MS/MS Molecular Networking Unveils the Chemical Diversity of Biscembranoid Derivatives, Neutrophilic Inflammatory Mediators from the Cultured Soft Coral Sarcophyton trocheliophorum.

Biscembranoids are the distinctive tetraterpenoids owing a 14/6/14 membered tricyclic scaffold that have been mainly discovered in the soft corals, especially the genera Sarcophyton, Lobophytum and Sinularia. Recent findings have demonstrated the great anti-inflammatory potential of biscembranoid analogues in human neutrophils, motivating more chemical and biological explorations targeting these marine-derived natural products. In the current study, the chemical diversity of biscembranoids derived from the cultured-type Sarcophyton trocheliophorum von Marenzeller was illustrated through MS/MS molecular networking (MN) profiling approach. Based on the MN patterns, the prioritization of unknown biscembranoid derivatives was putatively analyzed. As a result, the biscembrane targeting isolation afforded two new metabolites, sarcotrochelides A (1) and B (2), along with six known analogues (3-8). Their structures and relative configurations were determined by spectroscopic methods. In vitro neutrophil inflammatory inhibition was further investigated for all isolates based on reduced superoxide anion (O2•-) generation detections. Compounds 5-8 showed significant dose-dependently inhibitory effects, suggesting the cruciality of 6,7-dihydrooxepin-2(5H)-one moiety and saturated γ-lactone ring in their reactive oxygen species (ROS)-dependent anti-inflammatory properties.

Clinical Patterns of Traditional Chinese Medicine for Ischemic Heart Disease Treatment: A Population-Based Cohort Study.

Background and objectives: Traditional Chinese medicines (TCMs) are widely prescribed to relieve ischemic heart disease (IHD); however, no cohort studies have been conducted on the use of TCMs for patients with IHD. The aim of the study was to analyze TCM prescription patterns for patients with IHD. Materials and Methods: The retrospective population-based study employed a randomly sampled cohort of 4317 subjects who visited TCM clinics. Data were obtained from the National Health Insurance Research Database (NHIRD) of Taiwan for the period covering 2000 to 2017. Data analysis focused on the top ten most commonly prescribed formulae and single TCMs. We also examined the most common two- and three-drug combinations of TCM in single prescriptions. Demographic characteristics included age and sex distributions. Analysis was performed on 22,441 prescriptions. Results: The majority of TCM patients were male (53.6%) and over 50 years of age (65.1%). Zhi-Gan-Cao-Tang (24.76%) was the most frequently prescribed formulae, and Danshen (28.89%) was the most frequently prescribed single TCM for the treatment of IHD. The most common two- and three-drug TCM combinations were Xue-Fu-Zhu-Yu-Tang and Danshen" (7.51%) and "Zhi-Gan-Cao-Tang, Yang-Xin-Tang, and Gua-Lou-Xie-Bai-Ban-Xia-Tang" (2.79%). Conclusions: Our results suggest that most of the frequently prescribed TCMs for IHD were Qi toning agents that deal with cardiovascular disease through the promotion of blood circulation. The widespread use of these drugs warrants large-scale, randomized clinical trials to investigate their effectiveness and safety.

Anti-Inflammatory and Anti-oxidative Effects of Puerarin in Postmenopausal Cardioprotection: Roles of Akt and Heme Oxygenase-1.

During menopause, the sharp decline in estrogen levels leads to an increased risk of cardiovascular disease in women. The inflammatory response and oxidative stress are reportedly involved in the development of cardiovascular disorders postmenopause. In this study, we evaluated the cardioprotective effects of puerarin, a phytoestrogen derived from the root of Pueraria lobate, and investigated its underlying molecular mechanisms. Puerarin alleviated cytotoxicity and the production of reactive oxygen species (ROS) in lipopolysaccharide (LPS)- and hydrogen peroxide-stimulated H9c2 cardiomyoblasts. Puerarin scavenges free radicals and reduces apoptosis, thereby suppressing NADPH oxidase-1 and Bax activation to attenuate the production of ROS and restore Bcl-2 expression. Additionally, puerarin inhibited the expression of inducible nitric oxide synthase, cyclooxygenase-2, and nitric oxide production and decreased the hypertrophic phenotype under LPS stimulation. Treatment with puerarin reduced the levels of malondialdehyde and restored glutathione levels when facing oxidative stress. Mechanistically, puerarin inhibited both the LPS-induced Toll-like receptor 4/NF-[Formula: see text]B and mitogen-activated protein kinase signaling pathways. Furthermore, it reversed both the LPS-mediated downregulation of Akt activation and heme oxygenase-1 (HO-1) expression. The cardioprotective effects of puerarin were abolished by inhibitors of Akt and HO-1 and the estrogen receptor antagonist fulvestrant (ICI). This indicated that the estrogen receptor mediated by these two molecules plays important roles in conferring the anti-inflammatory and anti-oxidative functions of puerarin. These results demonstrate the therapeutic potential of puerarin for treating heart disease in postmenopausal women through Akt and HO-1 activation.

Chemometric-guided chemical marker selection: A case study of the heat-clearing herb Scrophularia ningpoensis.

The selection of medicinal plants' chemical markers focuses on bioactivity as the primary goal, followed by the nature of secondary metabolites, their stability, and availability. However, herbal medicines are valued for their complex and holistic pharmacological effects. A correct chemical marker can be carefully selected by a systematic clarification of their chemical-biological relationships. In the current study, the multi-informative molecular networking (MIMN) approach was employed to construct the anti-inflammatory metabolomic pattern of a heat-clearing herb, Scrophularia ningpoensis Hemsl. (S. ningpoensis). The MIMN molecular families characterized by cinnamic acid glycosides showed a higher bioactivity score compared with the other two major chemical classes (iridoid glycosides and iridoid-cinnamic acid glycosides). The Global Natural Product Social Molecular Networking (GNPS) and Reaxys database were used to assist in the putative annotation of eighteen metabolites from the bioactive and non-bioactive molecular families. The anti-inflammatory validation step was based on the detection of reactive oxygen species (ROS) generation by activated human neutrophils. All compounds from the bioactive MIMN molecular families dose-dependently inhibited the total ROS generation promoted by fMLF (IC50: 0.04-0.42 µM), while the compounds from non-bioactive MIMN clusters did not show any significant anti-inflammatory effect. The ROS-dependent anti-inflammatory activity of these cinnamic acid glycosides was attributed to their oxygen radical scavenging ability. The most abundant cinnamic acid glycoside, angoroside C (IC50: 0.34 µM) was suggested to be selected as a chemical marker for S. ningpoensis. In this study, the MIMN platform was applied to assist in the chemical marker selection of S. ningpoensis. The correct selection of markers will aid in the compilation and revision of herbal monographs and pharmacopeias resulting in the precise analysis and classification of medicinal plants on a scientific basis.

Probing Anti-Leukemic Metabolites from Marine-Derived Streptomyces sp. LY1209.

The unmet need for specific anti-leukemic agents for the treatment of acute lymphoblastic leukemia led us to screen a variety of marine-derived bacteria. The fermentation broth extract of Streptomyces sp. LY1209 exhibited the most potent anti-proliferative effect against Molt 4 leukemia cells. A chromatographic anti-proliferative profiling approach was applied to characterize the metabolites with bioactive potential. Among all the metabolites, the major anti-leukemic constituents were staurosporine and a series of diketopiperazines (DKPs), including one novel and two known DKPs identified from nature for the first time. The structures of these compounds were identified using extensive spectroscopic analysis. The anti-proliferative potential of these metabolites against the Molt 4 cancer cell line was also determined. According to the in silico analysis utilizing a chemical global positioning system for natural products (ChemGPS-NP), it was suggested that these DKPs are potential anti-microtubule and alkylating agents, while staurosporine was proposed to be a tyrosine kinase inhibitor. Our findings not only identified a series of anti-proliferative metabolites, but also suggested a strategic workflow for the future discovery of natural product drug leads.

Anti-Proliferative Potential of Secondary Metabolites from the Marine Sponge Theonella sp.: Moving from Correlation toward Causation.

Marine sponges have been recognized as a rich source of potential anti-proliferative metabolites. Currently, there are two sponge-derived anti-cancer agents (a macrolide and a nucleoside) isolated from the Porifera phylum, suggesting the great potential of this sponge as a rich source for anti-neoplastic agents. To search for more bioactive metabolites from this phylum, we examined the EtOAc extract of Theonella sp. sponge. We isolated seven compounds (1-7), including four 4-methylene sterols (1-4), two nucleosides (5 and 6), and one macrolide (7). Among them, theonellasterol L (1) was identified for the first time, while 5'-O-acetyl-2'-deoxyuridine (5) and 5'-O-acetylthymidine (6) were the first identified deoxyuridine and thymidine derivatives from the sponge Theonella sp. These structures were elucidated based on their spectroscopic data. The anti-proliferation activity of compounds 1-7 against the MCF-7, MDA-MB-231, T-47D, HCT-116, DLD-1, K562, and Molt 4 cancer cell lines was determined. The results indicated that the 14-/15-oxygenated moiety played an important role in the antiproliferative activity and the macrolide derivatives dominated the anti-proliferative effect of the sponge Theonella sp. The in silico analysis, using a chemical global positioning system for natural products (ChemGPS-NP), indicated an anti-proliferative mode of actions (MOA) suggesting the potential applications of the isolated active metabolites as anti-proliferative agents.