Bioassay-Guided Isolation of New Flavonoid Glycosides from Platanus × acerifolia Leaves and Their Staphylococcus aureus Inhibitory Effects.

Despite the rapid advances in drug R&D, there is still a huge need for antibacterial medications, specifically for the methicillin-resistant Staphylococcus aureus (MRSA). Inspired by the research where a viable class of MRSA inhibitors was found in the species Platanus occidentalis, a S. aureus inhibition screening-guided phytochemical reinvestigation on Platanus × acerifolia (London plane tree) leaves were performed with four flavonoid glycosides garnered, including two new compounds, quercetin-3-O-α-l-(2″-E-p-coumaroyl-3″-Z-p-coumaroyl)-rhamnopyranoside (E,Z-3'-hydroxyplatanoside, 1) and quercetin-3-O-α-l-(2″-Z-p-coumaroyl-3″-E-p-coumaroyl)-rhamnopyranoside (Z,E-3'-hydroxyplatanoside, 2). All of the isolates showed significant S. aureus ATCC 25904 inhibitory activity with MICs ranging from 4 to 64 µg/mL, suggesting the potential of discovering drug leads for the control of S. aureus from such a rich, urban landscaping plant in the Platanus genus.

ent-Abietane diterpenoids with anti-neuroinflammatory activity from the rare Chloranthaceae plant Chloranthus oldhamii.

Twelve new ent-abietane diterpenoids, chlorabietins A-L (), were isolated from the roots of Chloranthus oldhamii. Their structures and absolute configurations were determined by extensive spectroscopic analyses, X-ray diffraction, and experimental/calculated electronic circular dichroism (ECD) spectroscopy. Among the new isolates, chlorabietins D () and E () are the first two naturally occurring 8-spiro-fused 9,10-seco-ent-abietanes containing an unexpected cis-fused A/B ring system. Chlorabietin F () is a rare chinane-type diterpenoid featuring a hitherto unknown C-ring cleavage between C-13 and C-14, which might be derived from a common precursor of the above spiro-diterpenoid epimers and , and their biosynthetic relationships are briefly discussed. Meanwhile, chlorabietin I () is the first representative of the abietane-type diterpenoids possessing a tetrahydrofurano function bridging C-6 and C-19. Chlorabietins B (), C (), F (), and G () showed anti-neuroinflammatory effects by inhibiting the nitric oxide (NO) production in lipopolysaccharide (LPS)-activated murine BV-2 microglial cells, with IC50 values ranging from 16.4 to 33.8 µM.

Biginkgosides A-I, Unexpected Minor Dimeric Flavonol Diglycosidic Truxinate and Truxillate Esters from Ginkgo biloba Leaves and Their Antineuroinflammatory and Neuroprotective Activities.

Nine unexpected new flavonol glycoside cyclodimers in the truxinate (1-7, biginkgosides A-G, respectively) or truxillate [biginkgosides H (8) and I (9)] forms were isolated as minor components from the extract of Ginkgo biloba leaves. The new dimers possess an unusual cyclobutane ring formed by a [2+2]-cycloaddition between two symmetric (for compounds 1-5 and 7-9) or nonsymmetric (for 6) flavonol coumaroyl glucorhamnosides. A plausible biosynthetic pathway for these new compounds based on the frontier molecular orbital theory of cycloaddition reactions is briefly discussed. An antineuroinflammatory screening revealed that biginkgosides E (5) and H (8) inhibited nitric oxide production in lipopolysaccharide-activated BV-2 microglial cells, with IC50 values of 2.91 and 17.23 µM, respectively. Additionally, biginkgoside F (6) showed a significant neuroprotective effect (34.3% increase in cell viability at 1 µM) against Aß25-35-induced cell viability decrease in SH-SY5Y neuroblastoma cells.

Chlorabietols A-C, Phloroglucinol-Diterpene Adducts from the Chloranthaceae Plant Chloranthus oldhamii.

Three unprecedented phloroglucinol-diterpene adducts, chlorabietols A-C (1-3), were isolated from the roots of the rare Chloranthaceae plant Chloranthus oldhamii. They represent a new class of compounds, featuring an abietane-type diterpenoid coupled with different alkenyl phloroglucinol units by forming a 2,3-dihydrofuran ring. Their structures were elucidated by detailed spectroscopic analysis, molecular modeling studies, and electronic circular dichroism calculations. Compounds 1-3 showed inhibitory activity against protein tyrosine phosphatase 1B (PTP1B) with IC50 values of 12.6, 5.3, and 4.9 µM, respectively.

ent-Abietane-Type and Related Seco-/Nor-diterpenoids from the Rare Chloranthaceae Plant Chloranthus sessilifolius and Their Antineuroinflammatory Activities.

Fourteen new ent-abietane-type diterpenoids, sessilifols A-N (1-14), and three related new norditerpenoids (15-17) were isolated from Chloranthus sessilifolius. The absolute configurations were determined by single-crystal X-ray diffraction analysis, the modified Mosher's method, and/or the observed Cotton effects in their electronic circular dichroism spectra. Sessilifols A (1) and B (2) possess an uncommon five-membered C-ring rearranged by oxidative cleavage of the C-13/C-14 bond in abieta-7,13-diene followed by the formation of a new C-C bond between C-12 and C-14. Sessilifol C (3) is a rare 7,8-seco-9-spiro-fused ent-abietane, whereas sessilifol O (15) represents the first example of a naturally occurring 14-norabietane-type diterpenoid. Compounds 6 and 9 were found to have moderate antineuroinflammatory activities by inhibiting the nitric oxide production in lipopolysaccharide-stimulated murine BV-2 microglial cells, with IC50 values of 8.3 and 7.4 µM, respectively.

Leonurusoleanolides E-J, minor spirocyclic triterpenoids from Leonurus japonicus fruits.

Six new (leonurusoleanolides E-J, 1-6) and five known (7-11) nortriterpenoids were isolated and characterized from the dried fruits of Leonurus japonicus. They all contain a distinctive 19(18→17)-abeo-28-noroleanane-type spirocylclic skeleton with a trans or a cis acyl substituent at C-3 or C-23. Similar to the previously known leonurusoleanolides A/B (7/8) and C/D (9/10), compounds 1/2 and 3/4 were also found to exist as equilibrium mixtures of trans and cis isomers. The isolated pure compounds and mixtures were evaluated for their cytotoxicity against a small panel of human cancer cell lines (BGC-823 and KE-97 gastric carcinoma, Huh-7 hepatocarcinoma, Jurkat T cell lymphoblasts, and MCF-7 breast adenocarcinoma) using the CellTiter-Glo luminescent cell viability assay method. Among them, (2α,3ß,17R*,18ß)-3-O-(trans-caffeoyl)-19(18→17)-abeo-28-norolean-12-ene-2,18,23-triol (leonurusoleanolide J, 6) showed the most potent cytotoxic activity, with IC50 values less than 10 µM.

Chloranthones A - D: minor and unprecedented dinor-eudesmenes from Chloranthus elatior.

Four novel naturally occurring diastereoisomers of dinor-eudesmenes, named chloranthones A-D (1-4, resp.), were isolated as minor components from the EtOH extract of the aerial parts of Chloranthus elatior. The unprecedented framework was established using extensive 2D-NMR techniques. Their absolute configurations were deduced from the observed Cotton effects in their circular dichroism (CD) spectra. A plausible biosynthetic pathway to the dinor-eudesmenes is proposed.

Staphylococcus aureus biofilm: Formulation, regulatory, and emerging natural products-derived therapeutics.

Staphylococcus aureus can readily form biofilm which enhances the drug-resistance, resulting in life-threatening infections involving different organs. Biofilm formation occurs due to a series of developmental events including bacterial adhesion, aggregation, biofilm maturation, and dispersion, which are controlled by multiple regulatory systems. Rapidly increasing research and development outcomes on natural products targeting S. aureus biofilm formation and/or regulation led to an emergent application of active phytochemicals and combinations. This review aimed at providing an in-depth understanding of biofilm formation and regulation mechanisms for S. aureus, outlining the most important antibiofilm strategies and potential targets of natural products, and summarizing the latest progress in combating S. aureus biofilm with plant-derived natural products. These findings provided further evidence for novel antibiofilm drugs research and clinical therapies.

Terricoxanthones A-E, unprecedented dihydropyran-containing dimeric xanthones from the endophytic fungus Neurospora terricola HDF-Br-2 associated with the vulnerable conifer Pseudotsuga gaussenii.

An investigation on the secondary metabolites from a rice culture broth of the endophytic fungus Neurospora terricola HDF-Br-2 derived from the vulnerable conifer Pseudotsuga gaussenii led to the isolation and characterization of 34 structurally diverse polyketides (1-34). Seven of them are previously undescribed, including five unprecedented dihydropyran-containing (terricoxanthones A-E, 1-5, resp.) and one rare tetrahydrofuran-containing (terricoxanthone F, 6) dimeric xanthones. The structures were elucidated by spectroscopic methods and single-crystal X-ray diffraction analyses. Terricoxanthones each were obtained as a racemic mixture. Their plausible biosynthetic relationships were briefly proposed. Compounds 6, aspergillusone A (8), and alatinone (27) displayed considerable inhibition against Candida albicans with MIC values of 8-16 µg/mL. 4-Hydroxyvertixanthone (12) and 27 exhibited significant inhibitory activities against Staphylococcus aureus, with MIC values of 4-8 µg/mL. Furthermore, compounds 8 and 27 could disrupt biofilm of S. aureus and C. albicans at 128 µg/mL. The findings not only extend the skeletons of xanthone dimers and contribute to the diversity of metabolites of endophytes associated with the endangered Chinese conifer P. gaussenii, but could further reveal the important role of protecting plant species diversity in support of chemical diversity and potential sources of new therapeutics.

Carbopol 940-based hydrogels loading synergistic combination of quercetin and luteolin from the herb Euphorbia humifusa to promote Staphylococcus aureus infected wound healing.

With the increasing prevalence of Staphylococcus aureus infections, rapid emergence of drug resistance and the slow healing of infected wounds, developing an efficient antibiotic-free multifunctional wound dressing for inhibiting S. aureus and simultaneously facilitating wound healing have become a huge challenge. Due to their excellent biocompatibility and biodegradability, some carbopol hydrogels based on plant extracts or purified compounds have already been applied in wound healing treatment. In China, Euphorbia humifusa Willd. (EuH) has been traditionally used as a medicine and food homologous medicine for the treatment of furuncles and carbuncles mainly caused by S. aureus infection. In an earlier study, EuH-originated flavonoids quercetin (QU) and luteolin (LU) could serve as a potential source for anti-S. aureus drug discovery when used in synergy. However, the in vivo effects of QU and LU on S. aureus-infected wound healing are still unknown. In this study, we found a series of Carbopol 940-based hydrogels loading QU and LU in combination could disinfect S. aureus and also could promote wound healing. In the full-thickness skin defect mouse model infected with S. aureus, the wound contraction ratio, bacterial burden, skin hyperplasia and inflammation score, as well as collagen deposition and blood vessels were then investigated. The results indicate that the optimized QL2 [QU (32 µg mL-1)-LU (8 µg mL-1)] hydrogel with biocompatibility significantly promoted S. aureus-infected wound healing through anti-infection, anti-inflammation, collagen deposition, and angiogenesis, revealing it as a promising alternative for infected wound repair.

Quality problems in clinical practice guidelines and guideline appraisal studies: Should we tolerate or eradicate?

BACKGROUND: Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument have been widely used by scholars around the world to assess the methodological quality of clinical practice guidelines (CPGs). We sought to identify items or domains that are commonly scored low in the assessment, and to systematically review the issues that emerged when evaluators used the AGREE II tool for guideline quality assessment. METHODS: A systematic search was conducted to identify articles published in medically relevant databases from 2022 to 2023 regarding the use of the AGREE II tool for the assessment of CPGs. We extracted six quality domains and overall quality assessment data of CPGs included in the literature, and processed the data using descriptive statistical analysis, difference analysis, regression analysis, and correlation analysis. A seven-point Likert scale was used to assess the reporting quality of the included articles. RESULTS: 151 relevant publications were identified, including 2081 guidelines published between 1990 and 2022. The results of the regression analysis showed a statistically significant impact of all domains on overall guideline quality (p < 0.001; R2 = 0.777). Domain 1, 2, 3, 4, and 6 scores differed significantly over time (p < 0.001) and were increasing. The score was good for Domain 4 (median 78.00 [IQR: 62.75-89.00]; mean 74.34 [SD 18.85]) and Domain 1 (median 78.00 [IQR: 61.00-90.00]; mean 73.57 [SD 21.12]). Scores were generic for Domain 6 (median 58.33 [IQR: 25.00-83.33]; mean 53.98 [SD 34.13]), Domain 2 (median 53.00 [IQR: 33.30-72.10]; mean 53.30 [SD 24.52]) and Domain 3 (median 51.00 [IQR: 26.02-73.00]; mean 50.44 [SD 27.19]). The score was poor for Domain 5 (median 36.20 [IQR: 20.20-58.32]; mean 40.21 [SD 24.90]). In addition, the quality evaluation results of the included articles showed that 33.1% were evaluated as low and 11.9% as very low. CONCLUSIONS: AGREE II tools have facilitated the development of methodological quality for CPGs. Although the quality of CPGs has improved over time, some general low-quality problems still exist, and solving these problems will be an effective way for developers to upgrade the quality of guidelines. In addition, addressing critical issues in the evaluation of guidelines to present high-quality study reports would be another way to guide guideline development.

Casuarinines A-J, lycodine-type alkaloids from Lycopodiastrum casuarinoides.

Ten new lycodine-type alkaloids, named casuarinines A-J (1-10), along with eight known analogues (11-18), were isolated from the whole plant of Lycopodiastrum casuarinoides . The new structures were established by spectroscopic methods and chemical transformations. Casuarinines A-D (1-4) and J (10) are common lycodine alkaloids possessing four connected six-membered rings, while tricyclic casuarinines E-H (5-8) are the piperidine ring cleavage products. In particular, casuarinine I (9) has an unprecedented five-membered tetrahydropyrrole ring instead of the piperidine ring. A plausible biosynthetic pathway to 9 is proposed. Among the compounds reported, casuarinine H (8) exhibited significant neuroprotective effect against hydrogen peroxide (H2O2)-induced neuronal cell damage in human neuroblastoma SH-SY5Y cells, while casuarinines C (3) and I (9) showed moderate inhibitory activity against acetylcholinesterase (AChE).

Antibacterial and antibiofilm efficacy of the preferred fractions and compounds from Euphorbia humifusa (herba euphorbiae humifusae) against Staphylococcus aureus.

ETHNOPHARMACOLOGICAL RELEVANCE: Euphorbia humifusa Willd., known as Di-Jin-Cao in Chinese, has long been utilized as a traditional herb for the treatment of furuncles and carbuncles mainly caused by Staphylococcus aureus infection. Despite extensive chemical and pharmacological studies reported previously for E. humifusa, the antibacterial and antibiofilm activities against S. aureus as well as the related mechanism of action (MoA) remain largely obscure. AIM OF THE STUDY: To investigate the antibacterial and antibiofilm activities of the preferred fractions and compounds from E. humifusa against S. aureus and assess the associated MoA. MATERIALS AND METHODS: The bioactive fractions and compounds were obtained from the 75% ethanol extract of E. humifusa (75%-EEEH) with the assistance of the related antibacterial and antibiofilm screening. Their antibacterial activities were determined using the broth microdilution method, whilst the inhibition of biofilm formation and the disruption of preformed biofilm were assessed by crystal violet staining and confocal laser scanning microscopy (CLSM). To achieve more effective therapies, the combinatory effects of different components were also studied. The biofilm metabolic activities of isolated compounds were evaluated by 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) reduction assay. The scanning electron microscopy (SEM) and quantitative real-time polymerase chain reaction (qRT-PCR) were employed to explore the antibiofilm mechanism. RESULTS: Fractions DJC06 and DJC07 collected from the ethyl acetate extract of the 75%-EEEH exhibited antibacterial activity (MIC = 256 µg/mL) against S. aureus and further separation of these two fractions led to the isolation and characterization of 22 compounds. Among the isolates, luteolin (LU), quercetin (QU), and kaempferol (KA) are the verified components associated with the antibacterial and antibiofilm activities by displaying individual or combinational MIC values of 8-128 µg/mL and 70.9-99.7% inhibition for biofilm formation. Importantly, QU and KA can work in synergy with LU to significantly enhance the efficacy via destroying cell integrity, increasing membrane permeability, and down-regulating the biofilm-related gene expression. CONCLUSIONS: The preferred fractions and compounds from E. humifusa exerted desired antibacterial and antibiofilm efficacy against S. aureus via a MoA involving cell morphology disruption and altered genes expression. The findings herein not only support its traditional use in the treatment of furuncles and carbuncles, but reveal E. humifusa is a potential source for producing promising antibiofilm alternatives against S. aureus and highlight the isolated components (LU, QU, KA) that can potentiate the efficacy when used in synergy.

Eucalyptals D and E, new cytotoxic phloroglucinols from the fruits of Eucalyptus globulus and assignment of absolute configuration.

Two new phloroglucinols, named eucalyptals D (1) and E (2), along with a related known compound (euglobal-In-3, 3) were isolated from the fruits of Eucalyptus globulus. Their structures were established on the basis of extensive spectroscopic studies, revealing that they share a common 3,5-diformyl-isopentyl phloroglucinol unit, but each is instead coupled to a different sesquiterpenoid skeleton (aromadendrene in 1, cadinene in 2, and a spirosesquiterpene in 3). Compound 1 possessed an unusual seven-membered D ring with an ether bridge between C-2 of the aromadendrene moiety and C-2' of the aromatic unit. The absolute configuration of the isolates was defined by the comparison of experimental and calculated electronic circular dichroism (ECD) spectra. Compounds 1-3 exhibited significant in vitro cytotoxicities against a few human cancer cell lines (Huh-7, Jurkat, BGC-823, and KE-97) using the CellTiter-Glo™ luminescent cell viability assay method.

Upregulation of miR-144-3p protects myocardial function from ischemia-reperfusion injury through inhibition of TMEM16A Ca2+-activated chloride channel.

Myocardial ischemia/reperfusion injury (MIRI) is a major cause of acute cardiac injury that is associated with high morbidity and mortality, and for which specific treatments are lacking. In this study, we investigated the underlying molecular mechanism of miR-144-3p in the pathological process of MIRI. A mouse I/R injury model and H9c2 cardiomyocyte hypoxia/reoxygenation (H/R) model were used to simulate the ischemia/reperfusion process in vivo and in vitro, respectively, and the relative expression and regulatory effect of miR-144-3p were determined. The target of miR-144-3p was also verified by a luciferase reporter assay. We found that miR-144-3p was significantly downregulated in mouse myocardium subjected to I/R and cardiomyocytes subjected to H/R. Upregulation of miR-144-3p significantly attenuated MIRI in vivo and in vitro. A Ca2+-activated chloride channel-TMEM16A (ANO1)-was identified as a target gene of miR-144-3p through bioinformatic analysis. The interaction between miR-144-3p and the 3'-untranslated region of ANO1 was confirmed with dual-luciferase reporter assay, RNA immunoprecipitation assay, real-time quantitative polymerase chain reaction, and western blot analysis. Moreover, by targeting ANO1, miR-144-3p inhibited the activation of NLRP3 inflammasome inflammatory signals in myocardial cells. Collectively, the present study provides a novel insight into the role of miR-144-3p in the inhibition of MIRI, suggesting that the miR-144-3p/ANO1 axis may be a putative therapeutic target in myocardial ischemia.

Advanced natural products chemistry research in China between 2015 and 2017.

In this review, we intensively focus on the advances in research of natural products (NPs) discovery carried out by domestic scholars in China from 2015 through 2017. In general, a total of 1811 publications (1479 in English and 332 in Chinese) were accumulated regarding newly isolated NPs from plants, microorganisms, and marine sources. As a result, 277 selected papers concerning naturally occurring compounds with extraordinary frameworks, origins, and promising activities were discussed in this review article, mainly organized according to their structural classes and novelties.

LC-MS guided isolation of sinodamines A and B: Chimonanthine-type alkaloids from the endangered ornamental plant Sinocalycanthus chinensis.

Two previously undescribed chimonanthine-type [sinodamines A and B] and five related known dimeric tryptamine-derived alkaloids were isolated and characterized from the leaves of the endangered ornamental plant Sinocalycanthus chinensis under the guidance of LC-MS detection and dereplication analyses, along with conventional isolation procedures. Their structures were established on the basis of spectroscopic methods and chemical transformations. Sinodamine A can be regarded as the naturally occurring N-oxide derivative of its pseudo-mesomer sinodamine B. An acid-catalyzed Meisenheimer rearrangement from sinodamine A to its oxazine-form with a final equilibrium of 1:2 was observed by monitoring their NMR spectra. (-)-Folicanthine showed significant cytotoxicity against human lung carcinoma A549 and colorectal carcinoma HT29 cells, with IC50 values of 7.76 and 6.16 µM, respectively.

[Anti-HIV chemical constituents of aerial parts of Caragana rosea].

This study was intended to look for anti-HIV chemical constituents of aerial parts of Caragana rosea Turcz. Column chromatographic technique was used for the isolation and purification of constituents of Caragana rosea under the guide of anti-HIV assay. The structures were established on the basis of physical and chemical properties and spectroscopic data. Five compounds were obtained from the EtOAc fraction of aerial parts of Caragana rosea and identified as myricetin (1), mearnsetin (2), p-hydroxy cinnamic acid (3), cararosinol A (4) and cararosinol B (5). At the same time, one possible transformation route between cararosinol B and kobophenol A, another resveratrol tetramer isolated from this plant previously, was proposed. Compounds 4, 5 are new resveratrol tetramers, compounds 1 -3 were isolated from this plant for the first time. All compounds showed no activities in an in vitro assay against HIV-1.

[Effect of mesenchymal stem cells transplantation on heart function after acute myocardial infarction].

OBJECTIVE: To investigate whether mesenchymal stem cells (MSCs) transplantation after acute myocardial infarction (AMI) can improve heart function and decrease infarct size in rabbits and their correlation. METHODS: Twenty-four rabbits were randomly divided into AMI group and MSCs group, each n=12. Exogenous MSCs labeled with bromodeoxyuridine (BrdU) were injected into the border and central area of the ischemic myocardium. Heart function was assessed with echocardiography before transplantation of MSCs and in 6th week after the transplantation. Surviving MSCs in infarcted myocardium were identified by immunohistochemistry. Infarct size was measured histologically. Correlation of heart function and infarct size were analysed. RESULTS: Immunohistochemical stain revealed that BrdU-positive cells were seen in the infarcted myocardium in MSCs group but not in AMI group. Transplantation of MSCs was associated with a significant diminution of left ventricular end-diastolic dimension (LVEDD), and left ventricular end-systolic dimension (LVESD, both P<0.05), and left ventricular ejection fraction (LVEF) and fractional shortening (DeltaFS%)increased (both P<0.05) as compared with AMI group. Infarct size as measured histologically was significant smaller in MSCs group than AMI group (P<0.05). There were negative correlations between LVEF and infarct size in two groups (both P<0.01). CONCLUSION: Exogenous MSCs transplantation can improve heart function by decreasing infarct size and therefore it might be beneficial in the treatment of AMI.

Lignans from the shed trunk barks of the critically endangered plant Abies beshanzuensis and their anti-neuroinflammatory activities.

During a further and comprehensive phytochemical investigation on the shed trunk barks of the critically endangered plant Abies beshanzuensis, one new (1) and ten known (2-11) lignans with diverse structures were isolated. On the basis of spectroscopic methods, the new structure was established to be (7S,8R,8'R)-4'-methoxyl-α-conidendrin (1). Among the isolated lignans, (-)-matairesinol (5) and (-)-arctigenin (6) showed significant anti-neuroinflammatory activities by inhibiting the overproduction of nitric oxide in lipopolysaccharide-stimulated murine BV-2 microglial cells, with IC50 values of 11.5 and 19.0 µM, respectively.