Inhibition Activity of Compounds Isolated from Bamboo Shoot Skin (Phyllostachys pubescens).

This study targets the evaluation of melanin synthesis inhibition activity of the bamboo shoot skin as agro-waste. The total methanolic extract of bamboo peel extract was evaluated for its skin protective effects via measuring its melanin inhibitory activity and its suppression activity on the expression of tyrosinase mRNA levels. Results showed that bamboo peel extract has a good ability for the inhibition of melanin synthesis so further studies were performed for the isolation of its constituents. Twelve compounds have been isolated from the shoot skin of Phyllostachys pubescens. Their structures were elucidated based on extensive spectroscopic methods. The melanin inhibition potential of the isolates was tested with their collagen-production-promoting activity for the determination of active principles. Results showed that Betulinic acid, tachioside, and 1,2-dilinolenin significantly suppressed melanin production per cell compared to control. Triacontanol, tricin, and (+)-lyoniresinol 9'-O-glucoside also tended to decrease melanin production per cell. These findings indicated that the skin of bamboo shoots, a significant agricultural waste, is a useful natural source for further research on its potential for aging problems such hyperpigmentation and cognitive function impairment.

A Comprehensive In Silico Study of New Metabolites from Heteroxenia fuscescens with SARS-CoV-2 Inhibitory Activity.

Chemical investigation of the total extract of the Egyptian soft coral Heteroxenia fuscescens, led to the isolation of eight compounds, including two new metabolites, sesquiterpene fusceterpene A (1) and a sterol fuscesterol A (4), along with six known compounds. The structures of 1-8 were elucidated via intensive studies of their 1D, 2D-NMR, and HR-MS analyses, as well as a comparison of their spectral data with those mentioned in the literature. Subsequent comprehensive in-silico-based investigations against almost all viral proteins, including those of the new variants, e.g., Omicron, revealed the most probable target for these isolated compounds, which was found to be Mpro. Additionally, the dynamic modes of interaction of the putatively active compounds were highlighted, depending on 50-ns-long MDS. In conclusion, the structural information provided in the current investigation highlights the antiviral potential of H. fuscescens metabolites with 3ß,5α,6ß-trihydroxy steroids with different nuclei against SARS-CoV-2, including newly widespread variants.

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.

Deep Eutectic Solvents as Promising Green Solvents in Dispersive Liquid-Liquid Microextraction Based on Solidification of Floating Organic Droplet: Recent Applications, Challenges and Future Perspectives.

Deep eutectic solvents (DESs) have recently attracted attention as a promising green alternative to conventional hazardous solvents by virtue of their simple preparation, low cost, and biodegradability. Even though the application of DESs in analytical chemistry is still in its early stages, the number of publications on this topic is growing. Analytical procedures applying dispersive liquid-liquid microextraction based on the solidification of floating organic droplets (DLLME-SFOD) are among the more appealing approaches where DESs have been found to be applicable. Herein, we provide a summary of the articles that are concerned with the application of DESs in the DLLME-SFOD of target analytes from diverse samples to provide up-to-date knowledge in this area. In addition, the major variables influencing enrichment efficiency and the microextraction mechanism are fully investigated and explained. Finally, the challenges and future perspectives of applying DESs in DLLME-SFOD are thoroughly discussed and are critically analyzed.

Naturally Occurring Chromone Glycosides: Sources, Bioactivities, and Spectroscopic Features.

Chromone glycosides comprise an important group of secondary metabolites. They are widely distributed in plants and, to a lesser extent, in fungi and bacteria. Significant biological activities, including antiviral, anti-inflammatory, antitumor, antimicrobial, etc., have been discovered for chromone glycosides, suggesting their potential as drug leads. This review compiles 192 naturally occurring chromone glycosides along with their sources, classification, biological activities, and spectroscopic features. Detailed biosynthetic pathways and chemotaxonomic studies are also described. Extensive spectroscopic features for this class of compounds have been thoroughly discussed, and detailed 13C-NMR data of compounds 1-192, have been added, except for those that have no reported 13C-NMR data.

Ursolic acid treatment suppresses cuprizone-induced demyelination and motor dysfunction via upregulation of IGF-1.

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system, characterized by apoptotic death of mature oligodendrocytes, neuroinflammation, and motor dysfunction. A pentacyclic triterpenoid compound, ursolic acid (UA), has various pharmacological activities, such as anti-inflammatory, anti-oxidative, and anti-apoptotic effects. In the present study, we investigated the effects of UA on cuprizone-induced demyelination, which is a model of MS. Oral administration of UA effectively suppressed cuprizone-induced demyelination and motor dysfunction via the enhancement of IGF-1 levels in the demyelinating lesions. Our results suggest that UA might be therapeutically useful for demyelination in MS.

Association Between Serum ß-Alanine and Risk of Dementia.

We examined the association between serum concentrations of ß-alanine, a metabolite of carnosine and anserine, and the risk of dementia in a general population of elderly Japanese persons. In 2007, 1,475 residents of Hisayama, Japan, aged 60-79 years and without dementia were divided into 4 groups according to quartiles of serum ß-alanine concentrations (quartile 1, lowest; quartile 4, highest) and followed for a median of 5.3 years. During follow-up, 117 subjects developed all-cause dementia (Alzheimer in 77 cases and vascular dementia in 31). The risk of all-cause dementia decreased with increasing serum ß-alanine levels after adjustment for potential confounding factors (quartile 2, hazard ratio (HR) = 0.73 (95% confidence interval (CI): 0.45, 1.18); quartile 3, HR = 0.50 (95% CI: 0.28, 0.89); quartile 4, HR = 0.50 (95% CI: 0.27, 0.92); P = 0.01 for trend). A similar inverse association was observed for Alzheimer disease (quartile 2, HR = 0.78 (95% CI: 0.44, 1.38); quartile 3, HR = 0.53 (95% CI: 0.26, 1.06); quartile 4, HR = 0.53 (95% CI: 0.25, 1.10); P = 0.04 for trend) but not for vascular dementia. We found that higher serum ß-alanine levels were significantly associated with lower risks of all-cause dementia and Alzheimer disease. Because serum ß-alanine levels reflect intakes of carnosine/anserine, higher intakes of carnosine/anserine might be beneficial for the prevention of dementia.

Design, Synthesis and Anticancer Evaluation of New Substituted Thiophene-Quinoline Derivatives.

A series of new isoxazolyl, triazolyl and phenyl based 3-thiophen-2-yl-quinoline derivatives were synthesized adopting click chemistry approach. In addition, the synthesis of new useful synthon, (2-chloroquinolin-3-yl) (thiophen-2-yl) methanol, is reported. The obtained compounds were characterized by spectral data analysis and evaluated for their anticancer activity. All the derivatives were subjected to in vitro MTT cytotoxicity screening assay against a panel of four different human cancer cell lines, liver (HepG-2), colon (HCT-116), human cervical cancer (HeLa) and breast (MCF-7). Out of a library of 17 compounds, two compounds have been identified as potent and selective cytotoxic agents against HeLa and MCF-7 cell lines. SAR studies for such hybridized analogues were investigated and phenyl derivatives were proved to be more potent than isoxazole and triazole derivatives. Furthermore, the promising compounds were selected for in vitro inhibition of EGFR-TK and Topo II enzymes. Also, they were subjected to cell cycle arrest analysis and apoptosis assay on MCF-7 cells. Our recent finding highlights these thiophene-quinoline analogues as a promising class of compounds for further studies concerning new anticancer therapies.