Antiviral C-geranylated flavonoids from Artocarpus communis.

Ten C-geranylated flavonoids, along with three known analogues, were isolated from the leaves of Artocarpus communis. The chemical structures of these compounds were unambiguously determined via comprehensive spectroscopic analysis, single-crystal X-ray diffraction experiments, and quantum chemical electronic circular dichroism calculations. Structurally, artocarones A-I (1-9) represent a group of unusual, highly modified C-geranylated flavonoids, in which the geranyl chain is cyclised with the ortho-hydroxy group of flavonoids to form various heterocyclic scaffolds. Notably, artocarones E and G-I (5 and 7-9) feature a 6H-benzo[c]chromene core that is hitherto undescribed in C-geranylated flavonoids. Artocarone J (10) is the first example of C-9-C-16 connected C-geranylated aurone. Meanwhile, the plausible biosynthetic pathways for these rare C-geranylated flavonoids were also proposed. Notably, compounds 1, 2, 4, 8, 11, and 12 exhibited promising in vitro inhibitory activities against respiratory syncytial virus and herpes simplex virus type 1.

Biomimetic Synthesis of an Antiviral Cinnamoylphloroglucinol Collection from Cleistocalyx operculatus: A Synthetic Strategy Based on Biogenetic Building Blocks.

A synthetic strategy based on biogenetic building blocks for the collective and divergent biomimetic synthesis of cleistoperlones A-F, a cinnamoylphloroglucinol collection discovered from Cleistocalyx operculatus, has been developed. These syntheses proceeded successfully in only six to seven steps starting from commercially available 1,3,5-benzenetriol and involving oxidative activation of stable biogenetic building blocks as a crucial step. Key features of the syntheses include a unique Michael addition/ketalization/1,6-addition/enol-keto tautomerism cascade reaction for the construction of the dihydropyrano[3,2-d]xanthene tetracyclic core of cleistoperlones A and B, and a rare inverse-electron-demand hetero-Diels-Alder cycloaddition for the establishment of benzopyran ring in cleistoperlones D-F. Moreover, cleistoperlone A exhibited significant antiviral activity against acyclovir-resistant strains of herpes simplex virus type 1 (HSV-1/Blue and HSV-1/153).

Incidence and risk factor analysis for swelling after apical microsurgery.

BACKGROUND: Swelling after apical microsurgery is a postoperative reaction and may reduce quality of life during healing. AIM: To evaluate periapical swelling after apical microsurgery and determine potential risk factors. METHODS: Ninety-eight apical microsurgery patients were selected for this study. Before surgery, bone shadow volume and density of pathological tissue were measured by cone beam computed tomography. The other variables (age, gender, operative teeth number, fistula, preoperative swelling, drug use and preoperative root canal treatments) were assessed during examination. Swelling degree was confirmed by questionnaires for patients on postoperative days 1, 7, 14 and 21. Statistical analyses were performed to identify predictors for swelling. RESULTS: Majority of patients reported moderate (45.9%) or severe (34.7%) swelling on day 1, and moderate (44.9%) or mild (45.9%) on postoperative day 7. Ninety-nine percent of patients had no or mild swelling on postoperative day 14. The average swelling level peaked on day 1 postoperatively and gradually decreased. Of statistical significance, age, bone shadow volume and density of pathological tissue acted as predictors of swelling (P < 0.05). However, there was no significant difference in gender, tooth number, fistula, preoperative swelling, drug use, or preoperative root canal treatments (P > 0.05). CONCLUSION: Younger patients with larger shadow volume and density were significantly more likely to develop swelling after apical microsurgery.

Discovery and Biomimetic Synthesis of a Polycyclic Polymethylated Phloroglucinol Collection from Rhodomyrtus tomentosa.

Inspired by a previously reported biomimetic synthesis study, four new naturally occurring phloroglucinol trimers 1-4 with unusual 6/5/5/6/6/6-fused hexacyclic ring systems, along with two known analogues (5 and 6) and two known biogenetically related dimers (10 and 11), were isolated from Rhodomyrtus tomentosa. Their structures and absolute configurations were unambiguously elucidated by spectroscopic analysis, X-ray diffraction, and electronic circular dichroism calculation. By mimicking two potentially alternative biosynthetic pathways, the first asymmetric syntheses of 1-4 and the racemic syntheses of 5 and 6 were achieved in only five to six steps without the need for protecting groups. Furthermore, phloroglucinol dimers 10 and 11 exhibited significant in vitro antiviral activity against the respiratory syncytial virus.

Discovery of Neuritogenic Securinega Alkaloids from Flueggea suffruticosa by a Building Blocks-Based Molecular Network Strategy.

A combined strategy of building blocks recognition and molecular network construction, termed the building blocks-based molecular network (BBMN), was first presented to facilitate the efficient discovery of novel natural products. By mapping the BBMN of the total alkaloid fraction of Flueggea suffruticosa, three Securinega alkaloids (SEAs) with unusual chemical architectures, suffranidines A-C (1-3), were discovered and isolated. Compound 1 characterizes an unprecedented 8/5/6/5/6/6/6/6-fused octacyclic scaffold with a unique cage-shaped 3-azatricyclo[6.4.0.03,11 ]dodecane core. Compounds 2 and 3 are highly modified SEA dimers that incorporate additional C6 motifs. A hypothetical biosynthetic pathway for 1-3 was proposed. In addition, 1 significantly induced neuronal differentiation and neurite extension by upregulating eukaryotic elongation factor 2 (eEF2)-mediated protein synthesis.

Rhodomentosones A and B: Two Pairs of Enantiomeric Phloroglucinol Trimers from Rhodomyrtus tomentosa and Their Asymmetric Biomimetic Synthesis.

Rhodomentosones A and B (1 and 2), two pairs of novel enantiomeric phloroglucinol trimers featuring a unique 6/5/5/6/5/5/6-fused ring system were isolated from Rhodomyrtus tomentosa. Their structures with absolute configurations were elucidated by NMR spectroscopy, X-ray crystallography, and ECD calculation. The bioinspired syntheses of 1 and 2 were achieved in six steps featuring an organocatalytic asymmetric dehydroxylation/Michael addition/Kornblum-DeLaMare rearrangement/ketalization cascade reaction. Compounds 1 and 2 exhibited promising antiviral activities against respiratory syncytial virus (RSV).

Molecular mechanisms of bufadienolides and their novel strategies for cancer treatment.

Bufadienolides are cardioactive C24 steroids with an α-pyrone ring at position C17. In the last ten years, accumulating studies have revealed the anticancer activities of bufadienolides and their underlying mechanisms, such as induction of autophagy and apoptosis, cell cycle disruption, inhibition of angiogenesis, epithelial-mesenchymal transition (EMT) and stemness, and multidrug resistance reversal. As Na+/K+-ATPase inhibitors, bufadienolides have inevitable cardiotoxicity. Short half-lives, poor stability, low plasma concentration and oral bioavailability in vivo are obstacles for their applications as drugs. To improve the drug potency of bufadienolides and reduce their side effects, prodrug strategies and drug delivery systems such as liposomes and nanoparticles have been applied. Therefore, systematic and recapitulated information about the antitumor activity of bufadienolides, with special emphasis on the molecular or cellular mechanisms, prodrug strategies and drug delivery systems, is of high interest. Here, we systematically review the anticancer effects of bufadienolides and the molecular or cellular mechanisms of action. Research advancements regarding bufadienolide prodrugs and their tumor-targeting delivery strategies are critically summarized. This work highlights recent scientific advances regarding bufadienolides as effective anticancer agents from 2011 to 2019, which will help researchers to understand the molecular pathways involving bufadienolides, resulting in a selective and safe new lead compound or therapeutic strategy with improved therapeutic applications of bufadienolides for cancer therapy.

Absolute Configurations and Stereochemical Inversion Mechanism of Epimeric Securinega Alkaloids from Flueggea suffruticosa.

Three pairs of Securinega alkaloid epimers with a piperidin-2-yl moiety (1-6) were isolated from Flueggea suffruticosa, and their structures including absolute configurations were definitely characterized. An interconvertible C-2' epimerization process within each pair of epimers was observed. The following comprehensive experimental and theoretical investigations demonstrated an unusual stereochemical inversion mechanism of an N-substituted carbon stereogenic center, which was evidenced to be a protic solvent mediated process involving a tandem 1,4-elimination/1,4-addition as the key step.

Unprecedented Quassinoids from Eurycoma longifolia: Biogenetic Evidence and Antifeedant Effects.

Six new quassinoids (1-6) were isolated from the roots of Eurycoma longifolia, and their structures with absolute configurations were determined unambiguously by spectroscopic analyses and single-crystal X-ray crystallographic experiments. Compounds 1 and 2 are the first members of a new class of quassinoids with an unusual C26 carbon skeleton. Compound 6 features a C20 cage-like scaffold with an unprecedented densely functionalized 2,5-dioxatricyclo[5.2.2.04,8]undecane core. The discovery of the two C26 quassinoids 1 and 2 has provided firm evidence for the better understanding the biogenetic process from C30 triterpenoid precursors to quassinoids. Compound 5 exhibited significant antifeedant activity on the diamondback moth (DBM) larvae and excellent systemic absorption and accumulated properties in Brassica chinensis.

Discovery and Biomimetic Synthesis of a Phloroglucinol-Terpene Adduct Collection from Baeckea frutescens and Its Biogenetic Origin Insight.

A phloroglucinol-terpene adduct (PTA) collection consisting of twenty-four molecules featuring three skeletons was discovered from Baeckea frutescens. Inspired by its biosynthetic hypothesis, we synthesized this PTA collection by reductive activation of stable phloroglucinol precursors into highly reactive ortho-quinone methide (o-QM) intermediates and subsequently Diels-Alder cycloaddition. We also demonstrated, for the first time, the generation process of the active o-QM by performing dynamic NMR and HPLC-MS monitoring experiments. Moreover, the PTA collection showed significant antifeedant effect toward the Plutella xylostella larvae.

Leptosperols A and B, Two Cinnamoylphloroglucinol-Sesquiterpenoid Hybrids from Leptospermum scoparium: Structural Elucidation and Biomimetic Synthesis.

Leptosperols A and B (1 and 2), two cinnamoylphloroglucinol-sesquiterpenoid hybrids featuring unprecedented 1-benzyl-2-(2-phenylethyl) cyclodecane and 2-benzyl-3-phenylethyl decahydronaphthalene backbones, along with their biosynthetic precursor (3), were isolated from Leptospermum scoparium. Compounds 1 and 2 represent the first example of phloroglucinol derivatives biogenetically constructed by a De Mayo reaction. The biomimetic synthesis of leptosperol B (2) was achieved using the proposed biosynthetic pathway. In addition, compounds 1 and 2 showed significant anti-inflammatory effects in zebrafish acute inflammatory models.

Cleistocaltones A and B, Antiviral Phloroglucinol-Terpenoid Adducts from Cleistocalyx operculatus.

Two novel phloroglucinol-terpenoid adducts (1 and 2), featuring a rare 2,2,4-trimethyl-cinnamyl-ß-triketone unit, were isolated from the buds of Cleistocalyx operculatus. Their structures with absolute configurations were established by spectroscopic analyses, single-crystal X-ray diffraction, and quantum chemical calculations. Structurally, compound 1 represents a new carbon skeleton possessing a densely functionalized tricyclo[11.3.1.03;8]heptadecane bridged ring system with an unusual bridgehead enol. Compounds 1 and 2 exhibited significant in vitro antiviral activities against respiratory syncytial virus (RSV).

Hunterines A-C, Three Unusual Monoterpenoid Indole Alkaloids from Hunteria zeylanica.

Three new monoterpenoid indole alkaloids (MIAs), hunterines A-C (1-3), were isolated from Hunteria zeylanica. Compound 1 possesses a unique skeleton with an unprecedented azabicyclo[4.3.1]decane ring system. Compounds 2 and 3 are a pair of epimeric vobasinylindole alkaloid heterodimers. Their structures including absolute configurations were established by spectroscopic analyses, X-ray diffraction, computational calculation, and the modified Mosher's method. Plausible biogenetic pathways of 1-3 were also proposed. Alkaloid 1 showed moderate cytotoxic activity against the HepG2 cell line.

Catalytic asymmetric total syntheses of myrtucommuacetalone, myrtucommuacetalone B, and callistrilones A, C, D and E.

Herein, we describe a concise catalytic approach to the first asymmetric total syntheses of myrtucommuacetalone, myrtucommuacetalone B, and callistrilones A, C, D and E. The syntheses proceed in only 5-7 steps from the readily available compound 11, without the need for protecting groups. Key features of the syntheses include a unique organocatalytic asymmetric Friedel-Crafts-type Michael addition with high enantioselectivity and a broad substrate scope, a novel Michael-ketalization-annulation cascade reaction, and an oxidative [3 + 2] cycloaddition. Furthermore, the new compound 7 exhibited potent antibacterial activities against several multidrug-resistant strains (MRSA, VISA and VRE), and showed greater potency than vancomycin.

Correlation between Electroencephalogram Alterations and Frontal Cognitive Impairment in Esophageal Cancer Patients Complicated with Depression.

BACKGROUND: Some esophageal cancer patients complicated with depression exhibit cognitive impairments. Frontal electroencephalogram (EEG) may be used as a reliable biomarker for prefrontal-mediated cognitive functions. This study was to investigate alterations of EEG and frontal cognitive impairment in esophageal cancer patients complicated with depression and to assess their correlation. METHODS: Sixty-five esophageal cancer patients with depression (study group) and 62 healthy controls (control group) were included in this study. The study group were assigned into psychotic depressed (PD, n = 32) and nonpsychotic depressed (NPD, n = 33) subgroups based on complication with psychotic symptoms (Brief Psychiatric Rating Scale [BPRS] >35). EEG examination, Beck self-rating depression scale, and BPRS were used to assess clinical symptoms. Chi-square test, two independent sample t-test, one-way analysis of variance, and Kruskal-Wallis test were utilized to compare the variables between two groups. EEG abnormalities and scores of frontal cognitive function test were analyzed by partial correlation analysis in the PD and NPD subgroups. RESULTS: Compared with control group, the study group displayed greater scores either in the Stroop test (19.89 ± 2.05 vs. 24.12 ± 2.19, P = 0.006) or Color Trails Test (CTT; 11.92 ± 1.01 vs. 15.02 ± 1.63, P = 0.008), and reduced score (35.05 ± 2.01 vs. 32.11 ± 2.38, P = 0.007) in the verbal fluency test (VFT). Compared to NPD subgroup, PD subgroup exhibited increased scores in Stroop test (22.89 ± 2.07 vs. 25.38 ± 2.32, P = 0.009) and CTT (13.16 ± 1.71 vs. 15.82 ± 1.13, P = 0.008). Moreover, increased scores in Stroop test and CTT as well as scores in VFT were associated with the severity of depression. The study group had an abnormal frontal EEG, such as α forward, α asymmetry, α moderation, and increased θ activity relative to control group. Similarly, compared with NPD subgroup, PD subgroup displayed α forward, α asymmetry, and α moderation. The correlation test revealed that α forward and α asymmetry were negatively associated with VFT score, but positively correlated with the scores of CTT and the Stroop test in PD subgroup. In addition, α asymmetry in NPD subgroup was positively related to CTT scores. CONCLUSION: This study indicated that frontal cognitive impairment in esophageal cancer patients complicated with depression is associated with EEG alterations.

A Simple HPLC-MS/MS Method for Determination of Tryptophan, Kynurenine and Kynurenic Acid in Human Serum and its Potential for Monitoring Antidepressant Therapy.

The kynurenine pathway, in which tryptophan is metabolized to kynurenine and kynurenic acid, has been linked to depression. A rapid and highly reproducible liquid-chromatography-tandem mass spectrometry (LC-MS/MS) method were established for determining tryptophan, kynurenine and kynurenic acid in human serum. Biological samples were precipitated with methanol before separation on an Agilent Eclipse XDB-C18. The stable-isotope-labeled internal standards (kynurenine-13C415N and kynurenic acid-d5) were used for quantification. Detection was performed using multiple reaction monitoring in electrospray ionization mode at m/z 205.1→188.1 for tryptophan, m/z 209.1→146.1 for kynurenine, m/z 190.1→144.1 for kynurenic acid. Good linearity of analyte to internal standard peak area ratios was seen in the concentration range 1,000-50,000 ng/mL for tryptophan, 100-5,000 ng/mL for kynurenine and 1-60 ng/mL for kynurenic acid. Pooled drug-free human serum was purified using activated charcoal and the method was shown to be linear, with validation parameters within acceptable limits. The newly developed method was successfully used to determine concentrations of tryptophan, kynurenine and kynurenic acid in serum from 26 healthy volunteers and 54 patients with depression. Concentrations of tryptophan and kynurenine were lower in serum from depressed individuals than from healthy individuals.

Clinical trial of thalidomide combined with radiotherapy in patients with esophageal cancer.

AIM: To investigate the short-term efficacy and tolerability of radiotherapy plus thalidomide in patients with esophageal cancer (EC). METHODS: Serum samples from 86 EC patients were collected before, during, and after radiotherapy, and the vascular endothelial growth factor (VEGF) level was examined by ELISA. According to the change in serum VEGF level during radiotherapy, the patients were divided into two groups: in the drug group, VEGF level was increased or remained unchanged, and thalidomide was administered up to the end of radiotherapy; in the non-drug group, VEGF level was decreased and radiotherapy was given alone. Thirty healthy volunteers served as controls. The efficacy and safety of radiotherapy plus thalidomide therapy were investigated. RESULTS: The 86 EC patients had a significantly higher level of VEGF compared with the 30 healthy controls before radiotherapy (P < 0.01), and the VEGF level was significantly correlated with primary tumor size, lymph node metastasis, histopathologic type, and clinical stage (P < 0.01). Of 83 evaluable cases, VEGF level was significantly decreased after radiotherapy in 32 patients in the drug group (P < 0.05), with an effective rate of 71.88%. The incidence of dizziness and/or burnout in the drug group and non-drug group was 62.50% and 15.69%, respectively (P = 0.000), and the incidence of somnolence was 12.50% and 0%, respectively (P = 0.019). No significant differences were observed. CONCLUSION: Thalidomide can down-regulate serum VEGF level in EC patients, and combined with radiotherapy may improve treatment outcome. Thalidomide was well tolerated by EC patients.

Coronary heart disease risk equivalence in diabetes and arterial diseases characterized by endothelial function and endothelial progenitor cell.

AIMS: Peripheral Arterial Disease (PAD), Carotid Artery Disease (CAD), and Type 2 Diabetes Mellitus (DM) were considered as "Coronary Heart Disease (CHD) risk equivalents". Vascular endothelial dysfunction was recognized as an early event in the development of atherosclerosis. Involved in neovasculogenesis and maintenance of vascular homeostasis, endothelial progenitor cell (EPC) has been considered as a biological marker of cardiovascular disease. The purpose of this study was to assess the CHD risk equivalents concept by investigating the endothelial function and circulating EPC number in patients with CHD, PAD, CAD and T2DM. METHODS: There were four groups in the study: CHD (n = 19), AD [PAD and CAD (n = 17)], DM (n = 21) and healthy controls (HC, n = 20). PAD and CAD were assessed by ultrasonography. Coronal artery angiography was used to identify CHD. The diagnosis of T2DM was based on oral glucose tolerance test and medical history. Vascular endothelial function was assessed by flow-mediated brachial artery dilatation (FMD). Circulating EPC was quantified by flow cytometry. RESULTS: The circulating EPC numbers in four groups were CHD, 973 ± 96; AD, 1048 ± 97; T2DM, 1210 ± 125; HC, 1649 ± 112 cells/ml. There were no significant differences in circulating EPC numbers between CHD and AD groups (P > 0.05). Compared with CHD or AD group, T2DM group was associated with a slight increase in circulating EPC numbers (P < 0.05). The results of FMD were almost similar to the circulating EPC numbers(CHD, 4.06 ± 0.54; AD, 3.90 ± 0.48; DM, 3.85 ± 0.57; HC, 5.52 ± 0.67%)except that there was no significant difference among the CHD, AD and T2DM groups (P > 0.05). Age, glycosylated hemoglobin, low density lipoprotein cholesterol, systolic blood pressure, body mass index (BMI) and medical history were the independent risk factors of circulating EPC number in all the patients (P < 0.05). Age, total cholesterol, BMI and medical history were the independent risk factors of FMD in all of the patients (P<0.05). CONCLUSIONS: The results of this study supported the equivalents hypothesis and revealed that "CHD risk equivalents" were characterized by the consistent physiological changes of blood vessels in angiogenesis, repairing ability and endothelial function.

Theory of mind deficits in patients with esophageal cancer combined with depression.

AIM: To characterize the two components of theory of mind (ToM) in patients with esophageal cancer combined with depression. METHODS: Sixty-five patients with esophageal cancer combined with depression (depressed group) and 62 normal controls (control group) were assessed using reading the mind in the eyes test, faux pas task, verbal fluency test, digit span test and WAIS IQ test. The depressed group was divided into two subgroups including psychotic depressed (PD) group (32 cases) and nonpsychotic depressed (NPD) group (33 cases). The clinical symptoms of patients were assessed using Beck depression inventory version II and brief psychiatric reacting scale (BPRS). RESULTS: There was a significant difference between the depressed group and the control group on tasks involving ToM social perceptual components (mind reading: t = 7.39, P < 0.01) and tests involving ToM social cognitive components (faux pas questions: t = 13.75, P < 0.01), respectively. A significant difference was also found among the PD group, the NPD group and the control group on mind reading (F = 32.98, P < 0.01) and faux pas questions (χ² = 78.15, P < 0.01), respectively. The PD group and NPD group performed worse than normal group controls both on mind reading and faux pas questions (P < 0.05). The PD group performed significantly worse than the NPD group on tasks involving ToM (mind reading: F = 18.99, P < 0.01; faux pas questions: F = 36.01, P < 0.01). In the depressed group, there was a negative correlation between ToM performances and BPRS total score (mind reading: r = -0.35, P < 0.01; faux pas questions: r = -0.51, P < 0.01), and between ToM performances and hostile suspiciousness factor score (mind reading: r = -0.75, P < 0.01; faux pas questions: r = -0.73, P < 0.01), respectively. CONCLUSION: The two components of ToM are both impaired in patients with esophageal cancer combined with depression. This indicates that there may be an association between ToM deficits and psychotic symptoms in clinical depression.

Additional use of an aldosterone antagonist in patients with mild to moderate chronic heart failure: a systematic review and meta-analysis.

AIMS: Aldosterone antagonists (AldoAs) have been used to treat severe chronic heart failure (CHF). There is uncertainty regarding the efficacy of using AldoAs in mild to moderate CHF with New York Heart Association (NYHA) classifications of I to II. This study summarizes the evidence for the efficacy of spironolactone (SP), eplerenone (EP) and canrenone in mild to moderate CHF patients. METHODS: PubMed, MEDLINE, EMBASE and OVID databases were searched before June 2012 for randomized and quasi-randomized controlled trials assessing AldoA treatment in CHF patients with NYHA classes I to II. Data concerning the study's design, patients' characteristics and outcomes were extracted. Risk ratio (RR) and weighted mean differences (WMD) or standardized mean difference were calculated using either fixed or random effects models. RESULTS: Eight trials involving 3929 CHF patients were included. AldoAs were superior to the control in all cause mortality (RR 0.79, 95% CI 0.66, 0.95) and in re-hospitalization for cardiac causes (RR 0.62, 95% CI 0.52, 0.74), the left ventricular ejection fraction was improved by AldoA treatment (WMD 2.94%, P = 0.52). Moreover, AldoA therapy decreased the left ventricular end-diastolic volume (WMD -14.04 ml, P < 0.00001), the left ventricular end-systolic volume (WMD -14.09 ml, P < 0.00001). A stratified analysis showed a statistical superiority in the benefits of SP over EP in reducing LVEDV and LVESV. AldoAs reduced B-type natriuretic peptide concentrations (WMD -37.76 pg ml(-1), P < 0.00001), increased serum creatinine (WMD 8.69 µmol l(-1), P = 0.0003) and occurrence of hyperkalaemia (RR 1.78, 95% CI 1.43, 2.23). CONCLUSIONS: Additional use of AldoAs in CHF patients may decrease mortality and re-hospitalization for cardiac reasons, improve cardiac function and simultaneously ameliorate LV reverse remodelling.