Design and semisynthesis of oleanolic acid derivatives as VEGF inhibitors: Inhibition of VEGF-induced proliferation, angiogenesis, and VEGFR2 activation in HUVECs / 中国天然药物

Angiogenesis inhibitors targeting the VEGF signaling pathway are developed into drugs for the treatment of vaious diseases, such as cancer, rheumatoid arthritis, and age-related macular degeneration. Recent studies have revealed that oleanolic acid (OA), a natural pentacyclic triterpenoid, inhibited the VEGF/VEGFR2 signaling pathway and angiogenesis in HUVECs, which may represent an attractive VEGF inhibitor. In this paper, rational structural modification towards OA was performed in order to improve its inhibitory effects aganist VEGF and anti-angiogenesis potential. As a result, a series of novel OA derivatives, possessing α,β-unsaturated ketone system in ring A and amide functional group at C-28, were prepared and evaluated for cytotoxicity and their ability to inhibit VEGF-induced abnormal proliferation of HUVECs. The results showed that two promising derivatives, OA-1 and OA-16, exhibited no in vitro cytotoxicity against HUVECs but showed more potent inhibitory activity against VEGF-induced proliferation and angiogenesis in HUVECs, compared with OA. The results of Western blot indicated that OA-1 and OA-16 inhibited VEGF-induced VEGFR2 activation. Furthermore, small interfering RNA experiments were performed to confirm that both compounds inhibited VEGF-induced angiogenesis via VEGFR2. Thus, the present study resulted in the discovery of new promising OA-inspired VEGF inhibitors, which can serve as potential lead compounds for the treatment of angiogenesis-related diseases.

Qi-Tai-Suan, an oleanolic acid derivative, ameliorates ischemic heart failure via suppression of cardiac apoptosis, inflammation and fibrosis / 中国天然药物

Although anti-thrombotic therapy has been successful for prevention of deaths from acute myocardial infarction (MI), by far, there are few preventive and therapeutic options for ischemic heart failure (IHF) after MI. Qi-Tai-Suan (QTS) is an oleanolic acid (OA) derivative which once underwent a clinical trial for treating hepatitis. In this study, we investigated the potential cardioprotective effect of QTS on IHF. IHF mouse model was constructed by coronary artery ligation in male C57BL/6J mice, and the protective effects of QTS on IHF were examined by echocardiography measurement, histological and TUNEL analysis, etc. We found that QTS exhibited promising cardioprotective effect on IHF. QTS treatment significantly improved cardiac function of IHF mice and the symptoms of heart failure. Notably, QTS had much better oral bioavailability (F = 41.91%) in mice than its parent drug OA, and took effects mainly as its original form. Mechanistically, QTS ameliorated ischemic heart failure likely through suppression of cardiac apoptosis, inflammation and fibrosis. Taken together, QTS holds great promise as a preventive and therapeutic agent for ischemic heart failure and related diseases.

Identification of a new azoreductase driven prodrug from bardoxolone methyl and 5-aminosalicylate for the treatment of colitis in mice / 中国天然药物

For local treatment of ulcerative colitis, a new azoreductase driven prodrug CDDO-AZO from bardoxolone methyl (CDDO-Me) and 5-aminosalicylate (5-ASA) was designed, synthesized and biologically evaluated. It is proposed that orally administrated CDDO-AZO is stable before reaching the colon, while it can also be triggered by the presence of azoreductase in the colon to fragment into CDDO-Me and 5-ASA, generating potent anti-colitis effects. Superior to olsalazine (OLS, a clinically used drug for ulcerative colitis) and CDDO-Me plus 5-ASA, CDDO-AZO significantly attenuated inflammatory colitis symptoms in DSS-induced chronic colitis mice, which suggested that CDDO-AZO may be a promising anti-ulcerative colitis agent.

Alpha-hederin induces the apoptosis of oral cancer SCC-25 cells by regulating PI3K/Akt/mTOR signaling pathway

BACKGROUND: Oral cancer is one of the common malignant tumors of the head and neck. However, current treatments have numerous side effects, and drugs from natural sources may have better therapeutic potential. This research investigated the induction of apoptosis by α-hederin (α-HN), a constituent of Pulsatilla chinensis (Bunge) Regel, in the oral cancer cell line SCC-25 and its underlying mechanism. RESULTS: SCC-25 cells were treated with 50, 100, and 200 µmol/L α-HN. Cell proliferation; extent of apoptosis; activities of caspases-3, 8, and 9; and the expression of Bcl-2, Bax, phosphorylated (p)-phosphoinositide 3-kinase (PI3K), p-Akt, and p-mammalian target of rapamycin (mTOR) proteins were determined using the 3-(4,5)-2-thiazole-(2,5)-diphenyl tetrazolium bromide, flow cytometry, caspase activity detection kits, and western blot assays, respectively. The results showed that the proliferation of SCC-25 cells in the α-HN-treated groups decreased significantly, and the inhibitory effect was time and concentration dependent. Compared with cells in the control group, the extent of apoptosis increased significantly, caspase-3 and -9 activities were significantly enhanced, and the Bcl-2 level was lowered and the Bax level was elevated significantly in SCC-25 cells treated with α-HN for 48 h (P b 0.05). The expression of p-PI3K, p-Akt, and p-mTOR was also significantly lower in SCC-25 cells treated with α-HN than that in the control group (P b 0.05). CONCLUSION: These results indicate that α-HN can inhibit proliferation and induce apoptosis of SCC-25 cells and may exert these effects by inhibiting the PI3K/Akt/mTOR signaling pathway.

Oleanolic acid and ursolic acid inhibit peptidoglycan biosynthesis in Streptococcus mutans UA159

In this study, we revealed that OA and UA significantly inhibited the expression of most genes related to peptidoglycan biosynthesis in S. mutans UA159. To the best of our knowledge, this is the first report to introduce the antimicrobial mechanism of OA and UA against S. mutans.

Compositional studies and Biological activities of Perovskia abrotanoides Kar. oils

BACKGROUND: Current study has been designed to evaluate the chemical composition of essential and fixed oils from stem and leaves of Perovskia abrotanoides and antioxidant and antimicrobial activities of these oils. RESULTS: GC-MS analysis of essential oil identified 19 compounds with (E)-9-dodecenal being the major component in stem and hexadecanoic acid in leaves. In contrast, GC-MS analysis of fixed oil showed 40 constituents with α-amyrin the major component in stem and α-copaene in leaves. The antioxidant activity showed the highest value of 76.7% in essential oil from leaves in comparison with fixed oil from stem (45.9%) through inhibition of peroxidation in linoleic acid system. The antimicrobial assay tested on different microorganisms (e.g. E. coli, S. aureus, B. cereus, Nitrospira, S. epidermis, A. niger, A. flavus and C. albicans) showed the higher inhibition zone at essential oil from leaves (15.2 mm on B. cereus) as compared to fixed oil from stem (8.34 mm onS. aureus) and leaves (11.2 mm on S. aureus). CONCLUSIONS: The present study revealed the fact that essential oil analyzed from Perovskia abrotanoides stem and leaves could be a promising source of natural products with potential antioxidant and antimicrobial activities, as compared to fixed oil.

Pesticidal and pest repellency activities of a plant derived triterpenoid 2α, 3ß, 21ß, 23, 28-penta hydroxyl 12-oleanene against Tribolium castaneum

BACKGROUND: Tribolium castaneum (Herbst) is a major pest of stored grain-based products, and cause severe damage to cereal grains throughout the world. The present investigation was aimed to determine the pesticidal and pest repellent activities of 2α,3ß,21ß,23,28-penta hydroxyl 12-oleanene against T. castaneum. The compound 2α,3ß,21ß,23,28-penta hydroxyl 12-oleanene is a triterpenoid which was isolated from the roots of Laportea crenulata Gaud. Surface film technique was used for pesticidal screening, whereas, pest repellency property of the triterpenoid was determined by filter paper disc method. RESULTS: At 24 hours of exposure duration, significant mortality records (80% and 86%) were observed at doses 0.88 and 1.77 mg/cm². No significant change in mortality records was observed when duration of exposure was increased up to 48 hours. The triterpenoid showed significant repellency activity at doses 0.47 and 0.94 mg/cm². CONCLUSION: These data suggest that the triterpenoid 2α,3ß,21ß,23,28-penta hydroxyl 12-oleanene possess both pesticidal and pest repellency activities against T. castaneum and can be used in controlling the pest of grain-based products.

Effect of bioactive compounds extracted from euphorbious plants on hematological and biochemical parameters of Channa punctatus / Efeito de compostos bioativos extraídos de plantas eufórbicas sobre os parâmetros hematológicos e bioquímicos da Channa punctatus

Channa punctatus was exposed to four different concentrations of Rutin, Taraxerol and Apigenin. Changes in some hematological parameters of Channa punctatus were assessed to determine the influence of these compounds on test fish. Fish were exposed to sublethal concentrations (80 percent of LC50 of 24h) of these compounds for one week. Control fish were also administered for one week. Thereafter, blood samples were obtained from the control and experimental fish. Blood was assayed for selected hematological parameters (hematocrit, hemoglobin, red blood cell count, white blood cell count total plasma protein and plasma glucose concentration). The derived hematological indices of mean corpuscular hemoglobin concentration (MCHC), mean corpuscular hemoglobin (MCH) and mean corpuscular volume (MCV) were calculated. Sublethal concentrations of these compounds caused a dose dependent decrease in hemoglobin values coupled with a decrease in hematocrit values and red blood cell counts are an obvious indication of anemia. The total white blood cell counts and the differential white blood cell counts were decreased except for the lymphocytes, where there was a slight increase. Plasma protein and glucose were also lower in exposed fish when compared with control. The hematological indices MCH, MCHC, MCV were also lowered. The result from this study reveals high mortality rate and deleterious consequences on the health of fish subjected to acute exposure of Rutin, Taraxerol and Apigenin and therefore, should not be used directly in aquaculture without having the proper knowledge.

Channa punctatus foi exposta a quatro diferentes concentrações de Rutina, Taraxerol e Apigenina. Alterações de alguns parâmetros hematológicos da Channa punctatus foram acessados para determinar a influência destes compostos no peixe teste. Peixes foram expostos a concentrações sub-letais (80 por cento 0f LC50 em 24h) destes compostos por uma semana. Os peixes controles foram também expostos durante uma semana. A seguir, amostras de sangue foram obtidas do peixe controle e do experimental. O sangue foi estudado por parâmetros hematológicos selecionados (hematócrito, hemoglobina, contagem de células vermelhas e brancas, proteína plasmática total e concentração de glucose plasmática). Os índices hematológicos derivados da média da concentração corpuscular da hemoglobina (MCHC), a média de hemoglobina corpuscular (MCH) e a média de volume corpuscular (MCV), foram calculados. Concentrações sub-letais destes compostos causaram decréscimo dose-dependente dos valores da hemoglobina unidos a decréscimo de valores de hematócrito e das contagens de células sanguíneas vermelhas o que caracteriza indicação óbvia de anemia. As contagens totais de células brancas e a contagem diferencial destas células estavam diminuídas exceto pelos linfócitos que mostraram leve aumento. A proteína plasmática e a glicose estavam também baixas nos peixes expostos quando comparados com o controle. Os índices hematológicos MCH, MCHC, MCV estavam também diminuídos. Os resultados deste estudo revelam alto percentual de mortalidade e conseqüências deletérias à saúde de peixes submetidos à exposição aguda de Rutina, Talaxerol e Apigenina e portanto eles não devem ser usados diretamente em aquacultura sem conhecimento apropriado.