Isolation of Novel Compounds from Lepidium sativum Seeds and Evaluation of Their Potential Anti-tumor Activity.

Four undescribed compounds including a pair of enantiomers of a dihydroarylnaphthalene lignan [(±)-1], an arylnaphthalene lignan (2), and an indoleacetic acid ester (3), together with four known compounds (4－7), were isolated from the seeds of Lepidium sativum. Their structures were identified by HRMS and NMR spectroscopic data, and the absolute configuration of these compounds were assigned by ECD data in combination with quantum chemical calculations. Compound (-)-1 had weak inhibitory activity against HeLa cell line with an IC50 value of 60.23 ± 3.51 µM, and compound (+)-1 presented moderate inhibitory effect against HeLa cell line with an IC50 value of 19.99 ± 1.00 µM (IC50 value of the positive control was 0.40 ±0.02 µM).

Chemical profiling and mechanisms of Agarikon pill in a rat model of cigarette smoke-induced chronic obstructive pulmonary disease.

Background and aim: Agarikon pill (AGKP), a traditional Chinese herbal formula, and has been used for chronic obstructive pulmonary disease (COPD) treatment clinically. However, the active components and exact pharmacological mechanisms are still unclear. We aimed to investigate the therapeutic effects and mechanisms of AGKP on COPD and identify the chemical constituents and active compounds. Experimental procedure: The chemical components of AGKP were identified by ultrahigh-performance liquid chromatography coupled with quadrupole/orbitrap high-resolution mass spectrometry (UHPLC-Q-Orbitrap-HRMS). Network pharmacology analysis was performed to uncover the potential mechanism of AGKP. The efficiencies and mechanisms of AGKP were further confirmed in COPD animal models. Results and conclusion: Ninety compounds from AGKP, such as flavonoids, triterpenoids, saponins, anthracenes, derivatives, phenyl propionic acid, and other organic acids, were identified in our study. AGKP improved lung function and pathological changes in COPD model rats. Additionally, inflammatory cell infiltration and proinflammatory cytokine levels were markedly reduced in COPD rats administered AGKP. Network pharmacology analysis showed that the inflammatory response is the crucial mechanism by which AGKP exerts therapeutic effects on COPD rats. WB and PCR data indicated that AGKP attenuated the inflammatory response in COPD model rats. AGKP reduces the pulmonary inflammatory response through the PI3K/AKT and MAPK TLR/NF-κB signaling pathways and exerts therapeutic effects via inhibition of inflammation and mucus hypersecretion on COPD model rats.

Polyphenol-Rich Extract of Apocynum venetum L. Leaves Protects Human Retinal Pigment Epithelial Cells against High Glucose-Induced Damage through Polyol Pathway and Autophagy.

Diabetic retinopathy (DR) is a specific microvascular problem of diabetes, which is mainly caused by hyperglycemia and may lead to rapid vision loss. Dietary polyphenols have been reported to decrease the risk of DR. Apocynum venetum L. leaves are rich in polyphenolic compounds and are popular worldwide for their health benefits as a national tea drink. Building on previous findings of antioxidant activity and aldose reductase inhibition of A. venetum, this study investigated the chemical composition of polyphenol-rich extract of A. venetum leaves (AVL) and its protective mechanism on ARPE-19 cells in hyperglycemia. Ninety-three compounds were identified from AVL by LC-MS/MS, including sixty-eight flavonoids, twenty-one organic acids, and four coumarins. AVL regulated the polyol pathway by decreasing the expression of aldose reductase and the content of sorbitol, enhancing the Na+K+-ATPase activity, and weakening intracellular oxidative stress effectively; it also could regulate the expression of autophagy-related proteins via the AMPK/mTOR/ULK1 signaling pathway to maintain intracellular homeostasis. AVL could restore the polyol pathway, inhibit oxidative stress, and maintain intracellular autophagy to protect cellular morphology and improve DR. The study reveals the phytochemical composition and protective mechanisms of AVL against DR, which could be developed as a functional food and/or candidate pharmaceutical, aiming for retina protection in diabetic retinopathy.

Rupestonic Acid Derivative YZH-106 Promotes Lysosomal Degradation of HBV L- and M-HBsAg via Direct Interaction with PreS2 Domain.

Hepatitis B surface antigen (HBsAg) is not only the biomarker of hepatitis B virus (HBV) infection and expression activity in hepatocytes, but it also contributes to viral specific T cell exhaustion and HBV persistent infection. Therefore, anti-HBV therapies targeting HBsAg to achieve HBsAg loss are key approaches for an HBV functional cure. In this study, we found that YZH-106, a rupestonic acid derivative, inhibited HBsAg secretion and viral replication. Further investigation demonstrated that YZH-106 promoted the lysosomal degradation of viral L- and M-HBs proteins. A mechanistic study using Biacore and docking analysis revealed that YZH-106 bound directly to the PreS2 domain of L- and M-HBsAg, thereby blocking their entry into the endoplasmic reticulum (ER) and promoting their degradation in cytoplasm. Our work thereby provides the basis for the design of a novel compound therapy to target HBsAg against HBV infection.

Unveiling the anti-vitiligo, anti-inflammatory, and antitumor activities of sesquiterpene coumarins isolated from Ferula kuhistanica.

Six undescribed bicyclic sesquiterpene coumarins, kuhistanin A, ferukrin isovalerate, 9'ß,12'α - ferukrin isovalerate, (17'E)- 9'α, 12'ß - isomarcandin, (17'Z)- 9'α, 12'ß - isomarcandin and (17'E) - isomarcandin, together with nine known ones were isolated from the roots of Ferula kuhistanica Korovin. The structures of them were elucidated using NMR and HRESIMS data analysis. The relative configurations of the isolates were confirmed by NOE correlations and NMR calculation. The absolute configurations of them were confirmed by X-ray diffraction analysis and ECD calculation. Anti-vitiligo, anti-inflammatory and cytotoxicity of the isolates were tested. Acetyl feselol, feselol, ferusingensine I and farnesiferol A significantly increased the melanin content at the concentration of 10 µM. (17'E) - 9'α, 12'ß - isomarcandin exhibited strong cytotoxicity against HT-29 cell line with IC50 values of 8.94 ± 0.47 µM, and (17'E) - isomarcandin demonstrated strong cytotoxicity against Hela, A549 and HT-29 cell lines with IC50 values of 5.29 ± 0.25, 4.01 ± 0.20, and 4.16 ± 0.21 µM, respectively. This study concluded that, isolated compounds from F. kuhistanica demonstrated strong bioactivity towards anti-vitiligo and cytotoxicity and active compounds are suggested as anti-vitiligo and cytotoxicity agent for future drug development.

Guaianolide sesquiterpenes and their activity from Artemisia mongolica.

Seven undescribed sesquiterpenes, including three dimeric guaianolide sesquiterpenes artemongolides G-I (1-3) and four sesquiterpene lactones artemanomalide D-G (16-19), along with seventeen known compounds isoabsinthin (4), absinthin (5), 11-eptabsinthin (6), 11, 11'-bis-epiabsinthin (7), 10', 11'- epiabsinthin (8), anabsinthin (9), isoanabsinthin (10), absinthin D (11), anabsin (12), caruifolin D (13), gnapholide (14), caruifolin C (15), 1ß(R),10ß(S)-dihydroxy-3-oxo-11ß (S)H-4,11(13)-guaien-6α(S),12-olide (20), 1α,6α,8α-trihydroxy-5α,7ßH-guaia-3,10(14),11(13)-trien-12-oic acid (21), 1α,6α,8α-trihydroxy-5α,7ßH-guaia-3,9,11(13)-trien-12-oic acid (22), argyinolide J (23), artabsinolide A (24) were isolated from the plant Artemisia mongolica. The structures were determined by interpreting NMR, HRESIMS and ECD data. The X-ray crystal structure of 4, 7 and 8 were reported for the first time. In the anti-vitiligo activity test, compounds 2, 7, 12, 23 and 24 demonstrated activity in promoting melanogenesis at a concentration of 50 µM in B16 cells, with 8-methoxypsoralan (8-MOP) as a positive control. Further research on the mechanism revealed that artemongolides H (2) enhance the expression of MITF and TRPs by upregulating p-Akt and p-GSK-3ß, leading to an increase in ß-catenin content in the cell cytoplasm. Subsequently, ß-catenin translocates into the nucleus, resulting in melanogenesis. The results supported the regulation of melanogenesis by artemongolide H (2) through the Akt/GSK3ß/ß-catenin signaling pathway. The anti-inflammatory results demonstrated that compounds 4, 5, 6, 9 and 14 can inhibit the upregulation of IL-6 mRNA and CCL2 mRNA expression. Compound 12 specifically inhibited the upregulation of IL-6 mRNA expression. These compounds exhibited significant anti-inflammatory activities. The activity results revealed that these sesquiterpene compounds have the potential to become lead compounds for the treatment of vitiligo and inflammatory diseases.

New coumarin from the roots of Prangos pabularia growing wild in Tajikistan.

Dichloromethane and butanol extracts of the roots of Prangos pabularia were analyzed to determine chemical constituents and biological activity. The new coumarin 1, yuganin B ((5-(((2S,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-2-((2-oxo-2H-chromen-7-yl)oxy)tetrahydro-2H-pyran-3-yl)oxy)-3,4-dihydroxytetrahydrofuran-3-yl)methyl 4-hydroxy-3-methoxybenzoate) along with three phenolic and twenty-four known coumarins were isolated from the roots of Prangos pabularia, and the structures of these isolated compounds were elucidated by UV, HR-ESIMS, and 1 D and 2 D NMR spectroscopy. In addition, the anti-melanogenic effect of several of the isolated individual compounds and their inhibitory effect on B16 cells were evaluated. Isolating and testing compounds may proof to be useful in the treatment of hyperpigmentation and as a skin-whitening agent in the cosmetics industry.

Repurposing of Rutan showed effective treatment for COVID-19 disease.

Previously, from the tannic sumac plant (Rhus coriaria), we developed the Rutan 25 mg oral drug tablets with antiviral activity against influenza A and B viruses, adenoviruses, paramyxoviruses, herpes virus, and cytomegalovirus. Here, our re-purposing study demonstrated that Rutan at 25, 50, and 100 mg/kg provided a very effective and safe treatment for COVID-19 infection, simultaneously inhibiting two vital enzyme systems of the SARS-CoV-2 virus: 3C-like proteinase (3CLpro) and RNA-dependent RNA polymerase (RdRp). There was no drug accumulation in experimental animals' organs and tissues. A clinical study demonstrated a statistically significant decrease in the C-reactive protein and a reduction of the viremia period. In patients receiving Rutan 25 mg (children) and 100 mg (adults), the frequency of post-COVID-19 manifestations was significantly less than in the control groups not treated with Rutan tablets. Rutan, having antiviral activity, can provide safe treatment and prevention of COVID-19 in adults and children. Clinical Trial Registration: ClinicalTrials.gov, ID NCT05862883.

Synthesis and Characterisation of Chickpea Peptides-Zinc Chelates Having ACE2 Inhibitory Activity.

Tryptic hydrolysates of protein fractions obtained by the Osborne method from chickpea (Cicer arietinum L.) seeds interacted with zinc ions and the results of chelation were monitored by the Energy Dispersive X-Ray (EDX) technique. The glutelin hydrolysate (GluHyd) reacted with zinc ions and depicted a relatively higher zinc content. For this reason, the zinc complex of the glutelin hydrolysate (GluHyd-Zn) was studied deeper, and 11 peptides were identified in its more zinc-containing second fraction obtained after gel filtration. The peptide HKERVQLHIIPTAVGK showed a relatively higher chelating capacity (57.86 ± 2.14%). According to the result of the ICP-OS analysis, 1 mg peptide could chelate 381.61 ± 133.39 µg zinc, and the molar ratio of peptide-zinc was about 1:4. Spectral methods proved that side chain and C-termini carboxyl groups of the peptide mostly were involved in chelation and N atoms of amino side chains, imidazole group of histidine, and N-termini at some extents were occupied by the metal ions. Modeling of zinc-peptide interaction was done using Molecular Operating Environment (MOE) software. The results of the docking correlate with the experimental data.ACE2 inhibitory effect of HKERVQLHIIPTAVGK-Zn complex (IC50 = 1.5 mg/mL) was better than that of HKERVQLHIIPTAVGK (IC50 = 2.2 mg/mL).

Toad venom bufadienolides and bufotoxins: An updated review.

Bufadienolides, naturally found in toad venoms having steroid-like structures, reveal antiproliferative effects at low doses. However, their application as anticancer drugs is strongly prevented by their Na+ /K+ -ATPase binding activities. Although several kinds of research were dedicated to moderating their Na+ /K+ -ATPase binding activity, still deeper fundamental knowledge is required to bring these findings into medical practice. In this work, we reviewed data related to anticancer activity of bufadienolides such as bufalin, arenobufagin, bufotalin, gamabufotalin, cinobufotalin, and cinobufagin and their derivatives. Bufotoxins, derivatives of bufadienolides containing polar molecules mainly belonging to argininyl residues, are reviewed as well. The established structures of bufotoxins have been compiled into a one-page figure to review their structures. We also highlighted advances in the structure-modification of the structure of compounds in this class. Drug delivery approaches to target these compounds to tumor cells were discussed in one section. The issues related to extraction, identification, and quantification are separated into another section.

Comprehensive Study of Components and Antimicrobial Properties of Essential Oil Extracted from Carum carvi L. Seeds.

Carum carvi L. belongs to the Apiaceae family and is widely used as a vegetable, food spice, preservative, and herbal medicine. This study investigated the impact of essential oil extracted from Carum carvi L. seeds (CEO) on methicillin-resistant Staphylococcus aureus (MRSA) and its possible action mechanism. The dominant chemical components of CEO determined by GC-MS were carvone and limonene. It was observed that CEO had a considerable inhibitory effect against the growth of planktonic bacteria and biofilm in MRSA cells. Untargeted metabolomics based on GC-Q-TOF-MS was used to analyze the possible mechanism of the interaction of MRSA with CEO. It was determined that there were 63 different metabolites based on fold change values greater than 1.5 or less than 1.5, p < 0.05, VIP > 1, which demonstrated amino acid metabolism in MRSA was significantly affected by CEO. In conclusion, CEO has a potent antimicrobial property and has promising potential for use in food and drugs.

Quercetin 3-O-(6″-O-E-caffeoyl)-ß-D-glucopyranoside, a Flavonoid Compound, Promotes Melanogenesis through the Upregulation of MAPKs and Akt/GSK3ß/ß-Catenin Signaling Pathways.

Quercetin 3-O-(6″-O-E-caffeoyl)-ß-D-glucopyranoside is a flavonoid compound produced by various plants with reported antiprotozoal potential against E. histolytica and G. lamblia; however, its effects on skin pigment regulation have not been studied in detail. In this investigation, we discovered that quercetin 3-O-(6″-O-E-caffeoyl)-D-glucopyranoside (coded as CC7) demonstrated a more increased melanogenesis effect in B16 cells. CC7 exhibited no cytotoxicity or effective stimulating melanin content or intracellular tyrosinase activity. This melanogenic-promoting effect was accompanied by activated expression levels of microphthalmia-associated transcription factor (MITF), a key melanogenic regulatory factor, melanogenic enzymes, and tyrosinase (TYR) and tyrosinase-related protein-1 (TRP-1) and 2 (TRP-2) in the CC7-treated cells. Mechanistically, we found that CC7 exerted melanogenic effects by upregulating the phosphorylation of stress-regulated protein kinase (p38) and c-Jun N-terminal kinase (JNK). Moreover, the CC7 upregulation of phosphor-protein kinase B (Akt) and Glycogen synthase kinase-3 beta (GSK-3ß) increased the content of ß-catenin in the cell cytoplasm, and subsequently, it translocated into the nucleus, resulting in melanogenesis. Specific inhibitors of P38, JNK, and Akt validated that CC7 promotes melanin synthesis and tyrosinase activity by regulating the GSK3ß/ß-catenin signaling pathways. Our results support that the CC7 regulation of melanogenesis involves MAPKs and Akt/GSK3ß/ß-catenin signaling pathways.

Pyrrolizidine alkaloids from Jacobaea vulgaris Gaertn and theoretical studies on intramolecular interactions.

Two undescribed pyrrolizidine alkaloids, 13-dehydrosenkirkine (1) and chloromethylretrorsine (2), along with three known analogues, onetine (3), retrorsine (4), and usaramine N-oxide (5), were isolated from Jacobaea vulgaris Gaertn. The structures of the undescribed compounds were elucidated by extensive spectrometric and spectroscopic techniques, including HRESIMS, NMR, calculated 13C-NMR DP4+ analysis and comparison with experimental and calculated ECD spectra. The undescribed compounds were evaluated for their antitumour activity against HT29, HeLa, and HepG2 cells. In addition, the intramolecular interactions and quadrupolar couplings were revealed by investigating the geometrical and electronic properties of three typical otonecine-type PAs in DFT theory.

Bufadienolides from the Bufo viridis toad venom exert cytotoxic effects on cancer cells by inducing cell apoptosis and cell cycle arrest.

A series of bufadienolides were isolated from the Bufo viridis toad venom, and their cytotoxic activities against three human cancer cell lines (HeLa, HT-29, MCF7) and a non-cancer cell line (L-O2) were explored using the MTT assay in vitro. All of nine compounds exhibited cytotoxic activities against the three cancer cell lines, with compound D4 exhibiting potent cytotoxic activity against HeLa cells and was better than positive control. Herein, we further evaluated the effect of compound D4 on HeLa cells. The results revealed that compound D4 has excellent cytotoxic effect on HeLa cells by inhibiting cell colony formation and migration, promoting cell apoptosis, increasing reactive oxygen species (ROS) levels and arresting of HeLa cells in S and G2/M phases. These findings encourage further work on the chemistry and bioactivity of the Bufo viridis toad venom.

Monoterpenoid derivatives from Hyssopus cuspidatus Boriss. and their bioactivities.

Six undescribed monoterpenoids, together with twelve known compounds were isolated and identified from Hyssopus cuspidatus Boriss. Their structures were established by spectroscopic analysis, and the absolute configurations were established by ECD calculations and single-crystal X-ray diffraction crystallography. The isolated compounds were tested for their anti-inflammatory, antibacterial and antitumor activities. Most of the compounds showed potent anti-inflammatory activities. Among them, 3ß-hydroxy-7,8-dihydro-ß-ionone (8), oleanolic acid (17) and acetylpleamolic acid (18) showed strong anti-inflammatory activity against IL-6 and TNF-α in lipopolysaccharide (LPS) stimulated RAW 264.7 cells. Several compounds showed moderate inhibitory activities against Staphylococcus aureus, Candida albicans, and Escherichia coli. And (4S)-p-menth-l-ene-7,8-diol 8-O-ß-D-glucopyranoside (16) showed antitumor activities against MCF-8 and HT-29 cell lines with IC50 values of 93.39 ± 3.69 and 71.89 ± 2.94 µM, respectively. Oleanolic acid (17) showed moderate antitumor activity against HT-29 cell lines with an IC50 value of 52.62 ± 1.63 µM. In this study, the discovery of anti-inflammatory, antibacterial and antitumor components from H. cuspidatus could benefit further development and utilization of this plant.

Chemical components of Aconitum barbatum var. puberulum and their cytotoxic and antibacterial activities.

Nineteen compounds, including seventeen alkaloids O-methylarmepavine (1), (S)-6-methoxy-1-(4-methoxybenzyl)-2-methyl -1,2,3,4-tetrahydroisoquinolin-7-ol (2), (+)-(IR,laR)-lahydroxymagnocurarin (3), (6R,6aS,P)-(+)-corydine (4), (+)-N-methyllaurotetanine (5), magnoflorine (6), 3-hydroxy-1,2-dimethoxy-5-methyl-5H-dibenzoindol-4-one (7), imperialine (8), crispine B (9), (S)-1-(3-methoxyphenyl)-N-methylpropan-2-amine (10), methyl 2- (acetamino)benzoate (11), 2-carboxyoxanilic acid methylester (12), 4-[2-(methoxycarbonyl) anilino]-4-oxobutanoic acid methyl ester (13), N-methylcorydaldine (14), N-methyl-6,7- dimethoxyisoquinolone (15), (5S,6R,7S,8R)-5-amino-(2Z,4Z)-1,2,3-trihybuta-2,4-dienyloxypentane- 6,7,8,9-tetraol (16), nicotinic acid (17), and two megastigmane type compounds, S(+)- dehydrovomifoliol (18) and megastigmane (19), were isolated from the Aconitum barbatum var. puberulum Ledeb. Compounds 1-3 and 5-19 were isolated from this plant for the first time, of which compound 11 was isolated from natural source for the first time. Cytotoxicity evaluation revealed that compound 5 displayed mild cytotoxicity against the Hela cell lines (IC50 13.69 ± 0.036 µM). Antibacterial activity evaluation revealed that compounds 1 and 6 showed strong antibacterial activity against the Gram-positive bacterium, S. aureus.

Two new polyamine alkaloids from the Bufo viridis toad venom.

Two new polyamine alkaloids (bufonines A-B), together with four known alkaloids, bufotenidine (3), bufotenine (4), 1-(ß-d-ribofuranosyl)-lH-1,2,4-triazone (5) and proline (6) were isolated from the Bufo viridis toad venom. Their structures were identified by UV, HR-ESI-MS, NMR spectral analyses, and comparison of theoretical and experimental ECD data. All compounds were tested in vitro cytotoxicity against three human cancer cell lines (HT-29, A549 and Hela). None of the compounds showed cytotoxicity towards all tested cell lines. To the best of our knowledge, this is the first report of alkaloid components from Bufo viridis toad venom.

A new macrocyclic spermidine alkaloid from the aerial part of Hyssopus cuspidatus Boriss.

Hyssopus cuspidatus Boriss. grows in Xinjiang, China. A new macrocyclic spermidine alkaloid, namely hyssopusizine (1), along with sixteen known compounds were isolated and identified from the aerial parts of H. cuspidatus. Their structures were elucidated on the basis of spectroscopic data and comparison with the literature. Among them, fifteen compounds were isolated from H. cuspidatus for the first time. The absolute configuration of compound 1 was established by comparing the calculated and experimental ECD spectroscopic data. All isolated compounds were tested for their antioxidant and antimicrobial activities. Among them, compound 10 exhibited significant effects on ABTS free-radical scavenging activity with an IC50 value of 15.6 µM. Compounds 5-7 exhibited potent antioxidant activities against ABTS and DPPH. Most compounds exhibited moderate antimicrobial activities. Hyssopusizine (1) is the first macrocyclic spermidine alkaloid discovered from the Hyssopus genus.

Bioassay-guided preparation of antioxidant, anti-inflammatory active fraction from crabapples (Malus prunifolia (Willd.) Borkh.).

The aim of current study was to optimize the extraction process and purification of main components (MC) to obtain high antioxidant, anti-inflammatory effective fractions from crabapple (Malus prunifolia (Willd.) Borkh.). The effects of three variables including ethanol concentration A1, solid-liquid ratio A2, extraction temperature A3 were investigated and optimized by response surface methodology (RSM) coupled with Box-Behnken design (BBD). The adsorption/desorption characteristics of MC on the five types of macroporous resins were investigated. According to batch adsorption test, HPD-300 resins were selected for kinetics. The adsorption mechanism showed that the process was appropriate by pseudo-second-order kinetics model, and purification parameters of MC were optimized through adsorption/desorption experiments with the column packed by HPD-300 resin. The effective fractions were obviously superior to other fractions according to DPPH, ABTS, COX-2 and 15-LOX radical scavenging. This work implies that the purified active fraction with high contents of antioxidants and anti-inflammatory compounds from crabapple might be potential source for natural products and food industries.

Design, combinatorial synthesis and cytotoxic activity of 2-substituted furo[2,3-d]pyrimidinone and pyrrolo[2,3-d]pyrimidinone library.

A facile protocol was developed for the combinatorial synthesis of furo[2,3-d]pyrimidinone and pyrrolo[2,3-d]pyrimidinone library via a one-pot condensation, from 2-amino furans/pyrroles. Herein reported process required a similar reaction condition, providing mild access to two diverse series of natural product-like heterocycles. Both furo[2,3-d]pyrimidinones and pyrrolo[2,3-d]pyrimidinones were evaluated in vitro against a panel of human cancer cell lines including against human cancer HeLa (cervical), MCF-7 (breast) and HT-29 (colon) cell lines. Derivative 12n ((2-(4-chlorophenyl)-1-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrrolo[2,3-d]pyrimidin-4(1H)-one)) showed high activity (IC50 = 6.55 ± 0.31 µM) against the HeLa cell line. These products could be subjected to a various modification and therefore represent important skeletons for the anticancer drug discovery.