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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.

Metformin is one of the most prescribed agents in the treatment of type 2 diabetes. Its history goes back to the use of goat’s rue (Galega officinalis Linn., Fabaceae). G. officinalis is rich in galegine, a guanidine derivative with a blood glucose-lowering effect. Research based on the effects of guanidine rich on this traditional herbal medicine led to the development of metformin. Metformin continues to serve as a multi-target drug. Its benefits for treating/controlling several diseases were thoroughly discovered over time. These include health disorders such as cancers, obesity, periodontitis, cardiovascular, liver, skin, and renal disorders. Moreover, there is evidence to propose that metformin postpones the aging processes as well as modulates the microbiota to promote better health. So far, it is not fully understood, how metformin can accomplish such pleiotropic pharmacological and therapeutic effects. Metformin may decrease malignancy via suppressing the signal of insulin/IGF-1, avoiding the release of cytokines via NF-κB, and increasing the immune reaction to cancer cells. This chapter discusses the history of metformin discovery, chemistry, its role in diabetic patients, and proposed molecular mechanisms to shed more light on the diverse effects and its ability to target multiple signaling pathways.

Six phenolic compounds were isolated from the solid rice culture media of Alternaria sp., an endophyte isolated from the leaves of three desert plants, Lycium schweinfurthii Dammer (Solanaceae), Pancratium maritimum L. (Amaryllidaceae) and Cynanchum acutum L. (Apocynaceae).

Bassia indica and Agathophora alopecuroides could be utilized as potential sources of candidate compounds for the management of Alzheimer disease.

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.

Our effort to find new material for anti cancer from natural resources leads us to focus on stingless bee products such as honey, bee pollen, and propolis. The products were from seven stingless bees named Homotrigona fimbriata, Heterotrigona itama, Heterotrigona bakeri, Tetragonula sarawakensis, Tetragonula testaceitarsis, Tetragonula fuscobalteata, Tetragonula laeviceps. The stingless bee products were evaluated for their cytotoxicity effect on MCF-7, HeLa and Caco-2 cancer cell lines. This is the first time to be reported that the honey, ethanol extracts of bee pollen and propolis of H. fimbriata displayed more potent cytotoxicity than other stingless bee products. By chromatography and biological activity-guided fractionation, ethanol extract of propolis from H. fimbriata was fractionated and isolated its active compound named mangiferonic acid. Mangiferonic acid showed a cytotoxicity effect with IC50 values 96.76 µM in MCF-7, >110.04 µM in HeLa, and > 110.04 µM in Caco-2, respectively. These results exhibited the potential of ethanol extracts from propolis of H. fimbriata to be further developed for drug and experiments to verify the function are essential.

Natural products and traditional medicine products with known safety profiles are a promising source for the discovery of new drug leads. Natural products as sesame were reported to exhibit potential to protect from COVID-19 disease. In our study, the total methanolic extract of Sesamum indicum L. seeds (sesame) were led to isolation of seven known compounds, five lignan; sesamin 1, sesamolin 2, pinoresinol 3, hydroxymatairesinol 6, spicatolignan 7, together with two simple phenolic compounds; ferulic acid 4 and vanillic acid 5. All isolated compounds were evaluated in silico against three important SARS-CoV-2 protein targets; main protease (Mpro), papain-like protease (PLpro) and RNA-dependent RNA polymerase (RdRp) which possessed crucial role in replication and proliferation of the virus inside the human cell. The results revealed that compound 6 has the high affinity against the three main proteins, specially towards the SARS-CoV-2 Mpro that exceeded the currently used SARS-CoV-2 Mpro inhibitor darunavir as well as, exhibiting a similar binding energy at SARS CoV-2 PLpro when compared with the co-crystallized ligand. This activity continued to include the RdRp as it displayed a comparable docking score with remdesivir. Inferiorly, compounds 1 and 2 showed also similar triple inhibitory effect against the three main proteins while compound 7 exhibited a dual inhibitory effect against SARS CoV-2 PLPro and RdRp. Further molecular dynamic simulation experiments were performed to validate these docking experiments and to calculate their binding free energies (ΔGs). Compounds 1, 2, 3, 6, and 7 showed comparable binding stability inside the active site of each enzyme with ΔG values ranged from −4.9 to −8.8 kcal mol−1. All the compounds were investigated for their ADME and drug likeness properties, which showed acceptable ADME properties and obeying Lipinski's rule of five parameters. It can be concluded that the isolated compounds from sesame lignans could be an alternative source for the development of new natural leads against COVID-19.

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-β-D-glucopyranoside (5), quercetin 3-O-β-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.

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-β-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.

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/β-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.

Bassia indica (Wight) A.J. Scott, family Amaranthaceae, is a halophyte herb growing in extreme environments and hence deemed as a potential economic source of bioactive chemicals with functional properties. In our study, 25 compounds were obtained from B. indica. We aimed to assess the inhibitory effect of the methanol extract of B. indica and its isolated compounds on COX-2 and cytotoxicity activity against MCF-7, OVK-18, HepG2, and HCT116 tumor cells. Among the isolates, the triterpene oleanane saponin (23) displayed promising anti-inflammatory activity with an IC50 = 3.05 ± 0.15 μg/mL. Additionally, N- trans-feruloyl tyramine (11) exhibited significant cytotoxicity to OVK-18 with IC50 = 1.74 ± 1.56 μg/mL, whereas 6,7-dihydroxy coumarin (7) exhibited potent inhibition against the MCF-7 cell line with IC50 = 1.47 ± 0.22 μg/mL. Interestingly, compounds 1 and 25 exhibited remarkable cytotoxicity against HepG2 and HCT116 cells with IC50 < 0.1 μg/mL, while compounds 2, 4, 5, 6, and 9 exerted potent cytotoxicity against HepG2. Finally, B. indica is a potential source of candidate compounds for the development of anti-inflammatory and antitumor therapies.

The consumption of mushroom Ganoderma lingzhi (G. lingzhi) is believed to help people fight influenza. However, few scientific studies, particularly in animals, has addressed that. Here, a hot-water extract of G. lingzhi was orally or intranasally administered to mice infected with influenza A virus, following by a 21-day post-infection observation. An in vitro neuraminidase (NA) assay, with four subtypes of NA, was used to assess inhibition. The total content of triterpenoids and carbohydrates in the extract were determined with colorimetric assays. Results showed that intranasal administration of the extract reduced the severe weight loss in infected mice by 55.1%. Oral administration of the extract did not significantly interfere the virus infection. In addition, the extract strongly inhibited NA from influenza virus H1N1 and H5N1. These findings suggest that short-term oral consumption of hot-water extract of G. lingzhi has limited anti-influenza function, which also inform further research for its activity observed.

The present study aims to reveal the antibacterial potential of the wild mushrooms of Nepal. Despite the recognition of the medicinal potential of the natural resources in this country, a systematic study on the bioactivities of the wild mushrooms is still lacking. Therefore, in an attempt to fill this gap, ethanol extracts of 90 Nepalese wild mushroom samples were tested for antibacterial activity against Staphylococcus aureus and Propionibacterium acnes. Staphylococcus aureus was comparatively more susceptible with Inonotus clemensiae exhibiting the least minimum bactericidal concentration (MBC) of 100 μg/mL. The major compound in I. clemensiae was identified to be hispidin using high resolution liquid chromatography–electron spray ionization mass spectrometry (LC–ESI-MS) and nuclear magnetic resonance (NMR) analyses. Furthermore, the minimum inhibitory concentration (MIC) and MBC values of hispidin were determined to be 25 and 100 µg/mL for S. aureus and P. acnes, respectively. These findings show that the Nepalese wild mushrooms have the potential to be a novel addition to the functional ingredients industry due to their strong antibacterial potential.

In recent years, entomophagy has attracted increased attention, as it was recommended as a potential source of food by the Food and Agriculture Organization of the United Nations. In Japan, Oxya yezoensisis one of the most widely eaten insect species, but studies of its functionality as a food are limited. In this study, we reported the optimal characterization of the total phenolic compounds in methanolic extract (OME) and different fractions of OME. Additionally, the antioxidant and antiallergic activities of the OME fractions were evaluated. The results showed that the ethyl acetate-soluble fraction of OME has potential antioxidant activity, whereas the n-hexane-soluble fraction showed the strongest inhibition of β-hexosaminidase, which is one of the key factors in allergic reactions. It was concluded that phenolic compounds might contribute to the antioxidant activity while unsaturated fatty acids contribute to the antiallergy activity.

This article describes the biological activities of heartwood extracts from Yakushima native cedar (Cryptomeria japonica) and identifies their main active compounds. Black heartwood and red heartwood were each divided into two parts from the center (the pith) to outer heartwood (the cambium). The methanol extracts of those parts were screened for antioxidant and anti-lipase activities. The extract from the pith of the red heartwood showed the highest ORAC activity among the samples. Regarding anti-lipase activity, all the extracts showed relatively high activity (the IC50 value were 9.71–37.24 μg mL−1). In addition, four compounds were isolated and identified from the pith of red heartwood by NMR and MS analyses. Agatharesinol (3) and sequirin C (4) were thought to be the main active compounds responsible for the antioxidant and anti-lipase activities.

Propolis from 4 stingless bees ( Homotrigona apicalis, Wallacetrigona incisa, Tetragonula fuscobalteata, and Tetragonula fuscibasis) was investigated in the search for medicinal and cosmetic materials from tropical rainforest resources. Methanol extracts of the propolis were screened using antioxidant and antimelanogenesis assays (tyrosinase enzyme activity and melanin inhibitor in B16 melanoma). The extract of H. apicalis showed the strongest antioxidant activity, both in the 2,2-diphenyl-1-picrylhydrazyl and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) assays, with half-maximal inhibitory concentration values of 0.72 ± 0.01 (mg/mL) and 0.26 ± 0.00 (mg/mL), respectively. The H. apicalis extract also displayed the strongest inhibition of tyrosinase (53% at 100 µg/mL). In the B16 melanoma cell assay, the W. incisa extract showed the strongest inhibition of melanin (21%) and was less cytotoxic. The W. incisa extract was fractioned to isolate the compounds with biological activities. Two prenylated flavonoids were obtained, named broussoflavonol F and glyasperin A. Both showed potent antioxidant activities, as well as inhibiting melanin in B16 melanoma, but not tyrosinase activity. These results indicated the potential of methanol extract of W. incisa to be developed for cosmetic material, but further experiments are needed to verify the function.

An aliphatic ester of hydroxysalicylic acid (6), reported for the first time from a natural source in addition to five known compounds were isolated from the fermented Carica papaya L. preparation, a commercialized functional food. The known compounds were identified as 5-hydroxymethylfurfuraldehyde (1), trans-caffeic acid (2), butyl 4-hydroxybenzoate (butylparaben) (3), lycopene (4), benzyl isothiocyanate (5). Compounds 1 and 3 were reported for the first time from Papaya fruits through this study. The new compound showed a moderate antioxidant activity and a potent hair growth stimulating activity in vitro.

A new lanostane-type triterpenoid, lucidumol D (1) was isolated from the fruiting bodies of Ganoderma lingzhi. Its structure was elucidated on the basis of extensive 1D- and 2D-NMR studies as well as mass spectrometry. The cytotoxicity of lucidumol D against proliferation of several cancer cells were assayed by using MTT method and the obtained result suggested selective anti-proliferative and cytotoxic effects against MCF-7, HepG2, HeLa, Caco-2, and HCT-116. In comparison to lucidumol C (2) isolated previously by our group, the structure-activity relationship indicated that carbonyl function at C-11 is necessary to enhance the cytotoxicity.

In our effort to find materials for drugs and cosmetics from tropical natural resources, we screened 21 methanol extracts from 7 Macaranga trees species ( Macaranga bancana, Macaranga gigantea, Macaranga hulle ttii, Macaranga pruinosa, Macaranga tanarius, Macaranga trichocarpa, and Macaranga triloba) for antioxidant and antimelanogenesis. The antioxidant and melanogenesis (tyrosinase enzyme assay and melanin inhibitor in B16 melanoma) assays were used to determine the activities. The fractionation and the isolation of active compound were done by various chomatographic methods and the structure was determined by spectroscopic analysis data. We isolated a prenylated flavonoid, named Glyasperin A, from M. pruinosa leaf. This compound showed a potency as antioxidant and inhibited melanin in B16 melanoma but not tyrosinase activity. These results showed that the methanol leaf extracts of M. pruinosa could be developed for cosmetic applications especially as a skin whitening agent.

This study investigated in vitro the α-glucosidase inhibitory activity of resin from the Sakhalin fir tree ( Abies sachalinensis). The resin showed extremely high activity (IC50 of 17.3 µg/mL). We isolated 8 compounds from the resin and identified them. All of the compounds isolated from A. sachalinensis resin are reported for the first time in the present study. In an α-glucosidase inhibitory assay, 6 compounds—(holophyllane C (1), (−) -(24 E)-23-oxo-3,4- seco-9β H-lanosta-4(28),6,8(14),24-tetraen-3,26-dioic acid (2), abiesonic acid (3), (−) -(24 E)-23-oxo-3,4- seco-9β H-lanosta-4(28),7,24-triene-3,26-dioic acid (4), 3,4- seco-4(28),6,8(14),22Z,24-mariesapentaen-26,23-olide-3-oic acid (5), and (−) -abiesonic acid 3-methyl ester (6))—showed high activity (their IC50 values were 25.1, 20.9, 82.4, 20.5, 27.3, and 20.5 µg/mL, respectively). These compounds should contribute to the resin’s α-glucosidase inhibitory activity. From an industrial point of view, these findings provide new data to support that the resin of A. sachalinensis is a rich source of α-glucosidase inhibitors, which are highly valuable for their potential to be developed as functional health foods.

An adenine derivative, 9-β-D-glucopyranosyl adenine, reported for the first time from a natural source, in addition to nine known compounds were isolated from the seeds of Coix lacryma-jobi. Their structures were elucidated based on extensive spectroscopic and chemical studies. The isolated compounds and the ethanol extract have been assayed for melanin inhibition using B16-F10 melanoma cell line. The results of our study suggested the potential use of Coix lacryma-jobi seeds as a skin whitening agent and reveal the seeds to be a rich source of important phytochemicals with melanogenesis inhibitory activity. Among the isolated compounds, coixol (2) and 2-O-β-glucopyranosyl-7-methoxy-2H-1,4-benzoxazin-3(4H)-one (8) exhibited potent melanogenesis inhibitory activity with no obvious melanocytotoxicity. The rest of the compounds showed weak to moderate activity.

Rho-kinase enzymes are one of the most important targets recently identified in our bodies. Several lines of evidence indicate that these enzymes are involved in many diseases and cellular disorders. ROCK inhibitors may have clinical applications for cancer, hypertension, glaucoma, etc. Our study aims to identify the possible involvement of Rho-kinase inhibition to the multiple biological activities of adlay seeds and provide a rationale for their folkloric medicines. Hence, we evaluated Rho-kinase I and II inhibitory activity of the ethanol extract and 28 compounds derived from the seeds. A molecular docking assay was designed to estimate the binding affinity of the tested compounds with the target enzymes. The results of our study suggest a possible involvement of Rho-kinase inhibition to the multiple biological activities of the seeds. Furthermore, the results obtained with the tested compounds revealed some interesting skeletons as a scaffold for design and development of natural Rho-kinase inhibitors.

The degranulation of basophils stimulated by antigen is one of the allergic mechanisms of immediate hypersensitivity reactions. In a previous study, the β-hexosaminidase release of rat basophilic leukemia (RBL-2H3) cells stimulated by IgE cross-linking was specifically inhibited by ethanol extract of olive milled waste (OMW). OMW is a potential source of triterpenes, which show several biological activities. However, little is known about the effect of triterpenes in OMW on β-hexosaminidase release. Here we investigated anti-allergic triterpenes from the ethanol extract of OMW, and we discuss the structure–activity relationship. We subjected ethanol extract of OMW to activity-guided fractionation; this led to the isolation of five known triterpenes, i.e., maslinic acid (1), oleanolic acid (2), punicanolic acid (3), 2-O-acetylmaslinic acid (4), and epimaslinic acid (5) as well as one new triterpene, 11-oxo-maslinic acid (6). An anti-allergic assay revealed that 2-O-acetylmaslinic acid (4) and 11-oxo-maslinic acid (6) showed anti-allergic activity. Considering the structure–activity relationship of these triterpenes, it appears that the existence of a ketone group at C-11 or an acetyl group at C-2 would influence the anti-allergic activity.