Cytotoxic cardiac glycosides and coumarins from Antiaris toxicaria

Eight new cardiac glycosides/aglycones (antiaritoxiosides A–G, 1–7, and antiarotoxinin B, 8), two new coumarins (anticarins A–B, 41–42), and two new flavanones (antiarones L–K, 43–44) were isolated from trunk bark of Antiaris toxicaria together with 53 known compounds. The new structures were established by extensive analysis of spectroscopic data. Compound 1 (10-carboxy and 3α-hydroxy) and compounds 3–6 (10-hydroxy) contain unique substituents that are rarely found in cardiac glycosides. The cytotoxic effects of isolated compounds against ten human cancer cell lines, KB, KB-VIN, A549, MCF-7, U-87-MG, PC-3, 1A9, CAKI-1, HCT-9 and S-KMEL-2, were tested using the sulforhodamine B assay. Five compounds (12, 16, 20, 22, and 31) showed significant cytotoxicity against all ten cancer cell lines, with notable potency at the ng/mL level against some cell lines, which merits further development as clinical trial candidates

Rhodiola crenulata

Exposure to hypoxia leads to impaired pulmonary sodium transport, which is associated with Na,K-ATPase dysfunction in the alveolar epithelium. The present study is designed to examine the effect and mechanism of Rhodiola crenulata extract (RCE) and its bioactive components on hypoxia-mediated Na,K-ATPase endocytosis. A549 cells were exposed to hypoxia in the presence or absence of RCE, salidroside, or tyrosol. The generation of intracellular ROS was measured by using the fluorescent probe DCFH-DA, and the endocytosis was determined by measuring the expression level of Na,K-ATPase in the PM fraction. Rats exposed to a hypobaric hypoxia chamber were used to investigate the efficacy and underlying mechanism of RCE in vivo. Our results showed that RCE and its bioactive compounds significantly prevented the hypoxia-mediated endocytosis of Na,K-ATPase via the inhibition of the ROS-AMPK-PKCζ pathway in A549 cells. Furthermore, RCE also showed a comparable preventive effect on the reduction of Na,K-ATPase endocytosis and inhibition of AMPK-PKCξ pathway in the rodent model. Our study is the first to offer substantial evidence to support the efficacy of Rhodiola products against hypoxia-associated Na,K-ATPase endocytosis and clarify the ethnopharmacological relevance of Rhodiola crenulata as a popular folk medicine for high-altitude illness

Cardiac Glycosides from Antiaris toxicaria with Potent Cardiotonic Activity

An ethanolic extract of Antiaris toxicaria trunk bark showed potent in vitro cardiotonic effect on isolated guinea pig atria. Bioassay-guided fractionation of the extract led to identification of 9 new cardiac glycosides (1–9, named antiarosides A-I), antiarotoxinin A (10), and 18 known compounds. Their structures were established using MS and NMR spectroscopic studies, including homonuclear and heteronuclear correlation experiments. The ability of these cardiotonic compounds to produce positive inotropic action and their safety indexes were examined in comparison with those of ouabain, a classical inhibitor of Na+/K+-ATPase. Malayoside (23) was nearly equipotent and had a similar safety index to ouabain in guinea pig atria. However, the maximal positive inotropic effect and safety index of 23 in papillary muscle were better than those of ouabain. An electrophysiological recording showed that 23 inhibited sodium pump current in a concentration-dependent manner

Advanced Molecular Knowledge of Therapeutic Drugs and Natural Products Focusing on Inflammatory Cytokines in Asthma

Asthma is a common respiratory disease worldwide. Cytokines play a crucial role in the immune system and the inflammatory response to asthma. Abnormal cytokine expression may lead to the development of asthma, which may contribute to pathologies of this disease. As cytokines exhibit pleiotropy and redundancy characteristics, we summarized them according to their biologic activity in asthma development. We classified cytokines in three stages as follows: Group 1 cytokines for the epithelial environment stage, Group 2 cytokines for the Th2 polarization stage, and Group 3 cytokines for the tissue damage stage. The recent cytokine-targeting therapy for clinical use (anti-cytokine antibody/anti-cytokine receptor antibody) and traditional medicinal herbs (pure compounds, single herb, or natural formula) have been discussed in this review. Studies of the Group 2 anti-cytokine/anti-cytokine receptor therapies are more prominent than the studies of the other two groups. Anti-cytokine antibodies/anti-cytokine receptor antibodies for clinical use can be applied for patients who did not respond to standard treatments. For traditional medicinal herbs, anti-asthmatic bioactive compounds derived from medicinal herbs can be divided into five classes: alkaloids, flavonoids, glycosides, polyphenols, and terpenoids. However, the exact pathways targeted by these natural compounds need to be clarified. Using relevant knowledge to develop more comprehensive strategies may provide appropriate treatment for patients with asthma in the future

Rhodiola crenulata Extract Alleviates Hypoxic Pulmonary Edema in Rats

Sudden exposure of nonacclimatized individuals to high altitude can easily lead to high altitude illnesses. High altitude pulmonary edema (HAPE) is the most lethal form of high altitude illness. The present study was designed to investigate the ability of Rhodiola crenulata extract (RCE), an herbal medicine traditionally used as an antiacute mountain sickness remedy, to attenuate hypoxia-induced pulmonary injury. Exposure of animals to hypobaric hypoxia led to a significant increase in pathological indicators for pulmonary edema, including the lung water content, disruption of the alveolar-capillary barrier, and protein-rich fluid in the lungs. In addition, hypobaric hypoxia also increased oxidative stress markers, including (ROS) production, (MDA) level, and (MPO) activity. Furthermore, overexpression of plasma (ET-1), (VEGF) in (BALF), and (HIF-1α) in lung tissue was also found. However, pretreatment with RCE relieved the HAPE findings by curtailing all of the hypoxia-induced lung injury parameters. These findings suggest that RCE confers effective protection for maintaining the integrity of the alveolar-capillary barrier by alleviating the elevated ET-1 and VEGF levels; it does so by reducing hypoxia-induced oxidative stress. Our results offer substantial evidence to support arguments in favor of traditional applications of Rhodiola crenulata for antihigh altitude illness

Effects of Therapeutic Lifestyle Program on Ultrasound-diagnosed Nonalcoholic Fatty Liver Disease

To investigate the effects of varied therapeutic lifestyle programs on patients with ultrasound-diagnosed nonalcoholic fatty liver disease (NAFLD). Methods: A prospective, case-controlled study was conducted. A total of 54 subjects with NAFLD were subdivided into 3 groups: (1) diet plus exercise group (DPE group, n = 16); (2) exercise group (E group, n = 23); and (3) control group (C group, n = 15). The DPE group received a low-calorie balanced diet and regular high-intensity stationary bicycle exercise program for 10 weeks, while the E group received the same exercise protocol as the DPE group but without any changes in diet. Anthropometric indices, biochemical data, physical fitness data and liver ultrasound findings were recorded. A generalized estimating equation method was used to determine the differences among groups. Results: Compared with the C group, the DPE group demonstrated significant improvements in anthropometric indices, total cholesterol, insulin sensitivity, liver biochemistry, ultrasound finding and physical fitness, while the E group showed significant improvements in anthropometric indices, insulin sensitivity status, ultrasound finding and physical fitness but not liver biochemistry. Compared with the E group, the DPE group showed greater reduction in anthropometric indices (body mass index, body weight, abdominal circumference, hip circumference), total cholesterol, alanine aminotransferase, and γ-glutamyltransferase. Conclusion: Our data suggest that both 10-week diet-plus-exercise and exercise-only therapeutic lifestyle programs are effective for improving anthropometric indices, insulin sensitivity, ultrasound findings and physical fitness in ultrasound-diagnosed NAFLD patients. However, the range of improvement in patients on the diet-plus-exercise program is more obvious than that in patients on the exercise-only program. Moreover, the diet-plus-exercise program resulted in significant improvement in liver biochemistry, but the exercise-only program did not. In summary, diet plus exercise is more efficacious than exercise alone in the lifestyle modification treatment of NAFLD