No abstract

Human dihydroorotate dehydrogenase (HsDHODH) is a key enzyme of pyrimidine de novo biosynthesis pathway. It is located on the mitochondrial inner membrane and contributes to the respiratory chain by shuttling electrons to the ubiquinone pool. We have discovered ascofuranone (1), a natural compound produced by Acremonium sclerotigenum, and its derivatives are a potent class of HsDHODH inhibitors. We conducted a structure–activity relationship study and have identified functional groups of 1 that are essential for the inhibition of HsDHODH enzymatic activity. Furthermore, the binding mode of 1 and its derivatives to HsDHODH was demonstrated by co-crystallographic analysis and we show that these inhibitors bind at the ubiquinone binding site. In addition, the cytotoxicities of 1 and its potent derivatives 7, 8, and 9 were studied using human cultured cancer cells. Interestingly, they showed selective and strong cytotoxicity to cancer cells cultured under microenvironment (hypoxia and nutrient-deprived) conditions. The selectivity ratio of 8 under this microenvironment show the most potent inhibition which was over 1000-fold higher compared to that under normal culture condition. Our studies suggest that under microenvironment conditions, cancer cells heavily depend on the pyrimidine de novo biosynthesis pathway. We also provide the first evidence that 1 and its derivatives are potential lead candidates for drug development which target the HsDHODH of cancer cells living under a tumor microenvironment.

AS-1934 has potential advantages over current treatment options for H. pylori infection.

Bee products are best known as one of the beneficial natural products providing multiple pharmacological effects, such as antimicrobial, antiviral, anti-inflammatory and anticancer effects. The present study aimed to identify potent products derived from the stingless bee Trigona spp. from Luwu Utara (South Sulawesi, Indonesia), focussing on the water-soluble extract of propolis and bee pollen, against the proliferation of the human breast cancer MCF-7 cell line. The results from DPPH (2,2-diphenyl-1-picrylhydrazyl) method of antioxidant assay revealed that water-soluble propolis and bee pollen had high antioxidant activity, with half-maximal effective concentrations against DPPH radicals of 1.3 and 0.4 mg/ml, respectively. Additionally, water-soluble propolis and bee pollen exhibited a significant antiproliferative activity in MCF-7 cells, with IC 50 values of 10.8±0.06 and 18.6±0.03 mg/ml, respectively (P<0.05). Significant cytotoxic effects were observed after 24 h of treatment via microscopic and flow cytometric analysis, where a morphological change toward late apoptosis was observed. By contrast, honey had low antioxidant activity and no antiproliferative effect in MCF-7 cells. The water-soluble propolis also exerted its antiproliferative effect in the human keratinocyte HaCaT cell line. The antiproliferative activity was similar (P>0.05) at 24 and 48 h of treatment, with IC 50 at 2.7±0.06 mg/ml and <0.4 mg/ml, respectively. Notably, bee pollen was less toxic to HaCaT cells after 24 h of treatment than the water-soluble propolis, with IC 50 >50 mg/ml. Its antiproliferative activity was significantly increased after 48 h of treatment, with IC 50 at 9.6±0.07 mg/ml (P<0.05). In addition, similar to other poplar propolis, the high-performance liquid chromatography-ultraviolet and electrospray ionisation mass spectrometry analyses revealed that caffeic acid phenethyl ester was not the main bioactive compound of the samples examined. Furthermore, two major proteins (between ~50 and 75 kDa) were identified in the water-soluble propolis and bee pollen. The present results suggested that water-soluble propolis and bee pollen may have the potential to be elaborated further as a breast anticancer therapy.

Objective: Sonneratia alba leaves were used by the community for traditional medicine to cure muscle pain, back pain, antioxidants, rheumatism, malaria, wounds, tuberculosis (TB) and as a spermicide. S. alba leaves extract was easy to damage because of the light exposure, change of pH, weather and a long period of storage time. The problem can be solved by coating the extract with a microencapsulation technique. The purpose of this research was to formulate the microcapsules of S. alba leaves extract with solvent evaporation technique using Ethocel 10 cP and Eudragit E100 as a matrix. Methods: S. alba leaves were extracted using ethanol 96%. This extract was dried by a rotary evaporator. The microencapsulation process of S. alba leaves extract was done by solvent evaporation technique (O/W: oil in water). The formula of S. alba leaves extract microcapsules was designed into six formulas (Eudragit E100: EA1, EA2, EA3 and Ethocel 10 cP: EB1, EB2, EB3). Microcapsules of S. alba leaves extract were characterized for particle size in terms of surface morphology by scanning electron microscope (SEM) and encapsulation efficiency. Antioxidant activity of the formulation have been evaluated by DPPH method. Physical characterization on microparticles was performed by conducting entrapment efficiency and SEM picture. Results: In this research, the microparticles containing S. alba extract has been developed by using ethyl cellulose (Ethocel 10 cP) and eudragit (Eudragit E100) as the polymer matrix. The results showed that a high concentration of polymer (Ethocel 10 cP and Eudragit E100) used in microencapsulation resulted in better S. alba leaves extract microcapsules in terms of physical characteristics. Particle size of microcapsules containing S. alba leaves extract were in the range of 0.701 to 1.163 μm. Encapsulation efficiency (% EE) was categorized as poor because the value were ≤ 80% to which 74.386% (EB3) and 75.248% (EA1). SEM picture of EA1 (Eudragit E100) revealed that the surface of microcapsule were rough and porous. When Ethocel 10 cP was used as a polymer, a smoother surface and less visible pores of microcapsule were obtained. The antioxidant ability of S. alba leaves extract microcapsule showed that IC50 values were 53.26 ppm. Conclusion: It can be concluded that microcapsules of S. alba leaves extract can be prepared by solvent evaporation technique using Eudragit E100 and Ethocel 10 cP as polymer. S. alba leaves has potent antioxidant activity either as an extract or after being formulated into microcapsules.