Structural Revision of Guttiferone F and 30-epi-Cambogin.

Guttiferone F, a natural polyprenylated polycyclic acylphloroglucinol, was originally assigned as the 30-epimer of garcinol by NMR data analyses. Conversion of guttiferone F in the presence of acid afforded its cyclized form (2a), which was previously assigned as 30-epi-cambogin. However, the absolute configurations of guttiferone F and 2a have not been determined. Reinvestigation of the structures of those two compounds, using X-ray and NMR data analyses and chemical transformation, revealed that the original assignment of the C-30 absolute configuration in guttiferone F and 2a should be inverted. Guttiferone F is indeed garcinol, and 2a, which was previously identified as 30-epi-cambogin, is cambogin.

Polycyclic polyprenylated acylphloroglucinol congeners from Garcinia yunnanensis Hu with inhibitory effect on α-hemolysin production in Staphylococcus aureus.

α-Hemolysin (Hla) is an extracellular protein secreted by methicillin-resistant Staphylococcus aureus (MRSA) strains that plays a critical role in the pathogenesis of pulmonary, intraperitoneal, intramammary, and corneal infections, rendering Hla a potential therapeutic target. In this study, 10 unreported polycyclic polyprenylated acylphloroglucinol (PPAP) derivatives, garciyunnanins C-L (1-10), with diverse skeletons, were isolated from Garcinia yunnanensis Hu. The structures of these new compounds were determined by HRMS, NMR, electronic circular dichroism (ECD) calculations, single-crystal X-ray diffraction, and biomimetic transformation. Garciyunnanins C and D (1 and 2) were found to be potent Hla inhibitors in the anti-virulence efficacy evaluation against MRSA strain.

Uncariitannin, a polyphenolic polymer from Uncaria gambier, attenuates Staphylococcus aureus virulence through an MgrA-mediated regulation of α-hemolysin.

A global transcriptional regulator, MgrA, was previously identified as a key determinant of virulence in Staphylococcus aureus. An 80% EtOH extract of Uncaria gambier was found to attenuate the virulence of S. aureus via its effects on MgrA. Using bioassay-guided fractionation, a polyphenolic polymer, uncariitannin, was found to be the main bioactive constituent of the extract, and its structure was characterized using spectral and chemical analysis. The molecular weight and polydispersity of uncariitannin were determined by gel permeation chromatography-refractive index-light scattering analysis. An electrophoretic mobility shift assay showed that uncariitannin could effectively inhibit the interaction of MgrA with DNA in a dose-dependent manner. Treatment with uncariitannin could decrease the mRNA and protein levels of Hla in both the S. aureus Newman and USA300 LAC strains. Further analysis of Hla expression levels in the Newman ΔmgrA and Newman ΔmgrA/pYJ335-mgrA strains indicated that uncariitannin altered Hla expression primarily in an MgrA-dependent manner. A mouse model of infection indicated that uncariitannin could attenuate MRSA virulence. In conclusion, uncariitannin may be a potential candidate for further development as an antivirulence agent for the treatment of S. aureus infection.

α-Glucosidase inhibitive diarylheptanoids from Ottelia acuminata var. acuminata, a traditional vegetable of Bai Nationality in Yunnan.

Diabetes is an urgent health issue characterized by ethnic and regional variations, and is inseparable from the different dietary habits. It is worthy to note that the incidence of diabetes in Bai nationality has been reported to be much lower than Han in China. As a daily vegetable of Bai, the phytochemical and antidiabetic study of Ottelia acuminata var. acuminata had not been carried out. In this study, 41 metabolites with diverse diarylheptanoid (six new ones, Otteacumienes A-F), flavone, sesquiterpenoid, coumarin, lignan, polyacetylene, and alkaloid skeletons were characterized from O. acuminata var. acuminata. Among them, the racemic nature of 3 was characterized by chiral resolution and calculated ECD methods. The biological study revealed diarylheptanoids showed significant α-glucosidase inhibitory activities with 5 as the most effective one (60-fold stronger than acarbose). Molecular docking studies indicated that these structures have different binding cavities with acarbose. This study demonstrated that O. acuminata var. acuminata might correlated with the low incidence diabetes of Bai and the diarylheptanoids may have potential therapeutic value for diabetes mellitus.

Two Novel Phenylpropanoid Trimers From Ligusticum chuanxiong Hort With Inhibitory Activities on Alpha-Hemolysin Secreted by Staphylococcus aureus.

The emergence of antibiotic resistance in Staphylococcus aureus has necessitated the development of innovative anti-infective agents acting on novel targets. Alpha-hemolysin (Hla), a key virulence factor of S. aureus, is known to cause various cell damage and death. In this study, with bioassay-guided fractionation, a pair of unusual epimeric lignan trimers, ligustchuanes A and B (1 and 2), were isolated from the rhizomes of Ligusticum chuanxiong Hort, together with two known phthalides being identified by UPLC-QTOF-MS. To the best of our knowledge, trimers with rare C8-C9″-type neolignan and ferulic acid fragments have not been identified in any natural product. Both of them were isolated as racemic mixtures, and their absolute configurations were determined by comparing experimental and calculated ECD spectra after enantioseparation. Ligustchuane B exhibited an outstanding inhibitory effect on α-hemolysin expression in both MRSA USA300 LAC and MSSA Newman strains at concentrations of 3 and 6 µM, respectively. Notably, a mouse model of infection further demonstrated that ligustchuane B could attenuate MRSA virulence in vivo.

The anti-infective activity of Salvia miltiorrhiza against Staphylococcus aureus by attenuating accessory gene regulator system-mediated virulence.

Due to the rapid evolution of antibiotic resistance in Staphylococcus aureus, antivirulence therapy may be a promising alternative for the effective control of the spread of resistant pathogens. The Chinese Materia Medica has been widely used for the treatment of diseases and production of health foods, and it remains a valuable resource for the discovery of compounds possessing antivirulence activity. Through a Caenorhabditis elegans infection model, an EtOAc-soluble fraction of 80% EtOH extract of Salvia miltiorrhiza Bunge (SMEA) was found to possess potential anti-infective activity against S. aureus. Then, several in vitro assays indicated that SMEA had robust antivirulence activity at the dose of 400 µg mL-1, reducing hemolytic activity and α-hemolysin expression in S. aureus. Furthermore, at 100 mg kg-1, SMEA reduced abscess formation in the main organs of mice challenged with S. aureus. In order to identify the bioactive components of SMEA and investigate the mechanisms underlying the antivirulence activity, SMEA was separated using bioassay-guided fractionation. As a result, eight compounds were identified in SMEA. Among them, tanshinone IIB (TNB) showed strong antivirulence activity both in vitro and in vivo. Furthermore, at 24 µg mL-1, TNB significantly reduced the expression of RNAIII and psmα, indicating that the mechanism underlying TNB activity was related to the accessory gene regulator quorum sensing system. In conclusion, TNB's antivirulence properties make it a promising candidate for drug development against S. aureus infections.

Prenylated xanthones and biphenyls from Garcinia esculenta with antistaphylococcal activity.

One new xanthone, (±) garciesculenxanthone C (1), two new biphenyls, garciesculenbiphenyls A (2) and B (3), together with two known compounds, doitungbiphenyl B (4) and morusignin D (5), were isolated from Garcinia esculenta. The structures of new compounds were elucidated by spectroscopic analysis, and the absolute configuration of (±) garciesculenxanthone C (1) was assigned by a modified Mosher's method. All isolates were evaluated for their antistaphylococcal activities against Staphylococcus aureus Newman, USA300 LAC, USA400 MW2, and Mu50 strains. Among these, (±) garciesculenxanthone C (1) showed the best antistaphylococcal activity, and its effect was determined to be bactericidal by time-kill experiment.

Hepatotoxicity induced by psoralen and isopsoralen from Fructus Psoraleae: Wistar rats are more vulnerable than ICR mice.

Fructus Psoraleae (FP) causes cholestatic liver injury; however, its main toxic constituents that are responsible for causing hepatotoxicity remained undetermined in previous studies. In the present study, psoralen and isopsoralen, the two main constituents of FP, were administered orally to rats (80 and 40 mg/kg, respectively) and mice (320 and 160 mg/kg, respectively) for 28 days, followed by biochemical and histopathological examinations to evaluate their hepatotoxicity. The results showed that psoralen and isopsoralen could induce the toxic reactions of liver and other organs in rats, while mice were not sensitive to these two compounds. Furthermore, the corresponding results indicated that administration of psoralen and isopsoralen repressed the expression of CYP7A1, BSEP, MRP2 and SULT2A1 and increased the expression of FXR and MRP3 in the rat liver. In summary, the toxic reactions of psoralen and isopsoralen are different in different species. In this study, multiple organ toxicity, such as cholestatic liver injury, occurs in rats, but not in mice. Psoralen and isopsoralen are the two main toxic constituents of FP. In addition, psoralen and isopsoralen cause liver injury, possibly through inhibiting bile acid excretion in the liver, leading to the accumulation of toxin in hepatocytes.

[GK-2 prosthetic heart valve: a 20-year clinical experience].

OBJECTIVE: The aim of this study is to analyze our 20-year clinical results with 413 GK-2 mechanical heart valves. METHODS: 123 men and 204 women with a mean age of 38.62 +/- 10.14 years accepted cardiac valve replacements. Ninety-one percent had NYHA class III or IV heart function. The mitral position was in 205 patients, aortic position in 31 patients, aortic and mitral in 86 patients, and tricuspid position in 5. Altogether 296 mitral prosthetic valves and 117 aortic prosthetic valves were implanted. Follow-up is 91% and extended 0.5 to 19.6 years with cumulative 2440.7 patient-years. RESULTS: The early mortality was 3.36% (11/327). There were 24 late deaths (0.98% per patient-year). The actuarial probability of survival was 93.31% +/- 0.03% at 5 years, 89.59 +/- 2.1% at 10 years, 83.61% +/- 6.09% at 15 years. The linearized rate of thromboembolism was 0.29% pt-yr, the rate of bleeding event 0.49% pt-yr. In 91.98% of survivors NYHA functional performance have improved to class II or I. CONCLUSION: Early and long-term results in our hospital demonstrate that the GK-2 prosthetic heart valve exhibits excellent hemodynamic properties, mechanical durability and a low incidence of valve-related complications.