Antimicrobial indole alkaloids from Tabernaemontana corymbosa.

Four unreported monoterpene indole alkaloids, tabernaecorymines B-E (1-4), together with twenty-one known indole alkaloids (5-25) were obtained from the stem bark of Tabernaemontana corymbosa. Their structures and absolute configurations were elucidated by extensive spectroscopy, quantum chemical calculations, DP4+ probability analyses and Mo2(OAc)4-induced electronic circular dichroism experiment. The antibacterial and antifungal activities of these compounds were evaluated and some of them showed significant activity against Staphylococcus aureus,Bacillus subtilis, Streptococcus dysgalactiae and Candida albicans.

11,12-Diacetyl-carnosol Protects SH-SY5Y Cells from Hydrogen Peroxide Damage through the Nrf2/HO-1 Pathway.

Background: Oxidative stress-induced neurotoxicity plays a key role in Alzheimer's disease (AD). 11,12-Diacetyl-carnosol (NO.20), an acetylated derivative of carnosol extracted from rosemary, displays a high antioxidative effect in vitro. Purpose: We investigated the neuroprotective effect of NO.20 on H2O2-induced neurotoxicity in human neuroblastoma SH-SY5Y cells and its possible mechanism. Results: We found that NO.20 pretreatment (1 µM for 1 h) had cytoprotective effects and weakened H2O2-induced damage in SH-SY5Y cells by reducing viability loss, apoptotic rate, and reactive oxygen species production. In addition, NO.20 inhibited H2O2-induced mitochondrial dysfunctions: it alleviated mitochondrial membrane potential loss and cytochrome c release, decreased the Bax/Bcl-2 ratio, and reduced caspase-3 expression. NO.20 also downregulated malondialdehyde and upregulated glutathione. Furthermore, NO.20 pretreatment caused the nuclear translocation of the transcription factor NF-E2-related factor 2 (Nrf2), increasing heme oxygenase-1 (HO-1) expression in SH-SY5Y cells. Notably, we found that silencing Nrf2 using small interfering RNA (siRNA) suppressed the NO.20-induced HO-1 expression and abolished the neuroprotective effect of NO.20. Conclusion: These results demonstrate that NO.20 protects SH-SY5Y cells from H2O2-induced neurotoxicity by activating the Nrf2/HO-1 pathway. Thus, the neuroprotective and antioxidative stress effects of NO.20 may make it a promising neuroprotective compound for AD treatment.

Monoterpene indole N-oxide alkaloids from Tabernaemontana corymbosa and their antimicrobial activity.

Tabernaemontana corymbosa is a traditional folk medicine. In our research, six monoterpene indole N-oxide alkaloids and their parent alkaloids were obtained from the stem bark of T. corymbosa, including seven new alkaloids (1-7) and five known alkaloids (8-12). Their structures and absolute configurations were elucidated by extensive spectroscopy, quantum chemical calculations, and DP4+ probability analyses. The antimicrobial activity of the obtained compounds was evaluated, among which alkaloids 4, 8, 12 showed significant antimicrobial activity against Staphylococcus aureus with an MIC value of 6.25 µg/mL, while alkaloids 11, 12 showed moderate antimicrobial activity against Bacillus subtilis with an MIC value of 25 µg/mL.

Tabernaecorymine A, an 18-normonoterpenoid indole alkaloid with antibacterial activity from Tabernaemontana corymbosa.

Tabernaecorymine A, an 18-normonoterpenoid indole alkaloid with conjugated (E)-3-aminoacrylaldehyde fragment was obtained from the stem bark of Tabernaemontana corymbosa. Its structure was elucidated by extensive spectroscopic data analyses, and further verified by ACD/structure elucidator, electronic circular dichroism (ECD) analyses and density functional theory (DFT) chemical shift predictions. The compound exhibited significant antibacterial bioactivity against Streptococcus dysgalactiae with an MIC value of 3.12 µg/mL, which is better than the plant drug berberine.

New Monoterpenoid Indoles with Osteoclast Activities from Gelsemium elegans.

The well-known toxic medicine Gelsemium elegans is widely and historically used to treat bone fracture and skin ulcers by the folk people of China. Two new monoterpenoid indole alkaloids, gelselegandines D and E, together with the known analogue gelegamine A were isolated from G. elegans. Their structures were elucidated by means of spectroscopic techniques and quantum chemical calculations. All isolated compounds were tested for the effects on RANKL-induced osteoclast formation. Interestingly, gelselegandine E and gelegamine A, respectively, showed significant promoting and inhibitory activities on osteoclastogenesis, while gelselegandine D had no activity under the same concentration. This work suggested the different configurations for the carbons near the C-19/20 oxygen rings of the isolated compounds may be the key active groups on osteoclast formation and provided the evidence for the rationality as the traditional treatment for bone-related diseases of G. elegans.

Synthesis of pterodontic acid derivatives and the study of their anti-influenza A virus (H1N1) activity.

Laggera pterodonta (DC.) Benth, a folk herb widely distributes in southwest China, especially in Yunnan Province, demonstrates anti-pathogenic microorganisms, anti-inflammatory, inhibition of Helicobacter pylori activities in vitro et al. Interestingly, previous studies have shown that pterodontic acid (1), a eudesmane-type sesquiterpene isolated from L. pterodonta (DC.), displays excellent selective antiviral activity to H1N1 subtype of influenza A virus. At the same time, our group also discovered that the antiviral activity of 1 was relatively close to that activity of post-marketed ribavirin. Therefore, we consider that the synthesis of pterodontic acid (1) derivatives and evaluation of their anti-influenza A virus (H1N1) activities is of potential clinical significance. In this manuscript, a series of pterodontic acid derivatives were prepared and demonstrated significantly improved anti-influenza A virus (H1N1) activities, providing more opportunities for the treatment of respiratory viral diseases.

Ginsenoside Rb1 exerts antidepressant-like effects via suppression inflammation and activation of AKT pathway.

Depression-like behaviors caused by chronic stress are related to inflammation and microglia activation. Antidepressant therapy may contribute to inhibiting inflammation responses and microglia activation. Ginsenoside Rb1 (GRb1) is known to display antidepressant-like effect on chronic unpredictable mild stress-induced depressive rats. However, the antidepressant-like effects of GRb1 on chronic restraint stress (CRS) mice and the potential anti-inflammatory mechanisms are unclear. Here, we focused on the molecular mechanisms related to inhibition of inflammation response and the protection on microglia. Our results showed that GRb1 had an antidepressant effects via relieving the depression-like behaviors in CRS model. Furthermore, GRb1 increased the protein expressions of brain-derived neurotrophic factor and phospho- protein kinase B/ protein kinase B (p-AKT/AKT), and decreased the protein expressions of interleukin-1ß (IL-1ß), tumor necrosis factor α (TNF-α) and ionized calcium binding adapter molecule 1 in hippocampus, reduced the levels IL-1ß and TNF-α in serum. Finally, GRb1 lowered the protein expressions of IL-1ß and TNF-α in BV-2 microglia induced by lipopolysaccharides. Taken together, the results indicate that GRb1 prevents CRS-induced depression-like behaviors in mice, which may be related to anti-inflammatory effects in hippocampus, serum and microglia and activation of AKT pathway.

Resina Draconis Reduces Acute Liver Injury and Promotes Liver Regeneration after 2/3 Partial Hepatectomy in Mice.

AIM: To investigate the protective effects and possible mechanisms of action of resina draconis (RD) on acute liver injury and liver regeneration after 2/3 partial hepatectomy (PH) in mice. METHODS: 2/3 PH was used to induce acute liver injury. Mice were divided into three groups: sham, vehicle + 2/3 PH, and RD + 2/3 PH. Resina draconis was administered intragastrically after 2/3 PH into the RD + 2/3 PH group, and the same volume of vehicle (1% sodium carboxymethyl cellulose) was injected into the vehicle + 2/3 PH group and sham group mice. The index of liver to body weight (ILBW) and proliferating cell nuclear antigen (PCNA) were assayed to evaluate liver regeneration. Blood and liver tissues were collected for serological and western blotting analysis. RESULTS: Resina draconis protected against 2/3 PH-induced acute severe liver injury and promoted liver regeneration as shown by significantly increased ILBW compared with that of controls. 2/3 PH increased serum AST and ALT levels, which were significantly decreased by RD treatment, while 2/3 PH decreased serum TP and ALB, which were increased by RD treatment. In the RD + 2/3 PH group, PCNA expression was significantly increased compared with the 2/3 PH group. Further, hepatocyte growth factor (HGF), TNFα, and EGFR levels were increased in the RD group at postoperative days 2 and 4 compared with the those in the 2/3 PH group. CONCLUSION: Our results suggest that RD ameliorates acute hepatic injury and promotes liver cell proliferation, liver weight restoration, and liver function after 2/3 PH, probably via HGF, TNFα, and EGFR signaling.

Anti-inflammatory and analgesic activities of Neolamarckia cadamba and its bioactive monoterpenoid indole alkaloids.

ETHNOPHARMACOLOGICAL RELEVANCE: Neolamarckia cadamba has been used traditionally to treat inflammation, fever, and pruritus in the Dai ethnopharmacy in Yunnan province, P.R. China. However, according to literature survey, the action basis of anti-inflammatory and analgesic activities of this plant were rarely reported, which accounts for the original intentions of this investigation. AIM OF THE STUDY: The study aimed to investigate the anti-inflammatory and analgesic action of methanolic extract (ME), ethyl acetate (EA), and aqueous (AQS) fractions of N. cadamba and further explore the accurate compounds responsible for the activities of EA fraction. MATERIALS AND METHODS: The in vivo anti-inflammatory and analgesic activities of ME, EA, and AQS fractions at the doses of 200 and 400 mg/kg and two major constituents (compounds 5 and 7) at 50 and 100 mg/kg via intragastrically administrated, respectively, were evaluated by carrageenan-induced paw edema and acetic acid-stimulated writhing animal models. Aspirin (ASP) was used as the positive control at the dose of 200 mg/kg. The monoterpenoid indole alkaloids (MIAs) in EA fraction were phytochemically studied utilizing chromatographic techniques, and their structures and absolute configurations were established on the basis of multiple spectroscopic analyses and quantum computational chemistry method. Moreover, the in vitro anti-inflammatory activities of all the isolates were assessed by suppressing releases of LPS-activated inflammatory mediators (TNF-α, IL-1ß, and COX-2) in RAW 264.7 macrophage cells at a concentration of 10 µg/mL. Dexamethasone (DXM) was used as the positive control. RESULTS: Three fractions (ME, EA, and AQS) significantly ameliorated the paw edema caused by carrageenan and reduced the number of writhing induced by acetic acid in comparison to the control group at the doses of 200 and/or 400 mg/kg (in vivo). Subsequent phytochemical investigation of EA fraction led to the structural characterization of four new monoterpenoid indole alkaloids, neocadambines A-D (1-4), as well as eight known analogues (5-12). Neocadambine A possesses a novel 14-nor-MIA skeleton that could be derived from the corynantheine-type MIAs via oxidative cleavage of C3-C14 bond and subsequently degradation of C14. Moreover, the structure of a bioactive known MIA, cadambine acid (6), was reassigned by analysis of its NMR spectroscopic data. Further biological assays revealed that the major constituent 3ß-dihydrocadambine (7) significantly relieved the paw edema and decreased the number of writhing at 100 mg/kg in vivo. In addition, most of the isolates displayed remarkable in vitro anti-inflammatory effects by inhibiting the secretion of aforementioned inflammatory mediators (COX-2, IL-1ß, and TNF-α) at a concentration of 10 µg/mL, and compounds 4, 7, and 9 showed better anti-inflammatory effects than that of positive control, dexamethasone. CONCLUSIONS: This study further validated the anti-inflammatory and analgesic activities of N. cadamba, and revealed that monoterpenoid indole alkaloids could partly contribute to the efficacy of this ethnodrug. The major constituent 3ß-dihydrocadambine (7) showed significant anti-inflammatory activities both in vitro and in vivo, which suggested that it could be a promising anti-inflammatory lead compound. Our findings provided scientific justification to support the traditional application of N. cadamba for treating inflammatory and nociceptive disorders.

New aporphine alkaloids with selective cytotoxicity against glioma stem cells from Thalictrum foetidum.

Seven new isoquinoline alkaloids, 9-(2'-formyl-5', 6'-dimethoxyphenoxy)-1, 2, 3, 10-tetramethoxy dehydroaporphine (1), 9-(2'-formyl-5', 6'-dimethoxyphenoxy)-1, 2, 3, 10-tetramethoxy oxoaporphine (2), 3-methoxy-2'-formyl oxohernandalin (3), (-)-9-(2'-methoxycarbonyl-5', 6'-dimethoxyphenoxy)-1, 2, 3, 10-tetramethoxy aporphine (4), (-)-2'-methoxycarbonyl thaliadin (5), (-)-9-(2'-methoxyethyl-5', 6'-dimethoxyphenoxy)-1, 2, 3, 10-tetramethoxy aporphine (6), (-)-3-methoxy hydroxyhernandalinol (7), together with six known isoquinoline alkaloids (8-13) were isolated from the roots of Thalictrum foetidum. Their structures were elucidated by extensive spectroscopic measurements. Compounds 1 and 2 showed significant selective cytotoxicity against glioma stem cells (GSC-3# and GSC-18#) with IC50 values ranging from 2.36 to 5.37 µg·mL-1.

Immune-inhibitive phenyl-C1 substituent aporphine alkaloids from Thalictrum cirrhosum.

Five new phenyl-C1 substituent aporphine alkaloids, 6aR-2'-methoxycarbonyl-thaliadin (1), 6aR-2'-carboxyl-thaliadin (2), 6aR-3-methoxy-hernandalinol (3), 6aS-1,3,10-trimethoxy-natalamine (4), and 3-methoxy-2'-methoxycarbonyl-oxohernandalincin (5), together with sixteen known isoquinoline alkaloids (6-21) were isolated from the whole herb of Thalictrum cirrhosum (Levl.). Their structures were elucidated by extensive spectroscopic measurements, and six isoquinoline alkaloids showed significant inhibitory activity on concanavalin A-stimulated splenocytes proliferation with IC50 values 36-44 µM by the immunosuppressive bioassay.