Isolation, identification and anti-cancer activity of minor alkaloids from Triclisia subcordata

No abstrac

Isochondodendrine and 2[prime or minute]-norcocsuline: additional alkaloids from Triclisia subcordata induce cytotoxicity and apoptosis in ovarian cancer cell lines

Triclisia subcordata Oliv (Menispermeaceae) is used in herbal medicine for the treatment of cancer and other diseases in Africa. This study aims to isolate minor alkaloids present in this plant and assay their cytotoxic activities. Isochondodendrine and 2[prime or minute]-norcocsuline as two minor alkaloids together with the abundant cycleanine were isolated and identified by mass spectrometry and NMR spectroscopy. Both isochondodendrine and 2[prime or minute]-norcocsuline exhibited in vitro cytotoxicity in four ovarian cancer cell lines (A2780, IGROV-1, OVCAR-8, and OVCAR-4) with IC50 ranges of 3.5-17 [small mu ]M and 0.8-6.2 [small mu ]M respectively. These alkaloids showed mostly slightly weaker potencies when tested using normal human ovarian epithelial cells, IC50 = 10.5 +/- 1.2 [small mu ]M and 8.0 +/- 0.2 [small mu ]M for isochondodendrine and 2[prime or minute]-norcocsuline, respectively. The alkaloids induced apoptosis in ovarian cancer cells because they activated caspases 3/7, induced cleavage of PARP, increased the subG1 population in cell cycle analysis and increased Annexin V/propidium iodide staining. These observations suggest that isochondodendrine and 2[prime or minute]-norcocsuline contributing to the cytotoxic activity of T. subcordata may be suitable starting points for the future development of novel therapeutics to treat ovarian cancer

Biotransformation of artemisinin to a novel derivative via ring rearrangement by Aspergillus niger.

Artemisinin is a component part of current frontline medicines for the treatment of malaria. The aim of this study is to make analogues of artemisinin using microbial transformation and evaluate their in vitro antimalarial activity. A panel of microorganisms were screened for biotransformation of artemisinin (1). The biotransformation products were extracted, purified and isolated using silica gel column chromatography and semi-preparative HPLC. Spectroscopic methods including LC-HRMS, GC-MS, FT-IR, 1D and 2D NMR were used to elucidate the structure of the artemisinin metabolites.H-1 NMR spectroscopy was further used to study the time-course biotransformation. The antiplasmodial activity (IC50) of the biotransformation products of 1 against intraerythrocytic cultures of Plasmodium falciparum were determined using bioluminescence assays. A filamentous fungus Aspergillus niger CICC 2487 was found to possess the best efficiency to convert artemisinin (1) to a novel derivative, 4-methoxy-9,10-dimethyloctahydrofuro-(3,2-i)-isochromen-11(4H)-one (2) via ring rearrangement and further degradation, along with three known derivatives, compound (3), deoxyartemisinin (4) and 3-hydroxy-deoxyartemisinin (5). Kinetic study of the biotransformation of artemisinin indicated the formation of artemisinin G as a key intermediate which could be hydrolyzed and methylated to form the new compound 2. Our study shows that the anti-plasmodial potency of compounds 2, 3, 4 and 5 were ablated compared to 1, which attributed to the loss of the unique peroxide bridge in artemisinin (1). This is the first report of microbial degradation and ring rearrangement of artemisinin with subsequent hydrolysis and methoxylation by A.niger

The fine specificity of IgM anti-citrullinated protein antibodies (ACPA) is different from that of IgG ACPA

Pathophysiology and treatment of rheumatic disease

Sensitivity of the Atlantic meridional overturning circulation to South Atlantic freshwater anomalies

The sensitivity of the Atlantic Meridional Overturning Circulation (AMOC) to changes in basin integrated net evaporation is highly dependent on the zonal salinity contrast at the southern border of the Atlantic. Biases in the freshwater budget strongly affect the stability of the AMOC in numerical models. The impact of these biases is investigated, by adding local anomaly patterns in the South Atlantic to the freshwater fluxes at the surface. These anomalies impact the freshwater and salt transport by the different components of the ocean circulation, in particular the basin-scale salt-advection feedback, completely changing the response of the AMOC to arbitrary perturbations. It is found that an appropriate dipole anomaly pattern at the southern border of the Atlantic Ocean can collapse the AMOC entirely even without a further hosing. The results suggest a new view on the stability of the AMOC, controlled by processes in the South Atlantic. <br/

A linear 19-Mer plant defensin-derived peptide acts synergistically with caspofungin against Candida albicans biofilms.

Transplantation and autoimmunit

Stability of the Atlantic Meridional Overturning Circulation: A Review and Synthesis

The notion that the Atlantic Meridional Overturning Circulation (AMOC) can have more than one stable equilibrium emerged in the 1980s as a powerful hypothesis to explain rapid climate variability during the Pleistocene. Ever since, the idea that a temporary perturbation of the AMOC—or a permanent change in its forcing—could trigger an irreversible collapse has remained a reason for concern. Here we review literature on the equilibrium stability of the AMOC and present a synthesis that puts our understanding of past and future AMOC behavior in a unifying framework. This framework is based on concepts from Dynamical Systems Theory, which has proven to be an important tool in interpreting a wide range of model behavior. We conclude that it cannot be ruled out that the AMOC in our current climate is in, or close to, a regime of multiple equilibria. But there is considerable uncertainty in the location of stability thresholds with respect to our current climate state, so we have no credible indications of where our present‐day AMOC is located with respect to thresholds. We conclude by identifying gaps in our knowledge and proposing possible ways forward to address these gaps

Eddy-Permitting Ocean Circulation Hindcasts of Past Decades

International audienc